levoleucovorin and Liver-Neoplasms

The treatment of colorectal cancer liver metastases has seen significant improvement in recent years and, for certain patients, the long-term survival and even cure are possible. Despite this improvement, many more questions are yet to be answered: the optimal combination, duration, sequence of therapies, role of biologics and the timing of surgical resection are debated in the literature, with conflicting trial results.. In this review, the authors highlight the current trial evidence for systemic chemotherapy and biologic therapy for colorectal cancer liver metastases in both the pre and post-resection setting.. The treatment of colorectal liver metastases requires a multidisciplinary approach. The role of adjuvant chemotherapy with 5 fluorouracil and oxaliplatin in stage 3 colon cancer is well established. However, the options for patients with resectable or borderline liver metastases, either in the neoadjuvant or adjuvant settings, require further study. For patients with borderline resectable metastases, the combination of triplet chemotherapy with 5 fluorouracil, oxaliplatin and irinotecan (FOLFOXIRI) offers the best conversion rate. The role of biologic agents such as bevacizumab and EGFR inhibitors in these settings is less clear based on current evidence.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Oxaliplatin

Colorectal cancer is the second leading cause of cancer-related death worldwide. For metastatic colorectal cancer (mCRC) patients, it is recommended, as first-line treatment, chemotherapy (CT) based on doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI) and fluorouracil, leucovorin, and oxaliplatin (FOLFOX). In addition to CT, biological (targeted agents) are indicated in the first-line treatment, unless contraindicated. In this context, most of mCRC patients are likely to progress and to change from first line to second line treatment when they develop resistance to first-line treatment options. It is in this second line setting where Aflibercept offers an alternative and effective therapeutic option, thought its specific mechanism of action for different patient's profile: RAS mutant, RAS wild-type (wt), BRAF mutant, potentially resectable and elderly patients. In this paper, a panel of experienced oncologists specialized in the management of mCRC experts have reviewed and selected scientific evidence focused on Aflibercept as an alternative treatment.

Topics: Age Factors; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Drug Substitution; Fluorouracil; Genes, ras; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Mutation; Neovascularization, Pathologic; Organoplatinum Compounds; Proto-Oncogene Proteins B-raf; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Vascular Endothelial Growth Factor A

A 60 years old man has undergone hemodialysis due to chronic renal failure by diabetic nephropathy. A sigmoid colon cancer and multiple liver metastases(S2, S6)were found, and he had laparoscopic sigmoid colon resection first, it was local resection. The stage was pT3N2aH1, stage Ⅳ, and histopathological examination revealed that the tumor was well‒differentiated adenocarcinoma and RAS, BRAF mutation was negative. From the 4th week after surgery, mFOLFOX4 plus panitumumab( oxaliplatin 60 mg/m2[30% reduction]), continuous intravenous injection fluorouracil 600 mg/m2(regulated amount), rapid intravenous injection fluorouracil 400 mg/m2(regulated amount), Leucovorin 100 mg/m2(regulated amount), panitumumab 6 mg/kg(regulated amount)were given for 4 courses. Since partial response was obtained in both hepatic lesions, we underwent radiofrequency ablation for S6 lesion and laparoscopic partial hepatectomy for S2 lesion. Eight months have passed since the first visit, but no recurrence have been observed. The kidney is an organ that metabolizes many drugs, and it is necessary to adjust the drug volume and consider the timing of administration even in anticancer chemotherapy. We report that we experienced chemotherapy for colorectal cancer during hemodialysis with a review of the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colon, Sigmoid; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Renal Dialysis

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Digestive System Surgical Procedures; Fluorouracil; Focal Nodular Hyperplasia; Humans; Leucovorin; Liver Neoplasms; Male; Oxaliplatin; Prognosis; Rectal Neoplasms

Cystic fibrosis (CF) is a multisystem disease affecting the gastrointestinal (GI) tract as well as the lungs. As survival has increased significantly over the past few decades, complications not seen previously have become apparent. There is an overall increased rate of malignancy in CF, particularly from the GI tract and in the post-transplant population. The most common sites of malignancy are the pancreatico-biliary and digestive tract, as well as an increased rate of testicular cancer. Using an illustrative case of metastatic oesophageal malignancy which initially appeared to be hepatic in origin, we have reviewed the literature surrounding malignancy in CF with a particular focus on the GI tract.

Topics: Adenocarcinoma, Clear Cell; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cystic Fibrosis; Esophageal Neoplasms; Fatal Outcome; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds

Colorectal cancer is one of the most frequent cancers in the world and between 50% and 60% of patients will develop colorectal liver metastases (CRLM) during the disease. There have been great improvements in the management of CRLM during the last decades. The combination of modern chemotherapeutic and biological systemic treatments with aggressive surgical resection strategies is currently the base for the treatment of patients considered unresectable until few years ago. Furthermore, several new treatments for the local control of CRLM have been developed and are now part of the arsenal of multidisciplinary teams for the treatment of these complex patients. The aim of this review was to summarize and update the management of CRLM, its controversies and relevant evidence.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Electroporation; Fluorouracil; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Liver Transplantation; Margins of Excision; Microwaves; Organoplatinum Compounds; Prognosis; Radiofrequency Ablation; Reoperation

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Hence there is a need to identify new therapeutic agents that improve the current repertoire of chemotherapeutic drugs. The antitumor activity of curcumin has been reported for several tumors, including CRC. A recent phase I trial showed that curcumin is safe and tolerable adjunct to FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in patient-derived colorectal liver metastases at doses up to 2 g daily. Another trial revealed the effect of combining curcumin with FOLFOX in patients with inoperable colorectal cancer. The aim of current review was to summarize the current knowledge about possible molecular mechanisms of curcumin in CRC with particular emphasis on preclinical and early clinical studies of colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Curcumin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.. We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.. Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).. The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Treatment Outcome; Young Adult

The combination of fluorouracil, oxaliplatin, and irinotecan plus bevacizumab (FOLFOXIRI-Bev) is an established and effective first-line chemotherapy regimen for metastatic colorectal cancer. However, resection rates of metastases and overall survival with this schedule have never been systematically evaluated in published studies including, but not limited to, the TRIBE (TRIplet plus BEvacizumab) trial.. To assess the clinical efficacy of FOLFOXIRI-Bev, including outcomes and rates of surgical conversions.. A systematic review was conducted in October 2016 in concordance with the PRISMA guidelines of PubMed, the Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, Google Scholar, CINAHL, Ovid, and EMBASE using the terms FOLFOXIRI and bevacizumab and (colorectal cancer).. Clinical trials, retrospective case series, and prospective case series that used FOLFOXIRI-Bev for the treatment of initially unresectable metastatic colorectal cancer in humans were included. Individual case reports and retrospective case series with fewer than 10 patients were excluded.. Data were extracted independently by 2 reviewers on a predesigned, standardized form. Ultimately, data were aggregated to obtain the pooled effect size of efficacy, according to the random-effects model and weighted for the number of patients included in each trial.. Median overall survival and progression-free survival, overall response rates, and rates of R0 surgical conversions and overall surgical conversions.. Eleven FOLFOXIRI-Bev studies published between 2010 and 2016 met the inclusion criteria and were pooled for analysis. The studies included 889 patients, with 877 patients clinically evaluable for overall response rates. The objective response rate to FOLFOXIRI-Bev was 69% (95% CI, 65%-72%; I2 = 25%). The rate of overall surgical conversions was 39.1% (95% CI, 26.9%-52.8%), and the rate of R0 surgical conversions was 28.1% (95% CI, 18.1%-40.8%). Median pooled overall survival was 30.2 months (95% CI, 26.5-33.7 months) in 6 trials with data available, and progression-free survival was 12.4 months (95% CI, 10.0-14.3 months) in 9 trials with data available. In meta-regression analysis, variables significantly associated with conversion surgery were disease limited to the liver and a higher median number of cycles (close to 12).. For patients with surgically unresectable metastatic colorectal cancer, FOLFOXIRI-Bev is associated with a significant overall response rate. Such an effective regimen leads to a probability of surgical conversion of distant metastases approaching 40%, with more than one-fourth of patients having an R0 resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Survival Analysis; Treatment Outcome

For colorectal liver metastasis (CRLM) patients, hepatic resection is currently the sole cure offering the chance of long-term survival. Tumor shrinkage and planned liver remnant hypertrophy are the two key strategies for conversion of initially unresectable CRLM. First conducted in 2012, associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) allows rapid liver growth. As a means to induce hypertrophy, portal vein embolization (PVE) has been widely applied before extending hepatectomy. Recently, Peng et al. present a new approach of terminal branches portal vein embolization (TBPVE), offering an efficient way to amplify FLR and making chances for surgery in 2 weeks.. We reported a 61-year-old woman with synchronous hepatic metastasized carcinoma of the colon sigmoideum underwent TBPVE after 6 cycles of neoadjuvant therapy in order to perform a planned right trisectionectomy. Rapid liver remnant hypertrophy and remarkable tumor shrinkage were achieved, and laparoscopic sigmoidectomy and right trisectionectomy were successfully performed. The postsurgical course was uneventful and 7 months of recurrence-free survival have been witnessed.. The dual tactics of tumor shrinkage and planned rapid liver remnant hypertrophy will make concerted efforts to further increase the clinical candidacy for curative resection, which are valuable for further investigation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoembryonic Antigen; Carcinoma; Colon, Sigmoid; Colonoscopy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Fluorouracil; Hepatectomy; Humans; Hypertrophy; Laparoscopy; Leucovorin; Ligation; Liver; Liver Neoplasms; Liver Regeneration; Magnetic Resonance Imaging; Middle Aged; Neoadjuvant Therapy; Portal Vein; Prognosis; Treatment Outcome; Vascular Surgical Procedures

During the past 20 years, advances in systemic therapies have improved overall survival of patients with Colorectal cancer Liver metastases (CRLM) from 6 to 24 months. By reaching CRLM via their preferential arterial vascularization, hepatic arterial infusion of chemotherapy (HAIC) has demonstrated improvement in response rate and deepness of response. Improvement in deepness of response is potentially helpful to convert no surgical patient to surgery. Recent HAIC regimens, including HAIC-FUDR plus systemic oxaliplatin/irinotecan, or HAIC-oxaliplatin plus systemic 5FU and cetuximab yielded a 92% and 90% response rate respectively, and conversion to R0 surgery in 47% and 42% of patients, respectively. When HAIC delivered a drug ineffective through intravenous delivery, this rechallenge provided 62% response rate for HAIC. Nowadays, port-catheter implanted percutaneously by radiologists has 95% feasibility with primary patency equivalent to that of surgically implanted catheters, and secondary patency superior after radiologic revision. Retrospective studies demonstrated prolonged DFS of HAIC over IV chemotherapy in the adjuvant setting after surgery of CRLM. Drug eluting beads loaded with irinotecan (DEBIRI) were developed as drug carrier and embolization platform for treatment of CRLM by chemoembolization. DEBIRI allows for a very high level of SN-38 (SN-38 is the active compound of irinotecan) and a very high rate of complete l response at pathologic studies of treated metastases. DEBIRI was compared to systemic FOLFIRI in a phase III randomized trial including 74 patients with benefit in overall survival and disease-free survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheterization; Colorectal Neoplasms; Drug Carriers; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin

Apatinib is a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. Previous studies have suggested that apatinib is safe and effective in some solid tumors. We report one case with advanced hepatocellular carcinoma (HCC), who received apatinib combined with transhepatic arterial chemotherapy and embolization (TACE), and chemotherapy respectively. TACE was administered three times once a month, using lipiodol 10ml, oxaliplatin 150mg, and tegafur 1g. The dose of apatinib was 500 mg/d from day 4 to 24. After TACE, the patient received chemotherapy of regimen FOLFOX4, oxaliplatin intravenously at 85 mg/m2 on day 1, calcium levofolinate 200 mg/m2 on day 1 and 2, 5-fluorouracil 400 mg/m2 intravenously and 5-fluorouracil 600 mg/m2 intravenously pumped for 22h on day 1 and 2, cycled every two weeks for seven cycles. He took concurrently apatinib with a dose of 500mg daily from 1 to 10 days per cycle. He was confirmed as partial response (PR) by the Response Evaluation Criteria in Solid Tumors (RECIST). The level of serum alpha-fetoprotein (AFP) decreased from 60500 ng/ml to 12.7 ng/ml, and the progression free survival (PFS) time was more than eight months. It indicated that apatinib may be a superior choice for HCC patients.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Disease-Free Survival; Ethiodized Oil; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pyridines; Tegafur

We report a case of descending colon adenocarcinoma with neuroendocrine differentiation that was effectively treated with FOLFIRI plus bevacizumab. A 70-year-old man underwent a colonoscopy and was found to have a type 2 tumor of the descending colon. A well-to-moderately differentiated adenocarcinoma was diagnosed by biopsy. A preoperative CT scan showed paraaortic lymph node and liver metastasis, and that the tumor was directly invading the spleen. The patient underwent a left hemicolectomy with resection of the pancreas tail, spleen, and diaphragm. The pathological diagnosis was adenocarcinoma with less than 30% neuroendocrine differentiation in the primary tumor and almost 100% neuroendocrine differentiation in the metastatic lymph nodes. After surgery, FOLFIRI plus bevacizumab treatment was initiated. After 33 treatment cycles, the paraaortic lymph node and liver metastasis disappeared and the patient has remained progression-free to date. Adenocarcinoma with neuroendocrine differentiation of the colon is rare and an effective chemotherapy has not yet been established. We report this case with a review of the literature.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Camptothecin; Carcinoma, Neuroendocrine; Colon, Descending; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Prognosis

Resection of colorectal liver metastases is a treatment standard because patients experience long-term disease-free survival or are even cured after undergoing this procedure. Improved surgical techniques for liver resection in combination with downsizing liver metastases by chemotherapy, interventions to induce liver hypertrophy before resection, and the use of ablative techniques have allowed us to expand the indications for liver surgery and local treatment in situations with limited metastatic colorectal cancer. Resectability and identification of patients who might benefit from liver surgery and local ablative techniques are key factors for the treatment of patients with colorectal cancer. Despite the wide acceptance of liver surgery and ablative techniques, there are many open questions on the management of limited metastatic disease, such as which patients benefit from an aggressive surgical approach, what the indications for ablative and other local techniques are, and what the role of chemotherapy is for patients with resectable or resected disease. Unfortunately, results of randomized trials are only available for a limited number of these questions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; ErbB Receptors; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

Primary liver cancer, mainly consisting of hepatocellular carcinoma (HCC), is one of common malignancies worldwide, and prevalent among the Chinese population. A diagnosis of early stage HCC has proven to be very difficult because of its insidious feature in onset and development. At the time of diagnosis, most HCC cases are locally advanced and/or distant metastatic, which results in difficulty to be treated and poor prognosis. For advanced HCC, systemic therapy is frequently adopted as an important palliative method. In recent years, clinical studies and observations have often reported about systemic anti-cancer therapy of advanced HCC, including molecular target therapy, systemic chemotherapy and immunotherapy. In this article, we review these treatment modalities to provide a reference for clinicians.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Deoxycytidine; Fluorouracil; Humans; Immunotherapy; Leucovorin; Liver Neoplasms; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Organoplatinum Compounds; Transforming Growth Factor beta

Liver metastases are often the dominant site of metastatic disease in colorectal cancer. Selective internal radiation therapy (SIRT) involves embolising radiolabeled spheres (SIR-Spheres) into the arterial supply of the liver. This review assesses the effectiveness and toxicity of SIRT in the treatment of metastatic colorectal cancer liver metastasis when given alone or with systemic or regional hepatic artery chemotherapy. We reviewed only randomised controlled trials comparing SIRT and chemotherapy (systemic and/or regional) with chemotherapy alone, or comparing SIRT alone with best supportive care. Only four randomized trials were identified. Due to heterogeneity of the patients and treatments received it was not possible to perform a formal meta-analysis, therefore this is a descriptive analysis only. All studies included patients with either liver only or liver dominant metastatic colorectal cancer. Two trials compared SIRT alone and SIRT with chemotherapy first line. The first with only 21 patients revealed a significant improvement in PFS and median survival with SIRT. The larger second study SIRFLOX of 530 patients comparing SIRT and current standard first line FOLFOX chemotherapy (+/- bevacizumab) with standard FOLFOX+/-bevacizumab alone. There was no improvement in overall PFS with addition of SIRT. In chemotherapy refractory patients SIRT and systemic chemotherapy (fluorouracil) improved progression free survival but not overall survival. A final study (63 patients) compared SIRT and regional chemotherapy (floxuridine) with regional chemotherapy alone in first line showed no significant difference in progression free survival and median survival. There remains a lack of evidence that SIRT improves survival or quality of life in patients with metastatic colorectal cancer. The overall survival results from SIRFLOX combined with FOXFIRE and FOXFIRE Global are awaited.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Microspheres; Organoplatinum Compounds; Quality of Life; Yttrium Radioisotopes

The objective of the treatment of colorectal cancer patients with unresectable liver metastases should be clearly defined at the outset. Potentially resectable patients should be distinguished from clearly unresectable patients. In defining resectability, it is important to take into account both anatomic characteristics and patient characteristic (comorbidities, symptoms, age). According to this evaluation, treatment should be tailored to each patient. The most widely accepted standard is doublet cytotoxic regimen plus biotherapy (anti-EGFR or anti-VEGF antibodies according to RAS status, but some patients could benefit from an intensified regimen, as triplet chemotherapy ± bevacizumab, or intraarterial treatments (hepatic arterial infusion, radioembolization or chemoembolization), in order to allow resectability. It is therefore very important to discuss the treatments with a multidisciplinary team, including an experienced surgeon, an interventional radiologist and an oncologist. On the other hand, some patients could benefit in terms of quality of life and decreased toxicity from less intense treatment when resection is not an objective. First-line monotherapy or a maintenance strategy with biotherapy and/or cytotoxics could be discussed with these patients, and treatment holidays should be considered in selected patients. Finally, in patients with secondary resection of liver metastases, specificity should be considered in choosing the best adjuvant treatment, such as response to preoperative treatment and individual risk of relapse, which many in some cases justify intensification with hepatic arterial infusion in an adjuvant setting.

Topics: Adenocarcinoma; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease Management; Embolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Practice Guidelines as Topic; Radiotherapy, Adjuvant; Tomography, X-Ray Computed

Recently, bevacizumab has become a key drug for treatment of metastatic colorectal cancer. Molecularly targeted agents such as bevacizumab can cause life-threatening adverse effects, though they are generally considered less toxic than cytotoxic drugs. Here, we review the case of a 76-year-old male rectal cancer patient with liver metastasis who suffered extensive bowel necrosis after administration of 5-fluorouracil-based chemotherapy with bevacizumab, and required a subtotal colectomy and end-ileostomy. Microscopic findings revealed extensive mucosal necrosis in the resected colon specimen and necrosis at the muscularis propria of the descending colon. Pathological findings suggested that the mucosal damage induced by chemotherapy may be exacerbated by treatment with bevacizumab, resulting in extensive necrosis.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colectomy; Colon; Fatal Outcome; Fluorouracil; Humans; Ileostomy; Leucovorin; Liver Neoplasms; Male; Necrosis; Organoplatinum Compounds; Rectal Neoplasms

The patient was a 70-year-old woman with sigmoid colon cancer and metastases in the liver and the paraaortic lymph nodes. We performed sigmoidectomy along with lymph node dissection. The solitary hepatic metastasis was 3 cm in diameter; however, hepatectomy was not performed because metastases in the paraaortic lymph nodes persisted. The serum carcino embryonic antigen(CEA)level was above 200 ng/mL, both preoperatively and postoperatively. After surgery, chemo- therapy was initiated. Initially, weekly 5-fluorouracil and l / -Leucovorin(5-FU/l-LV)therapy was administered 4 times. Subsequently, 5-FU/folinic acid plus oxaliplatin(FOLFOX4)therapy was administered 12 times every 2 weeks. Thereafter, S-1 therapy(orally, 40 mg twice a day, 28 days, followed by 14 days of rest)was initiated. After 3 months of chemotherapy, serum CEA levels decreased rapidly to within the normal limit. Paraaortic lymph node metastases and the hepatic metastasis disappeared after 3 months and 11 months, respectively. S-1 therapy was continued for over 7 years. Currently, it has been over 1 year since the discontinuation of S-1 therapy, and complete response has been maintained for over 9 years since the surgery.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Organoplatinum Compounds; Oxonic Acid; Sigmoid Neoplasms; Tegafur

The rationale for hepatic intra-arterial chemotherapy (HACT) is based on the predominantly arterial vascularization of liver metastases (HM). The intra-arterial route of administration thus increases the exposure of tumor cells to cytotoxic agents while limiting systemic toxicity. Chemotherapy is administered through a catheter placed in the gastroduodenal artery by either a surgical or percutaneous approach. Several anticancer agents can be administered to hepatic metastases from colorectal cancer (HMCRC) by HACT. Fluorodeoxyuridine (FUDR), used mainly in the United States, has a high intrahepatic extraction rate but also has intrinsic hepatobiliary toxicity. The HACT route is less suitable for irinotecan, since its active metabolite requires first-pass metabolism. In France, oxaliplatin is the most commonly used agent administered by HACT in combination with intravenous chemotherapy according to a 5-FU-Leucovorin protocol. The three main indications for HACT are: (1) potentially resectable HMCRC, (2) adjuvant treatment after resection of HMCRC in patients at high risk of intrahepatic recurrence, (3) palliative treatment of patients with primarily intra-hepatic disease that is definitely unresectable. In the setting of potentially resectable HMCRC, HACT can increase the chemotherapeutic response rate and improve the rate of secondary resectability. In the adjuvant setting, HACT seems to improve disease-free survival after complete resection of HMCRC in patients at high risk of intrahepatic recurrence. Finally, in the palliative setting, HACT prolongs progression-free survival, even in patients whose disease has progressed with intravenously administered oxaliplatin.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Floxuridine; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Treatment Outcome

The treatment of metastatic colorectal cancer (mCRC) has evolved considerably in the last decade, currently allowing most mCRC patients to live more than two years. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor play an important role in the current treatment of these patients. However, only antibodies directed against EGFR have a predictive marker of response, which is the mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Cetuximab has been shown to be effective in patients with KRAS wild-type mCRC. The CRYSTAL study showed that adding cetuximab to FOLFIRI (regimen of irinotecan, infusional fluorouracil and leucovorin) significantly improved results in the first-line treatment of KRAS wild-type mCRC. However, results that evaluate the efficacy of cetuximab in combination with oxaliplatin-based chemotherapy in this setting are contradictory. On the other hand, recent advances in the management of colorectal liver metastases have improved survival in these patients. Adding cetuximab to standard chemotherapy increases the response rate in patients with wild-type KRAS and can thus increase the resectability rate of liver metastases in this group of patients. In this paper we review the different studies assessing the efficacy of cetuximab in the first-line treatment of mCRC.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Clinical Trials as Topic; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Ligands; Liver Neoplasms; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome; Vascular Endothelial Growth Factor A

Colorectal liver metastasis (CLM) is common worldwide. Targeted therapies with monoclonal antibodies have been proven effective in numerous clinical trials, and are now becoming standards for patients with CLM. The development and application of anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies represents significant advances in the treatment of this disease. However, new findings continue to emerge casting doubt on the efficacy of this approach. The Kirsten rat sarcoma viral oncogene (KRAS) has been proven to be a crucial predictor of the success of anti-EGFR treatment in CLM. Whereas a recent study summarized several randomized controlled trials, and showed that patients with the KRAS G13D mutation significantly benefited from the addition of cetuximab in terms of progress-free survival (PFS, 4.0 mo vs 1.9 mo, HR = 0.51, P = 0.004) and overall survival (OS, 7.6 mo vs 5.7 mo, HR = 0.50, P = 0.005). Some other studies also reported that the KRAS G13D mutation might not be absolutely predictive of non-responsiveness to anti-EGFR therapy. At the same time, "new" RAS mutations, including mutations in neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) and exons 3 and 4 of KRAS, have been suggested to be predictors of a poor treatment response. This finding was first reported by the update of the PRIME trial. The update showed that for patients with non-mutated KRAS exon 2 but other RAS mutations, panitumumab-fluorouracil, leucovorin, and oxaliplatin (FOLFOX)4 treatment led to inferior PFS (HR = 1.28, 95%CI: 0.79-2.07) and OS (HR = 1.29, 95%CI: 0.79-2.10), which was consistent with the findings in patients with KRAS mutations in exon 2. Then, the update of the PEAK trial and the FIRE-III trial also supported this finding, which would reduce candidates for anti-EGFR therapy but enhance the efficacy. In first-line targeted combination therapy, the regimens of cetuximab plus FOLFOX was called into question because of the inferior prognosis in the COIN trial and the NORDIC-VII trial. Also, bevacizumab plus oxaliplatin-based chemotherapy was questioned because of the NO16966 trial. By the update and further analysis of the COIN trial and the NORDIC-VII trial, cetuximab plus FOLFOX was reported to be reliable again. But bevacizumab plus oxaliplatin-based chemotherapy was still controversial. In addition, some trials have reported that bevacizumab is not suitable for conversion therapy. The resul

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Disease-Free Survival; ErbB Receptors; Exons; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Mutation; Organoplatinum Compounds; Practice Guidelines as Topic; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); Randomized Controlled Trials as Topic; ras Proteins; Treatment Outcome; Vascular Endothelial Growth Factor A

A 64-year-old male with fatigue and icterus was referred to our hospital. Computed tomography(CT)demonstrated multiple liver metastases and colonoscopic examination revealed advanced rectal cancer, which was diagnosed as moderately- differentiated adenocarcinoma without KRAS mutation. His serum total bilirubin level was 15.6 mg/dL. We started combination chemotherapy with 5-fluorouracil, Leucovorin and oxaliplatin(modified FOLFOX6)at a 20% lower than standard dosage for safety. When his bilirubin fell to 2.3 mg/dL after 4 courses of mFOLFOX6, the doses of 5-fluorouracil and oxaliplatin were increased to standard doses, and treatment with bevacizumab of 5 mg/kg every 2 weeks was begun. After another 3 courses of chemotherapy, his bilirubin was normalized to 0.8 mg/dL. No significant toxicity was observed. Combination chemotherapy with mFOLFOX6 plus bevacizumab was effective and feasible in this case of metastatic rectal cancer with icterus due to diffuse liver metastases.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Fatal Outcome; Fluorouracil; Humans; Jaundice; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms

With modern multimodality therapy, patients with resected colorectal cancer (CRC) liver metastases (CLM) can experience up to 50-60 % 5-year survival. These improved outcomes have become more commonplace via achievements in multidisciplinary care, improved definition of resectability, and advances in technical skill.. Even patients with synchronous and/or extensive bilateral disease have benefited from novel surgical strategies. Treatment sequencing of synchronous CRC with CLM can be simplified into the following three paradigms: (classic colorectal-first), simultaneous (combined), or reverse approach (liver-first). The decision of whether to treat the CLM or CRC first depends on which site dominates oncologically and symptomatically. Oxaliplatin with 5-fluorouracil/leucovorin (FOLFOX) and irinotecan with 5-fluorouracil/leucovorin (FOLFIRI) are the foundations of modern chemotherapy. Although each regimen has positively impacted survivals, both have the potential for negative effects on the non-tumor liver. Oxaliplatin is associated with vascular injury (sinusoidal ballooning, microvascular injury, nodular regenerative hyperplasia, and long-term fibrosis) but not steatosis. Irinotecan has been associated with steatohepatitis, especially in patients with obesity and diabetes. Steatohepatitis from irinotecan is the only chemotherapy-associated liver injury (CALI) associated with increased mortality from postoperative hepatic insufficiency. Extended duration of preoperative chemotherapy is also associated with CALI.. To determine resectability and to prevent overtreatment with systemic therapy, all patients should receive high-quality cross-sectional imaging and be evaluated by a hepatobiliary surgeon before starting chemotherapy. Even as chemotherapy improves, liver surgeons will continue to play a central role in treatment planning by offering the best chance for prolonged survival-safe R0 resection with curative intent.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheter Ablation; Chemical and Drug Induced Liver Injury; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Treatment Outcome

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25% of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Meta-Analysis as Topic; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Randomized Controlled Trials as Topic

Selected patients with unresectable colorectal liver metastases (CLM) may be rendered resectable after systemic chemotherapy. We reviewed the evidence of downsizing systemic chemotherapy followed by rescue liver surgery in patients with initially unresectable CLM.. Literature search of databases (Medline and PubMed) to identify published studies of neoadjuvant chemotherapy followed by liver resection in patients with initially unresectable CLM was undertaken and focused on response rate of chemotherapy and survival outcomes.. Ten observational studies were reviewed. A total of 1,886 patients with initially unresectable CLM underwent systemic chemotherapy. An objective response was observed in 64% (range, 43-79%) of patients after systemic chemotherapy. Of these, 22.5% underwent macroscopically curative liver resection. Median overall survival was 45 (range, 36-60) months with 19% of patients alive and recurrence-free.. Current evidence suggests that downsizing systematic chemotherapy followed by rescue liver resection is safe and effective for selected patients with initially unresectable CLM. Further studies are required to examine response rates and secondary resectability using new targeted molecular therapy-based regimens.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Metastasectomy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Premedication; Survival Rate; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Pancreatic Neoplasms; Prostatic Neoplasms; Review Literature as Topic; Tomography, X-Ray Computed; Treatment Outcome

A 69-year-old man visited our hospital because of melena and anemia. Colonoscopy revealed a type 3 tumor at sigmoid colon, and by abdominal CT, we detected a sigmoid colon cancer invading the urinary bladder with a single liver metastasis. The patient required sigmoidectomy with partial hepatectomy and total urinary bladder resection. Preoperative chemotherapy with mFOLFOX6 was initiated as a part of multidisciplinary therapy. After the 6th course was completed, CT revealed a reduction in the primary tumor's size and the disappearance of liver metastasis. After the 8th course was completed, we performed urinary bladder conserving sigmoidectomy. The pathological diagnosis of the surgical specimen was tub1, pSS, ly0, v0, pN0, and pStage II. Down-sizing chemotherapy might improve the quality of life(QOL)of colon cancer patients with extensive invasion of the urinary bladder.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Sigmoid Neoplasms; Tomography, X-Ray Computed; Urinary Bladder

We report a case of a 58-year-old man suffering from advanced colon cancer with liver metastases. After the sigmoidectomy and left lateral segmentectomy, mFOLFOX6+bevacizumab was initiated. The mFOLFOX6+bevacizumab therapy was performed for 15 courses, but it was stopped because of an increase in serum levels of tumor markers(CEA and CA19-9). For the next treatment, FOLFIRI+panitumumab therapy was performed. At the beginning of the second course, he suffered from dyspnea. Computed tomography showed ground-glass opacities and traction bronchiectasis in both lung fields. He was diagnosed with interstitial pneumonitis induced by irinotecan or panitumumab. Corticosteroid therapy consisting of methyl- prednisolone(1 g/day)administered for three days was significantly effective for treating respiratory failure. Two courses of the therapy were performed, and he was discharged without aftereffects. As with other EGFR tyrosine kinase inhibitors, the frequency of interstitial pneumonitis induced by irinotecan in Japan may increase to European and American levels.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Methylprednisolone; Middle Aged; Organoplatinum Compounds; Panitumumab; Tomography, X-Ray Computed

Liver metastasis from colorectal cancer has become a common disease associated with the increase of primary colorectal cancer in Japan. The standard treatment for resectable liver metastases is still complete liver resection. Recent advances in systemic chemotherapy have introduced another strategy, i.e., conversion chemotherapy, for patients with initially diagnosed unresectable liver metastases. The conversion rate after neo-adjuvant chemotherapy is increasing with multidisciplinary approaches. Long-term clinical data have not been established yet. Indications for liver resection after neo-adjuvant chemotherapy; optimal chemotherapy regimens; and histological changes in the normal liver are important research issues for the future.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Molecular Targeted Therapy; Organoplatinum Compounds; Survival Rate

As pharmacokinetics in patients undergoing haemodialysis is different from patients with normal renal function, it remains unclear whether chemotherapy can be performed safely for patients with haemodialysis as well as those who have normal renal function. Here, we report a case with recurrence of rectal cancer who received FOLFIRI with bevacizumab chemotherapy under haemodialysis, and obtained good tumor control. A 47-year-old woman had undergone haemodialysis for 10 years due to chronic renal failure. At 45 years of age, she received abdominoperineal resection due to rectal cancer (pStage II). Four months after the surgery, liver metastasis was found, for which partial resection of the liver and adjuvant chemotherapy [UFT (400 mg/body)/UZEL (75 mg/body)] were performed. Eighteen months after the liver resection, multiple lung metastases were found. Therefore, intensive chemotherapy using FOLFIRI (CPT-11: 90 mg/m2) with bevacizumab (2.5 mg/m2) was performed. Severe neutropenia (grade 3, 4), but not non-hematologic adverse events such as diarrhea and bevacizumab-specific adverse events, was observed. As she did not recover easily from neutropenia in spite of treatment with G-CSF, a dose reduction of the FOLFIRI regimen was gradually performed. Although chemotherapy was conducted approximately monthly, the tumor response reflected a stable disease 8 months after 8 courses of chemotherapy. We suggest that it is important to investigate the pharmacokinetics of toxic agents such as CPT-11, (SN38) for dose modification, and for the safe and continuous chemotherapy of patients receiving haemodialysis.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Rectal Neoplasms; Recurrence

More than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis.. In these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/- irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability.. The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients' characteristics in the CHARTA trial.. Clinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Multicenter Studies as Topic; Organoplatinum Compounds; Randomized Controlled Trials as Topic

Surgical resection of liver metastases of colorectal cancer can improve clinical outcome and even cure some patients with metastatic disease. For patients with unresectable liver metastases, the ultimate treatment goal is to let them become eligible for resection. In recent years, considerable attention has been paid to molecular targeted therapies to improve the efficacy of the available chemotherapeutic regimens in order to increase the downsizing rate of liver metastases and increase resectability. This overview will focus on the oncological management and chemotherapeutic options of patients with unresectable liver metastases.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoplasm Staging; Organoplatinum Compounds; Panitumumab; Time Factors

Metastatic colorectal cancer has evolved from a paradigm that was previously centered upon the use of systemic chemotherapy to one of multimodality therapy. Hepatectomy, pulmonary metastasectomy, and cytoreductive surgery with hyperthermic intraperitoneal chemotherapy are surgical procedures that are now routinely performed in specialized institutions treating patients with metastatic colorectal cancer. Emerging evidence suggests that in selected patients, these procedures are safe and may be beneficial in contributing to long-term survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Hyperthermia, Induced; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Lung Neoplasms; Organoplatinum Compounds; Peritoneal Neoplasms; Pneumonectomy

Resection of colorectal liver metastases (CLM) is the ultimate aim of treatment strategies in most patients with liver-confined metastatic colorectal cancer. Long-term survival is possible in selected patients with initially resectable or unresectable CLM. As a majority of patients have unresectable liver disease at the outset, there is a clear role for chemotherapy to downstage liver disease making resection possible. Studies of systemic chemotherapy with or without biologic therapy in patients with unresectable CLM have resulted in increased response rates, liver resection rates and survival. A sound physiologic rationale exists for the use of hepatic arterial infusion (HAI) therapy. Studies have shown that HAI with floxuridine combined with systemic chemotherapy increases response rates and liver resection rates in those patients with initially unresectable CLM. Toxicity from preoperative chemotherapy, biologic therapy and HAI therapy may adversely affect hepatic resection but can be kept minimal with appropriate monitoring. All conversion strategies should be decided by a multidisciplinary team.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Therapy; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Floxuridine; Fluorouracil; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Survival Analysis; Treatment Outcome

There is limited experience in treating advanced colorectal cancer diagnosed during pregnancy because it is a rare occurrence; however, the incidence of colorectal cancer complicating pregnancy is expected to increase in the future. The combination of cancer and pregnancy is complicated and causes many dilemmas and concerns for the physician and patient. A delay in treatment may compromise maternal survival; however, therapy for the cancer may be harmful to the fetus. We present a case of a 26-year-old woman pregnant with twins who was diagnosed with metastatic colon cancer and treated with 5-fluorouracil, leukovorin, and oxaliplatin (FOLFOX) from 13 weeks gestational age to birth. The patient gave birth to healthy twins without malformations at 33 weeks gestational age. At follow-up examination, the 2-year-old twins are developing normally. The patient herself died 1 year after the initial cancer diagnosis. This shows a case in which the administration of FOLFOX during the second and third trimester of pregnancy caused no fetal harm. These findings are similar to those of previous studies in which systemic chemotherapy administered during the second and third trimester was relatively safe. However, we know that chemotherapy should be avoided during the first trimester.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Organoplatinum Compounds; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Pregnancy, Twin

In UICC stage I a selected group of patients with T1 tumours and a low risk profile regarding simultaneous lymph node metastases can be treated by endoscopic resection alone, if the tumour is thereby completely removed. In UICC stage II an adjuvant chemotherapy (CT) should not be routinely performed. However, in high risk UICC stage II patients (T4 tumour, less than 12 examined lymph nodes, emergency surgery, intraoperative tumour perforation), an adjuvant CT with infusional 5-FU/FA should be recommended. The state of the art in UICC stage III is an adjuvant CT with FOLFOX. In this tumour stage no beneficial effect of CT involving irinotecan or monoclonal antibodies has been documented. Due to CT-induced side effects an infusional 5-FU/FA protocol or oral capecitabine should be given in patients older than 70 years. In stage UICC IV with resectable liver metastases, surgical resection of the primary tumour and the metastases should be implemented. Since no conclusive data are currently available regarding the beneficial effect of neoadjuvant, perioperative or adjuvant CT in this setting, the therapeutic strategy should be individually discussed between surgeons and oncologists (tumour board). In cases of non-resectable liver metastases a neoadjuvant CT should be performed, preferentially with a FOLFOX protocol in combination with targeted therapies, i.e., the monoclonal antibody cetuximab, aimed at tumour regression with radical metastasectomy as the secondary intent (R0). Patients with UICC stage II colon cancer and microsatellite instability (MSI) apparently experience a better prognosis but do not profit from an adjuvant CT with 5-FU/FA alone. If a CT is under consideration for these patients, the MSI status should be determined on tumour tissue. In cases of a positive result a combination CT, i.e., with FOLFOX, should be given. The relevance of the MSI status in other tumour stages is as yet unknown. Before targeted therapies, i.e., cetuximab or panitumumab, are initiated, the KRAS status needs to be determined, since therapies with antibodies against the epithelial growth factor receptor (EGFR) are only effective in tumours bearing the KRAS wild-type.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Cooperative Behavior; Drug Delivery Systems; Fluorouracil; Humans; Interdisciplinary Communication; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Metastasectomy; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Patient Care Team; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Organoplatinum Compounds

The resection of liver metastases offers the option of long-term survival for patients with colorectal carcinoma. With regard to resectability three clinical situations can be identified: patients with resectable liver metastases, those with potentially resectable liver metastases and patients with disseminated metastatic disease. Patients with potentially resectable liver metastases should be treated with regimens with high response rates. According to a metaanalysis patients with resectable liver metastases have a better disease-free survival with the combination of resection and chemotherapy. If neoadjuvant therapy is planned in resectable patients the FOLFOX regimen is the schedule with the highest level of evidence. In potentially resectable liver metastases the regimens FOLFIRI/cetuximab and FOLFOXIRI have demonstrated higher response and resection rates in phase III trials. During neoadjuvant therapy resectability should be regularly reevaluated. Operations should be planned as soon as resectability is achieved because a longer therapy will increase morbidity and because of uncertainty over the approach to patients with complete remission.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Prognosis; Randomized Controlled Trials as Topic

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optim

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Vitamin B Complex

Radioembolization with yttrium-90 microspheres ((90)Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent (90)Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for (90)Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, (90)Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, (90)Y-RE with resin microspheres is significantly more effective than (90)Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoembolization, Therapeutic; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Glass; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Microspheres; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome; Yttrium Radioisotopes

Neoadjuvant chemotherapy is increasingly being used to enlarge the cohort of patients who can be offered hepatic resection for malignancy. However, the impact of these agents on the liver parenchyma itself, and their effects on clinical outcomes following hepatic resection remain unclear. This review identifies patterns of regimen-specific chemotherapy-induced hepatic injury and assesses their impact on outcomes following hepatic resection for colorectal liver metastases (CLM).. An electronic search was performed using the MEDLINE (US Library of Congress) database from 1966 to May 2007 to identify relevant articles related to chemotherapy-induced hepatic injury and subsequent outcome following hepatic resection.. The use of the combination of 5-flourouracil and leucovorin is linked to the development of hepatic steatosis, and translates into increased postoperative infection rates. A form of non-alcoholic steatohepatitis (NASH) related to chemotherapy and otherwise known as chemotherapy-associated steatohepatitis (CASH) is closely linked to irinotecan-based therapy and is associated with inferior outcomes following hepatic surgery mainly due to hepatic insufficiency and poor regeneration. Data on sinusoidal obstruction syndrome (SOS) following treatment with oxaliplatin are less convincing, but there appears to be an increased risk for intra-operative bleeding and decreased hepatic reserve associated with the presence of SOS. Intra-arterial floxuridine therapy damages the extrahepatic biliary tree in addition to causing parenchymal liver damage, and has been shown to be associated with increased morbidity after hepatic resection.. Agent-specific patterns of damage are now being recognized with increasing use of neoadjuvant chemotherapy prior to surgery. The potential benefits and risks of these should be considered on an individual patient basis prior to hepatic resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Fatty Liver; Floxuridine; Fluorouracil; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Irinotecan; Leucovorin; Liver; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Risk Factors

Liver metastases from colorectal cancer (CRC) have a poor prognosis. Despite recent advances in the management of advanced disease with chemotherapy, liver resection remains the only hope for cure for patients with colorectal liver metastases. Approximately 15% of patients with stage IV CRC referred to specialist centers have metastatic liver disease deemed to be resectable at presentation. Over the last five years, combination chemotherapeutic regimens, namely 5-fluorouracil/folinic acid with irinotecan or oxaliplatin and, more recently, integrating targeted monoclonal antibodies, have been shown to downsize the tumour burden to an extent that sometimes allows initially unresectable metastases to be excised. Five-year survival rates following liver resection range between 25% and 55% compared with 0% and 5% for non-operated patients. Beyond liver resection, the rationale for "pseudo-adjuvant" chemotherapy lacks scientific evidence, despite some promising data. However, perioperative chemotherapy for resectable lesions is gaining ground in current practice. In this article we review the state of the art treatment for CRC liver metastases and, considering the results of recent trials, try to determine the appropriate role of chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheter Ablation; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

Cardiotoxicity is a rare but serious complication of 5-fluorouracil therapy. Coronary vasospasm and, less frequently, acute myocarditis have been identified as underlying mechanisms. We report a case of severe toxicity in a relatively young and fit male patient being treated for metastatic colonic adenocarcinoma displaying characteristics that cannot be explained by either mechanism alone.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Cardiovascular Agents; Colonic Neoplasms; Coronary Vasospasm; Fluorouracil; Heart Diseases; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Myocarditis; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome; Ventricular Dysfunction, Left

Surgery is the only curative option for patients with liver metastases of colorectal cancer, but few patients present with resectable hepatic lesions. Chemotherapy is increasingly used to downstage initially unresectable disease and allow for potentially curative surgery. Standard chemotherapy regimens convert 10%-20% of cases to resectable disease in unselected populations and 30%-40% of those with disease confined to the liver. One strategy to further increase the number of candidates eligible for surgery is the addition of active targeted agents such as cetuximab and bevacizumab to standard chemotherapy. Data from a phase III trial indicate that cetuximab increases the number of patients eligible for secondary hepatic resection, as well as the rate of complete resection when combined with first-line treatment with the FOLFIRI regimen. The safety profiles of preoperative cetuximab or bevacizumab have not been thoroughly assessed, but preliminary evidence indicates that these agents do not increase surgical mortality or exacerbate chemotherapy-related hepatotoxicity, such as steatosis (5-fluorouracil), steatohepatitis (irinotecan), and sinusoidal obstruction (oxaliplatin). Secondary resection is a valid treatment goal for certain patients with initially unresectable liver metastases and an important end point for future clinical trials.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

The liver is the primary metastatic site in patients with colorectal cancer, and the only hope for a cure or prolonged survival in patients with liver metastases is provided by surgical resection. Advances obtained in non-resectable metastatic disease using new chemotherapeutic agents raise important questions about the use of neoadjuvant and adjuvant chemotherapy in patients with resectable liver metastases. Two major randomized studies have yielded positive results. First, a combined intra-arterial plus systemic fluoropyrimidine-based chemotherapy regimen demonstrated a relapse-free survival benefit when compared to systemic 5-fluorouracil-leucovorin therapy alone. This approach is still restricted to specialized centres, however, due to technical limitations and locoregional toxicities. Secondly, an EORTC trial demonstrated the superiority of peri-operative FOLFOX-4 chemotherapy in comparison to surgery alone. Oxaliplatin and irinotecan can induce substantial liver damage, especially steatohepatitis and vascular lesions, but the impact of these lesions on postoperative morbidity and survival remains unclear. Ongoing and planned trials will assess the addition of anti-angiogenic and anti-epidermal growth factor receptor agents to chemotherapy regimens.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Liver; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome

Liver metastases are often the dominant site of metastatic disease in colorectal cancer. Selective internal radiation therapy (SIRT) involves embolising radiolabeled spheres (SIR-Spheres) into the arterial supply of the liver with the aim of improving the control of liver metastases.. To assess the effectiveness and toxicity of SIRT in the treatment of metastatic colorectal cancer liver metastasis when given alone or with systemic or regional hepatic artery chemotherapy.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane library 2008 issue 2, MEDLINE (1966 to October 2008), EMBASE (1980 to October 2008), and Pubmed (October 2008). The proceedings of ASCO (1985 to 2008) and ASCO GI (2004 to 2008) were also searched. The manufacturers of SIR-Spheres were contacted and asked whether they were aware of any other unpublished studies.. Randomised controlled trials comparing SIRT and chemotherapy (systemic and/or regional) with chemotherapy alone, or comparing SIRT alone with best supportive care in patients with metastatic colorectal cancer.. Two authors (AT/TP) extracted data and assessed the trial quality. The study authors were contacted and individual patient data was obtained. Results were analysed separately for patients with and without extra-hepatic disease.. A single study of 21 patients compared SIRT and systemic chemotherapy (fluorouracil and leucovorin) with chemotherapy alone. There was a significant improvement in progression free survival and median survival associated with SIRT, both for the total studied population and for those disease limited to the liver. There was an increase in toxicity with the use of SIRT. A second study of 63 eligible patients compared SIRT and regional chemotherapy (floxuridine) with regional chemotherapy alone. There was no significant difference in progression free survival and median survival seen with SIRT, in either the total patient group or in the 22 patients with disease limited to the liver. There was no significant increase in toxicity with the addition of SIRT to regional chemotherapy. There were no randomised studies comparing SIRT with best supportive care in patients with refractory disease, and no randomised studies assessing the effect of SIRT in patients with resectable liver metastases.. There is a need for well designed, adequately powered phase III trials assessing the effect of SIRT when used with modern combination chemotherapy regimens. Further studies are also needed for patients with refractory disease with a particular focus on the impact on quality of life.

Topics: Antimetabolites, Antineoplastic; Colorectal Neoplasms; Combined Modality Therapy; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Microspheres; Radiotherapy; Randomized Controlled Trials as Topic; Yttrium Radioisotopes

A 79-year-old woman with colon cancer and multiple liver metastases was admitted to our hospital for systemic chemotherapy. She underwent first cycle of modified FOLFOX6 chemotherapy. She was confused on treatment day 5. Blood test revealed her serum ammonia level to be 121 microg/dl. We diagnosed 5-fluorouracil (5FU)-induced hyperammonemia. Conservative treatment resulted in improvement of metal status. The reason for hyperammonemia after administration of 5FU was the excess production of ammonium from metabolites of 5FU.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

To compare mRNA levels in cancer cells and protein levels in cancerous tissue in order to evaluate the expression of dihydropyrimidine dehydrogenase (DPD).. The materials were resected specimens of primary colorectal cancer (n=88) and synchronous liver metastasis (n=15). The expression of DPD mRNA in cancer cells was quantified by reverse-transcriptase polymerase chain reaction (RT-PCR) using cancer cells obtained by micro-dissection of paraffin-embedded specimens (Danenberg tumor profiling method). The protein level of DPD was determined by enzyme -linked immunosorbent assay (ELISA).. There was no relationship between the level of DPD mRNA and the level of DPD protein in primary colorectal cancers and liver metastases. The level of DPD protein tended to be higher in liver metastases than in primary lesions (p=0.08) without a significant relationship between the two values. There was no relationship between primary colorectal lesions and liver metastases in terms of the expression of DPD mRNA. The efficacy of 5-fluorouracil (5-FU or UFT)/Leucovorin did not correlate with the expression level of DPD mRNA or DPD protein of primary lesions (n=18).. We should note the discrepancy of results between the two different methods and the lack of a relationship between the levels of DPD expression in primary lesions and liver metastases, when considering the efficacy of 5-FU-based regimens according to the DPD expression level in primary colorectal cancers.

Topics: Antimetabolites, Antineoplastic; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Enzyme-Linked Immunosorbent Assay; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

This review examines the development of hepatic arterial infusion (HAI) of chemotherapy over the past 40 years. Liver metastases are mainly supplied by the hepatic artery, and high levels of intratumoral drug delivery are achievable with the use of HAI. Floxuridine, 5-fluorodeoxyuridine is commonly used, but intra-arterial oxaliplatin and mitomycin- C also have advantages. The dramatic responses observed with HAI plus systemic therapy offer the possibility of resection and cure in select patients. Resectability of liver-limited colorectal cancer metastases should be considered as an endpoint for all patients. Hepatic arterial infusion may be used in palliative, neoadjuvant, and adjuvant settings. Herein, combinations of systemic chemotherapy with HAI are discussed, along with the role of newer cytotoxic and biologic agents. The first-pass extraction of some drugs given by regional perfusion in the liver limits systemic side effects. Toxicity includes catheter-related complications and biliary and gastrointestinal ulcers. The role of HAI therapy for the treatment of unresectable and resectable disease, as well as the use of other regional strategies such as embolization and ablation, are discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Mitomycin; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

The patient was a 79-year-old woman. We became introduction consultation than a nearby doctor in alpha-fetoprotein(AFP)high level. Abdominal ultrasonography showed 30mm great tumor in liver lateral segment area and gastric fiber showed type2 tumor which is AFP producing gastric cancer. On admission AFP level is high(403ng/ml). Multiple liver metastases were noted it by abdominal angiography. We started FLAP(5-fluorouracil, leucovorin, etoposide, cisplatin)combination chemotherapy by a diagnosis of AFP producing gastric cancer StageIV. It is reduction of a liver tumor after one course, and the stomach lesion almost disappeared after three courses end points.

Topics: Adenocarcinoma; Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Stomach Neoplasms

The liver is a frequent site of metastatic disease for colorectal cancer patients. Approximately 15% of patients have liver metastases at diagnosis and another 50% develop metastatic disease to the liver over the course of their disease. Advances in systemic chemotherapy and surgical techniques for hepatic resection have led to longer survival times for these patients. There is no doubt that unresectable patients benefit from systemic chemotherapy. For patients who have resectable disease, the timing of chemotherapy is still not clear. This review addresses the pros and cons of presurgical chemotherapy. The benefits of preoperative chemotherapy include decreasing tumor size, controlling micrometastatic disease, assessing activity of chemotherapy, improving chemotherapy tolerance, and perhaps allowing some prediction of the success of liver resection. The risks for presurgical chemotherapy include liver toxicity, the risk for progression or growth of new sites, secondary splenomegaly, selection of resistant clones, and the possibility of leaving behind active tumor that is no longer seen because of a complete radiographic response. The challenge for the future is to develop a multidisciplinary team approach that can design the best treatment plan for patients with liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Patient Selection; Preoperative Care; Survival Analysis; Treatment Outcome

Colorectal cancers have been the first cancers to benefit from an efficient anti-angiogenic treatment, represented by bevacizumab, which has been approved for first-line metastatic treatment in combination with reference chemotherapies and which is under study in the adjuvant setting. Other gastro-intestinal malignancies appear less responsive to anti-angiogenic therapy, but inhibitors of the VEGF receptors (sorafenib, sunitinib, axitinib) are in development with encouraging results. The safety profile of anti-angiogenic agents is quite different from that of classical chemotherapy and may require a modification of treatment strategies.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Hepatocellular; Colorectal Neoplasms; Esophageal Neoplasms; Fluorouracil; Gastrointestinal Neoplasms; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Stomach Neoplasms

The modern treatment of colorectal cancer. Present and future. Fluorouracyl has been the mainstay of treatment for colorectal cancer for decades. The addition of folinic acid to 5FU, the use of infusional, rather than bolus 5FU, and the combination of new active agents such as irinotecan and oxaliplatin with 5FU/LV have each led to increase in effectivity. Oral formulations of fluoropyrimidines can replace the infusional 5FU therapy with better convenience. The authors review the current progress with the use of novel molecular targeted therapies that are tumor specific with better toxicity profile than chemotherapy. The integration of the new biological response modifier therapeutic possibilities in the chemotherapy protocols may result prolongation in survival, in metastatic patients the presently 2 years survival will approach 3 years. Combining these drugs with chemotherapeutics in the adjuvant setting we hope to raise further the presently achieved 78% of 3 years disease free survival by oxaliplatin plus 5FU therapy. As the variation of agents has been increased, choosing the most effective treatment strategy has become increasingly complex.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Immunologic Factors; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise infighting colorectal cancer.

Topics: Administration, Oral; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Therapy, Combination; Fluorouracil; History, 20th Century; History, 21st Century; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Randomized Controlled Trials as Topic

Hepatic metastases from colorectal carcinoma (CRC) were once thought to portend a uniformly grim outcome; however, improvements in chemotherapeutic and surgical approaches have led to significant advances as well as new clinical challenges. Some 60% of the 150,000 patients diagnosed with CRC each year in the United States will develop hepatic metastases. Only a fraction of these metastases are resectable at the time of presentation, but an increasing number of patients are able to undergo resection after neoadjuvant chemotherapy. Additionally, recent trials have demonstrated the efficacy of using chemotherapy with bevacizumab as first-line therapy for metastatic CRC, but how this treatment will affect surgical resection is unknown. Herein, we review the recent literature regarding neoadjuvant chemotherapy for hepatic metastases from CRC, discuss key aspects of the basic science of hepatic regeneration with regard to angiogenic mediators, and outline the key problems to be solved so that a rational strategy can be developed to treat patients with hepatic colorectal metastases in the age of neoadjuvant chemotherapy and antiangiogenic drugs.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Vascular Endothelial Growth Factor A

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Cisplatin; Combined Modality Therapy; Deoxycytidine; Doxorubicin; Etoposide; Femoral Neoplasms; Gemcitabine; Head and Neck Neoplasms; Humans; Ifosfamide; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Methotrexate; Middle Aged; Neoadjuvant Therapy; Osteosarcoma; Palliative Care; Salvage Therapy; Scalp; Skin Neoplasms; Thoracotomy

Topics: Antimetabolites, Antineoplastic; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms

New results presented at ASCO Conference in 2003 added further important data to our knowledge on successful use of irinotecan in colorectal cancer (CRC). Irinotecan - just like oxaliplatin - given as neoadjuvant therapy with 5-FU - folinic acid (FUFA) can render originally unresectable liver or lung metastases of CRC resectable, giving the hope of long-term survival for a proportion of patients. Irinotecan combined with 5-FU is an essential part of the most successful palliative sequential chemotherapy of stage IV CRC. Sequential FOLFIRI before or after FOLFOX combination ensures the longest possible progression-free and overall survival for metastatic CRC patients in the palliative setting. In order to achieve the longest survival time, sequential use of both 5-FU, irinotecan and oxaliplatin is necessary. The French GERCOR Group achieved 26 months median overall survival with the sequential use of continuous infusional FUFA, oxaliplatin and irinotecan combinations in stage IV CRC. The analysis of large phase III trials using 5-FU, irinotecan and oxaliplatin revealed that the higher proportion of patients was treated with all three drugs, the longer overall survival was achieved. If applied with caution, toxicity and efficacy of irinotecan in elderly patients is not significantly different from that seen in younger population. The anti-VEGF bevacizumab increases the efficacy of first-line irinotecan therapy, while the addition of cetuximab restores irinotecan sensitivity in second line treatment of stage IV CRC. The combination of irinotecan with oral capecitabine is safe and effective in advanced CRC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Survival Analysis; Treatment Outcome

OncoSurge is a combined modality strategy for the management of colorectal cancer with hepatic metastases. It has emerged as a result of new and expanded patient selection criteria for resectability of metastases, coupled with more effective neoadjuvant and postoperative chemotherapy. By bringing together these developments in surgery and medical oncology, the new approach promises to increase significantly the resectability rate and long-term survival in colorectal cancer patients with liver metastases. Surgery for colorectal liver metastases should now be considered across a range of clinical circumstances that would historically have been contraindications to resection. These contraindications include multiple or bilobar metastases, large tumour size, a Dukes stage C or poorly differentiated primary tumour, synchronous detection of metastases with the primary tumour, disease in elderly patients, or a resection margin of less than 1 cm. None of these criteria should necessarily exclude a patient from resection, because although they may be associated with a less favourable prognosis they do not exclude the possibility of long-term survival. Non-resectable extrahepatic disease and portal lymph node involvement, however, remain contraindications to resection in most circumstances. Retrospective studies of neoadjuvant therapy have indicated that a regimen based on low dose oxaliplatin, 5-fluorourucil (5-FU) and leucovorin increased the overall resectability rate of patients presenting with hepatic colorectal metastases from 20% to 30%, with 13.6% of patients with unresectable metastases becoming eligible for curative resection. More recently, studies using more potent oxaliplatin-based regimens have reported significantly higher resectability rates of at least 40%, with 5-year survival of 50% reported in one large study among patients whose liver metastases were resected after initial neoadjuvant therapy for unresectable tumours. Following resection, postoperative therapy based on a combination of hepatic artery infusion (HAI) and systemic chemotherapy reduces hepatic recurrence and increases survival, but more potent systemic therapy is required to reduce the rate of extrahepatic recurrence. Studies are now in progress combining HAI with oxaliplatin-based systemic therapy to address this issue. By combining a more inclusive approach to surgery with more effective neoadjuvant and postoperative chemotherapy, the OncoSurge treatment model is likely to increa

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Survival Rate

This focuses on review one of the methods of locoregional treatment - intraarterial hepatic infusion. Metastatic hepatic malignancies are the leading cause of cancer death. Surgical resection of metastatic hepatic malignancies has been the only established treatment modality offering potential for cure. Although surgical resection has significantly improved survival, only 5-20 percent of patients with colorectal carcinoma metastatic to the liver are surgical candidates. Conventional systemic (intravenous) chemotherapy with fluoropirimidines is effective only for 10-21 percent of patients with metastatic colorectal carcinoma. The limitations of surgical resection and the limited efficacy and generalized toxicity of systemic chemotherapy have sparked considerable interest in intraarterial hepatic infusion and especially in combination of systemic and intraarterial chemotherapy.

Topics: Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Carmustine; Colorectal Neoplasms; Cross-Over Studies; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Meta-Analysis as Topic; Mitomycin; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors

Metastatic colorectal cancer has a poor prognosis, and the majority of patients are left with palliative measures. The development seen using palliative chemotherapy is reviewed.. A systematic approach to the literature-based evidence was aimed at.. The continuous improvements during the past 13-15 years have been documented in several large conclusive trials. At the end of the 1980s, the evidence that chemotherapy should be used at all was very limited, whereas presently most patients can be offered two lines of chemotherapy based upon good scientific evidence. Median survival has gradually improved from below 6 months to above 18 months in some recent trials. Several important issues remain to be solved, such as the best sequence of treatments, what regimens to use in various situations, when to start and when to stop if a response is seen, and whether cure may be possible in a small subset of patients.. Progress has been rapid in advanced colorectal cancer. This is likely a result of well-designed trials in collaboration between academy and industry, showing a great interest in the disease. Future collaborations may hopefully introduce new treatment concepts, further improving outcome.

Topics: Antimetabolites, Antineoplastic; Camptothecin; Colorectal Neoplasms; Disease Progression; Enzyme Inhibitors; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Palliative Care; Quinazolines; Survival Analysis; Tegafur; Thiophenes; Thymidylate Synthase; Topoisomerase I Inhibitors; Treatment Outcome; Uracil

Liver metastases concern half of patients with colorectal cancer, and are frequently unresectable, jeopardizing patient outcome. Owing to increased efficacy, chemotherapy can render initially inoperable patients amenable to potentially curative resection. The 34% 5-year and 20% 10-year survival of patients resected following neoadjuvant chronomodulated chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin is similar to that of patients whose disease was operable at diagnosis. Recently, a group of 16 patients were treated with irinotecan and became resectable after treatment. Their survival (56% at 3 years) matches that of patients treated with other forms of chemotherapy. The poor prognosis of patients with non-resectable hepatic metastases might now be improved by the combination of chemotherapy and surgery.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonography, Computed Tomographic; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Survival Analysis

Colon cancers arise only rarely in the course of a pregnancy. Yet colon obstruction, perforation and metastatic spread seem to occur more frequently in this setting than with the average colon cancer. Perhaps this is due to the immunotolerance which accompanies pregnancy. No case of epidermoid (squamous cell) cancer of the colon has been previously described in a pregnant woman. This conjunction has a catastrophic prognosis: the diagnosis of colon tumor is delayed since symptoms are masked by the pregnancy, and epidermoid colon cancer is a particularly aggressive lesion. A major sub-diaphragmatic surgical procedure can be performed with reasonable safety to mother and fetus. Radiotherapy is contraindicated. Neo-adjuvant chemotherapy can be administered although the risks to the fetus are not well known. During the first trimester, a therapeutic abortion can be proposed to optimise the treatment of the mother. During the second and third trimesters, treatment of the mother exposes the fetus to the risk of malformations or premature delivery; delay in maternal treatment in hopes of prolonging the pregnancy in order to obtain a viable neonate diminish the chances of maternal survival.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cesarean Section; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Disease Progression; Diseases in Twins; Down Syndrome; Fatal Outcome; Female; Fetal Death; Fluorouracil; Humans; Intestinal Perforation; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy, Multiple

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colectomy; Colorectal Neoplasms; Fluorouracil; Humans; Informed Consent; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Neoplasm Recurrence, Local

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Neoplasm Recurrence, Local; Pain; Palliative Care; Practice Guidelines as Topic; Prognosis

Radiofrequency ablation (RFA) of malignant liver lesions is considered a procedure with low morbidity. However, RFA performed close to hilar structures carries the risk of heat-induced biliary tract damage and subsequent septic episodes.. We performed an analysis of complications in 42 patients with 211 liver lesions treated with a combined approach of liver resection and RFA.. One patient died due to postoperative liver failure. There was one case of temporary liver dysfunction, one vena cava thrombosis, and six febrile episodes. Four of the six febrile episodes were related to bile duct injuries. They became evident 3-5 weeks after the procedure. All four patients were treated successfully by the placement of stents within the biliary tract. None of the patients developed a hepatic abscess.. Biliary tract damage is a complication that can occur weeks after RFA. Immediate endoscopic intervention can obviate the occurrence of prolonged septic complications.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract; Carcinoma, Hepatocellular; Catheter Ablation; Chemotherapy, Adjuvant; Cholangiopancreatography, Endoscopic Retrograde; Colorectal Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fever; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Postoperative Complications; Radiotherapy, Adjuvant; Retrospective Studies; Stents; Thrombosis; Treatment Outcome; Vena Cava, Inferior

5-fluorouracil (5-FU) plus leucovorin (LV) therapy is the most widely used regimen with a high evidence as the first-line treatment for advanced colorectal cancer (CRC), as well as CPT-11 as the second-line. Recently, it is reported in several randomized prospective studies that convenient oral combination of UFT and LV has equal efficacy and less adverse effect. Intrahepatic arterial infusion (IHA) therapy shows high response rate in the treatment of liver metastasis. Survival benefit of IHA has to be disclosed by further clinical trials. Prospective studies showed that 6 months' administration of 5-FU and LV after curative resection of Dukes' C CRC contributes to a patients' better survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic; Tegafur; Uracil

Gestational trophoblastic disease is a fascinating group of pregnancy disorders characterised by abnormal proliferation of trophoblast, ranging from benign to malignant. Because the disease is uncommon, there is a need to formulate management with the assistance of collective information.. A review of available information from English written literature was undertaken, especially data reported by registries around the world (Charing Cross Hospital in England, the North-western University and the New England area in the USA as well as our own experience in Queensland, Australia). Where possible, collated data from relevant studies were analysed to answer some of the questions posed in clinical practice, with reference to metastatic disease to liver and brain, twinning of molar gestation and coexisting fetus, and placental-site tumour.. We found that molar gestation can be classified according to its clinical presentation which influences the time taken to reach human chorionic gonadotropin (HCG) 'negativity' and the risk of persisting disease. Categorisation of risk is the basis for choice of chemotherapy to achieve good outcomes. Metastases to liver and brain remain problems in management; the development of 'new' metastases during chemotherapy is a very poor prognostic factor. In the variant of twinning with molar gestation and coexisting fetus, it is important to elucidate the fetal karyotype in planning management: a 69XXX fetus is not salvageable but a normal 46XX or 46XY fetus faces the prospect of early preterm delivery. The placental-site tumour is very rare; localised disease is curable by surgery; chemotherapy is less effective in disseminated disease. From collated worldwide data, the recurrence rate after one mole is 1.3% and after two or more is 20%. Reproductive outcome in subsequent pregnancies, even after multidrug chemotherapy, is not different from the general population. Because of the increased risk long-term of second tumours after multidrug chemotherapy a closer surveillance of these patients is necessary.. In general, the disease in its persisting or malignant form is 'a cancer model par excellence' because of an identifiable precursor condition, a reliable HCG marker, and sensitivity of the disease to cytotoxic drugs. With current management, retention of fertility is possible and normal reproductive outcome assured.

Topics: Brain Neoplasms; Female; Gestational Trophoblastic Disease; Humans; Hydatidiform Mole; Leucovorin; Liver Neoplasms; Methotrexate; Neoplasms, Second Primary; Pregnancy; Queensland; Recurrence; Registries

Topics: Adult; Antineoplastic Agents; Bile Ducts, Intrahepatic; Diagnosis, Differential; Female; Fluorouracil; Humans; Infarction; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Tomography, X-Ray Computed

THE SITUATION: With around 35.000 new cases per year and a 40% mortality rate, colorectal cancer is a real problem of health care in France. Chemotherapy for metastatic disease has completely changed during the ten last years with the emergence of promising new drugs such as oxaliplatin and irinotecan. Oral 5-FU prodrugs have also shown an interesting efficacy in this setting.. Showed increased response rate, progression free survival with both drugs, and overall survival, only with the irinotecan-based regimen. Moreover, after aggressive first-line chemotherapy, some patients can undergo surgical resection of the metastases, initially considered as unresectable. We still do not know if these aggressive first-line therapies should be proposed to all metastatic patients or only to a selected subgroup. The best strategies remain to be evaluated.. Of colorectal cancer, a 6-month 5-FU/folinic acid postoperative chemotherapy is actually the standard for the management of patients with positive lymph nodes (stage III). In stage II patients the benefit of such treatment remains controversial. The benefit of using oxaliplatin or irinotecan in association with 5-FU/folinic acid as adjuvant therapy is under investigation.. In this 21st century, chemotherapy has a major place in the therapeutic management of colorectal cancer patients.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Postoperative Care; Prodrugs; Quinazolines; Randomized Controlled Trials as Topic; Thiophenes; Time Factors

The treatment of patients with metastatic colorectal cancer has changed dramatically over recent years. The more optimal use of 5-fluorouracil (5-FU) in association with folinic acid (FA), the development of new drugs such as irinotecan and oxaliplatin and of the oral fluoropyrimidines, capecitabine and UFT, have contributed to increased therapeutic options and to the improved outcome of patients with metastatic colorectal cancer. It is shown that combination therapy with 5-FU/FA and irinotecan or oxaliplatin is more active than 5-FU/FA in the first-line treatment of advanced colorectal cancer. Irinotecan and oxaliplatin are also active in the second-line treatment of colorectal cancer. The oral fluoropyrimidines seem to have an activity comparable to that of intravenous 5-FU/FA in the first-line treatment of metastatic colorectal cancer. New agents acting on novel targets are under development: epidermal growth factor inhibitors, vascular endothelial growth inhibitors, COX-2 inhibitors and farnesyl transferase inhibitors might play a role in the future in the treatment of colon cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Pyrimidines; Risk Factors; Severity of Illness Index; Treatment Outcome

Colon cancer remains the third most common cancer, and cause of cancer-related death in the United States. Greater public awareness and acceptance of screening programs have contributed significantly to increasingly earlier detection of colon cancer and decreased mortality. Advances made in the understanding of this disease, both in terms of its clinical behavior and molecular pathogenesis, have translated into major improvements in its therapy. Several large randomized trials during the last two decades have helped the oncology community forge a successful multi-modality treatment strategy against colon cancer. These studies have defined the role of adjuvant therapy for colon cancer after curative surgery. Despite all the advances, a large number of patients continue to succumb to this disease, and the search for better therapies is still necessary. In this article, we discuss the evolution and the current state of adjuvant chemotherapy in colon cancer and briefly review new developments.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Prognosis; Risk Factors

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Palliative Care; Survival Rate

Oxaliplatin is a platinum compound that inhibits DNA synthesis, primarily by causing intrastrand cross-links in DNA. Oxaliplatin has a broad spectrum of antineoplastic activity and has demonstrated a lack of cross-resistance with other platinum compounds. In patients with metastatic colorectal cancer, intravenous oxaliplatin has been trialled as a monotherapy and in combination with other agents. The highest response rates were achieved when oxaliplatin was used in combination with fluorouracil/folinic acid (leucovorin; calcium folinate), typically > or = 50% in the first-line setting and 13 to 45% as a second-line therapy. First-line triple therapy with oxaliplatin and fuorouracil/folinic acid achieved significantly higher response rates and longer median progression-free survival than fluorouracil/folinic acid therapy alone. However, no significant difference in the median duration of overall survival was found. This may be a consequence of the subsequent use of oxaliplatin and/or surgery after disease progression in patients who relapsed after fluorouracil/folinic acid therapy alone. Neoadjuvant therapy with oxaliplatin/fluorouracil/folinic acid has proven beneficial in enabling surgical removal of previously unresectable liver metastases. In 2 studies, surgery with curative intent was performed in 16 and 51% of patients with initially unresectable liver metastases following oxaliplatin/fluorouracil/folinic acid therapy; the 5-year survival rates were 40 and 50%, respectively. In patients with advanced ovarian cancer, first-line therapy with oxaliplatin/cyclophosphamide achieved an objective response rate which did not differ significantly from that of cisplatin/cyclophosphamide (33 vs 42%). In addition, oxaliplatin has shown efficacy in patients with platinum-pretreated ovarian cancer and achieved objective response rates similar to paclitaxel in this setting (16 vs 17%). Promising results have also been found with oxaliplatin in patients with non-Hodgkin's lymphoma, breast cancer, mesothelioma and non-small cell lung cancer. Reversible, cumulative, peripheral sensory neuropathy is the principle dose-limiting factor of oxaliplatin therapy. Haematological and gastrointestinal toxicities occur frequently but are generally mild to moderate in intensity.. Oxaliplatin in combination with fluorouracil/folinic acid is an effective treatment option for patients with metastatic colorectal cancer, both as a first-line therapy and in patients refractory to previous chemotherapy. Although preliminary results failed to show any overall survival advantage of this regimen over fluorouracil/folinic acid alone, this may be a consequence of trial design and requires further examination. Additional clinical investigation of oxaliplatin in patients with other cancers is warranted given the promising results achieved in early trials, most notably in patients with platinum-pretreated ovarian cancer.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biotransformation; Clinical Trials as Topic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Metabolic Clearance Rate; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Tumor Cells, Cultured

Although the liver is the most common site of metastatic disease from a variety of tumor types, isolated hepatic metastases most commonly occur from colorectal cancer and, less frequently, from neuroendocrine tumors, gastrointestinal sarcoma, ocular melanoma, and others. Complete evaluation of the extent of metastatic disease, both intrahepatically and extrahepatically, is important before considering treatment options. Based on a preponderance of uncontrolled studies for hepatic metastatic colorectal carcinoma, surgical resection offers the only potential for cure of selected patients with completely resected disease, with 5-year survival rates of 25% to 46%. Systemic and hepatic arterial infusion chemotherapy may be useful treatment options in patients with unresectable disease and possibly as an adjuvant treatment after liver resection. Other techniques of local tumor ablation, including cryotherapy and radiofrequency ablation, although promising, remain unproved. Management of hepatic metastases from neuroendocrine tumors and other noncolorectal primary tumors should be individualized based on the patient's clinical course, extent of disease, and symptoms.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Colonic Neoplasms; Fluorouracil; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Rectal Neoplasms; Treatment Outcome

Since the developments in systemic chemotherapy of metastasized colorectal cancer have not resulted in substantial gains in survival times, we wished to improve the course of isolated nonresectable colorectal liver metastases (CPLM) by hepatic arterial infusion treatment.. Patients (pts) with CRLM have a worse fate than those pts whose liver metastases could be resected. Systemic (i.v.) chemotherapy for CRLM/colorectal metastases does not improve survival to a relevant level (median survival time (med. surv.) after 5-Fluorouracil + Folinic Acid (5-FU + FA) i.v.: 6.4-14.3 months (m)). Hepatic artery infusion (HAI) with 5-Fluorode-oxyuridine (5-FUDR) has been demonstrated in a metaanalysis of randomized trials to be superior to i.v. treatment/palliative care (med. surv.: 15 vs. 10 m). The benefit of HAI with 5-FUDR, although recommended as treatment for CRLM, is severely compromised by the 5-FUDR induced hepatotoxicity, leading eventually to sclerosing cholangitis (SC)/liver scirrhosis. We have stepwise developed a protocol for HAI of CRLM, which is superior to HAI with 5-FUDR, and, most evidently, to systemic chemotherapy.. Between 1982-1997, 222 CR (L) M patients were treated within subsequent protocols (Table). In protocol A, 68 CRLM pts received HAI with 5-FUDR (A1: nonrandomized pts; A2: randomized pts). In protocol B (randomized pts.), 46 pts received 5-FUDR i.a. (via HAI) + i.v. In protocol C, systemic chemotherapy with 5-FU + FA was conducted in 34 pts with metastasized colorectal cancers, including CRLM. In protocol D 5-FU + FA was delivered via HAI in 25 pts with CRLM. In protocol E, based on in vitro phase II studies and the results of protocol D, Mitoxantrone and Mitomycin C were added to 5-FU + FA (MFFM). Fifty (50) CRLM pts received HAI with MFFM.. The response rates, med. surv. times, systemic toxicity and SC rates are shown in the table. HAI with MFFM produced objective responses in 66%, the med. surv. was 27.4 m, and no SC occurred. The ports surgically placed for HAI, e.g., in protocols D and E, functioned in 90%, 82%, and 76% 6, 9, and 11 m after start of the HAI. Quality of life in protocol E was high. Nine pts from protocols D + E with either partial (PR, 7 pts) or complete (CR, 2 pts) remissions received a secondary liver resection without hospital mortality, and 7/9 pts are living 2-58 m after liver resection, 2/9 pts died 11 and 22 m after resection. [table: see text]. Our learning curve to achieve optimal treatment of CRLM resulted in a protocol using HAI with MFFM. The results of this protocol (E) including the high remission rate, long median survival time, good port function, high quality of life, and, most interestingly, the possibility to downstage and resect primarily nonresectable metastases, seem to be superior to HAI with 5-FUDR of 5-FU + FA and to systemic chemotherapy with 5-FU + FA. This hypothesis is currently examined in a phase III study (HAI with MFFM vs. 5-FU + FA i.v.).

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitoxantrone; Randomized Controlled Trials as Topic; Survival Analysis

Colorectal cancer, one of the most common malignancies among adults, is rare in adolescence. This low incidence coupled with non-specific symptoms and aggressive natural history leads to a poorer prognosis than in reported adult series. This article describes two cases of colorectal cancer in adolescents and reviews the literature regarding this rare condition. Earlier diagnosis and a greater understanding of the natural history may lead to improved treatment with concomitant improvements in survival.

Topics: Adenocarcinoma; Adolescent; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colon; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Tomography, X-Ray Computed

Five-year survival after simple resection of liver metastases from colorectal carcinoma ranges from 20 to 40%. The aim was to study the reliability and long term results of adjuvant intra-arterial chemotherapy after resection of colorectal liver metastases.. From 1991 to 1997, 30 patients after a complete resection of liver metastases from colorectal cancer were included (16 men, 14 women, mean age: 62 years). There were 2 stage I, 19 stages II, 2 stages III, 5 stages IV and 2 stages V according to Gayowski staging system. During laparotomy, a catheter was placed in the gastroduodenal artery in order to perfuse the proper hepatic artery. Chemotherapy included 5 Fluorouracil (12 mg/m2) and Leucovorin (200 mg/m2) and was administered once a week during six months. Mean follow-up was 52 months.. Adjuvant intra-arterial chemotherapy had to be interrupted before six months in 9 patients because leukopenia (n = 2), infection or obstruction of the catheter (n = 5), duodenal migration of the catheter (n = 1) and occurrence of multiple extrahepatic metastases (n = 1). No death was in relation with the method. Five-year survival rate was 41.8% for the global series. Five-year disease free survival rate was 21.4%. Causes of death were: hepatic recurrence only (n = 3), extrahepatic + hepatic recurrence (n = 4), extrahepatic recurrence (n = 2). Two patients died of another carcinoma (esophagus, ovary), without evidence of recurrence of the colorectal carcinoma. At the present, there is a recurrence in 4 living patients.. Although the benefit on survival is not significant, these results suggest a longest time of remission in patients with adjuvant intra-arterial chemotherapy. Trials comparing and/or combining this method to intravenous chemotherapy should be proposed in patients after resection of colorectal liver metastases.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Survival Rate

Salvage treatment with 5-fluorouracil (5-FU) with or without leucovorin may induce responses in patients with advanced colorectal cancer whose disease progresses after adjuvant therapy with the same drugs. Similarly, restarting a regimen containing 5-FU can be beneficial in patients with advanced disease who had previously responded to the therapy or experienced disease stabilization but whose treatment was interrupted. Administering 5-FU by continuous intravenous (i.v.) infusion may result in a tumor response after disease progression on bolus 5-FU i.v. injection. Adding the platinum compound oxaliplatin to 5-FU and leucovorin may provide synergistic antineoplastic activity, even in patients with disease refractory to 5-FU. Chronomodulation of therapy decreases toxicity and increases dose intensity, response rate, and possibly survival time in some studies. Hepatic arterial infusion of chemotherapeutic agents is not routinely recommended in patients who have metastases limited to the liver and whose disease has failed to respond to prior 5-FU because of the associated costs and complications and the lack of data supporting the use of this approach after disease progression on i.v. 5-FU. A multicenter phase III trial has been completed in which patients whose colorectal cancer had progressed after first-line treatment with 5-FU were randomized to receive irinotecan 300 to 350 mg/m2 every 3 weeks or infusional 5-FU with or without leucovorin (Proc Am Soc Clin Oncol 17:256A, 1998 [abstr 984]). The 5-FU was administered according to investigator choice as a 24-hour, 48-hour, or continuous infusion. The results of this trial, which have been submitted for publication, should help to clarify the relative value of re-treatment with a 5-FU-containing regimen versus use of irinotecan in patients with disease progression after first-line 5-FU.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Salvage Therapy

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Mitomycin; Mitoxantrone

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Aspartate Carbamoyltransferase; Aspartic Acid; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Combined Modality Therapy; Dipyridamole; Drug Administration Schedule; Drug Synergism; Enzyme Inhibitors; Female; Fluorouracil; Humans; Immunologic Factors; Infusions, Intravenous; Injections, Intravenous; Interferons; Leucovorin; Liver Neoplasms; Male; Methotrexate; Middle Aged; Multicenter Studies as Topic; Neoplasm Proteins; Nucleotides; Palliative Care; Phosphonoacetic Acid; Randomized Controlled Trials as Topic; Thymidylate Synthase

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Palliative Care; Randomized Controlled Trials as Topic; Time Factors

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Humans; Leucovorin; Liver Neoplasms; Lymphoma, B-Cell; Male; Methotrexate; Neoplasm Invasiveness; Pancreatic Neoplasms; Prednisone; Remission Induction; Retroperitoneal Neoplasms; Stomach Neoplasms; Vincristine

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Immunotherapy; Infusions, Intravenous; Leucovorin; Levamisole; Liver Neoplasms; Neoplasm Staging; Portal Vein; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Rectal Neoplasms; Treatment Failure

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Interferons; Leucovorin; Liver Neoplasms; Methotrexate; Phosphonoacetic Acid

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Heparin; Humans; Leucovorin; Levamisole; Liver Neoplasms; Semustine

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Methotrexate

5-Fluorouracil (5-FU) modulation with either folinic acid (FA) or methotrexate (MTX) has improved 5-FU's potential cytoreductivity. We combined MTX and FA with 5-FU to further augment 5-FU's cytoreductivity. Patients (n = 34) with advanced colorectal carcinoma were first given intravenous MTX (escalated from 30 mg/m2 to 70 mg/m2). FA (100 mg/m2) was infused 17-24 hr later, followed by 5-FU (600 mg/m2). Oral rescue doses of FA were begun 24 hr after MTX. Patients were treated every 2 weeks. No previously treated patient (n = 6) responded. Eight of the remaining 28 (29%) (95% confidence interval, 15-47%) patients achieved a PR. Median survival was 9.3 months. Toxicity (primarily gastrointestinal) necessitated dosage modification in 10 patients (29%). These results, in addition to a literature review, reveal that the manipulation of 5-FU by two modulating agents does not improve the response rate seen with single-agent modulation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Remission Induction; Survival Rate; Treatment Outcome

Hepatic metastases are a major cause of mortality in patients with colorectal carcinoma. The rationale for regional therapy is presented. The randomized studies are reviewed and they demonstrated a significantly higher response rate with hepatic arterial therapy versus systemic therapy. Survival information is difficult to evaluate because some of the studies are small and some had a crossover design, but two studies demonstrate a significant improvement in 2-year survival after hepatic arterial therapy versus systemic therapy. New modalities to increase response rate and decrease toxicity are presented.

Topics: Colorectal Neoplasms; Floxuridine; Hepatic Artery; Humans; Infusion Pumps; Infusions, Intra-Arterial; Leucovorin; Liver Function Tests; Liver Neoplasms; Randomized Controlled Trials as Topic

Topics: Antineoplastic Agents; Colorectal Neoplasms; Floxuridine; Fluorouracil; Forecasting; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Liver Neoplasms; Mitomycin; Survival Rate

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Methotrexate; Mitomycin; Nitrosourea Compounds; Pyrimidines; Semustine

This article delineates the current status of clinical research into the chemotherapeutic treatment of advanced colorectal cancer. The data reviewed indicate that, despite an extensive series of trials, no new agents with significant activity have been identified. The most active single agent remains 5-fluorouracil (5-FU); efforts to enhance or modulate the activity of this drug with methotrexate, cisplatin, folinic acid, and N-(phosphonacetyl)-L-aspartic acid (PALA) are described. Of these approaches, combinations of 5-FU and folinic acid have been the most successful. Two recently reported studies suggest that patient survival is improved by this combination compared with 5-FU alone. Specialized applications of chemotherapy are also reviewed. Included is a description of the results of a recently conducted randomized trial of hepatic intra-arterial 5-fluorodeoxyuridine (FUDR) versus FUDR administered systemically. This study confirmed the improved response rate for patients receiving intra-arterially administered fluoropyrimidines but failed to substantiate a survival advantage over patients receiving intravenous therapy. Finally, newly evolving therapies such as hepatic-arterial chemoembolization, the use of new intra-arterial drugs, and high-dose systemic chemotherapy are reviewed. Directions for further clinical and basic scientific research are outlined.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Interferons; Interleukin-2; Leucovorin; Liver Neoplasms; Tumor Necrosis Factor-alpha

The development of safe arterial access devices and totally implantable or portable infusion pumps for intrahepatic chemotherapy has generated a renewed interest in regional treatment of liver metastases from colo-rectal primaries. Several phase II trials have been carried out, mostly using prolonged infusion of fluorinated pyrimidines showing very high activity for this method of treatment with response rates up to 80%. Randomized trials between systemic and regional therapy have confirmed the higher efficacy of arterial treatment in inducing objective responses but neither of the two studies with a follow-up long enough to assess survival data showed a clear advantage for the patients receiving intraarterial chemotherapy. Gastroduodenitis, ulcers and chemical hepatitis are frequently observed in patients treated with intrahepatic arterial chemotherapy but their incidence can be substantially reduced by a careful surgical procedure during the implant of the arterial catheter and by a close follow-up during chemotherapy. Since toxicity can be serious and no definitive improvement of survival has been shown, this modality of treatment is still applicable only in an investigational setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Floxuridine; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Random Allocation

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colonic Neoplasms; Doxorubicin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Rectal Neoplasms; Semustine; Vincristine

Primary tumour resection (PTR) is still a selection for patients with low tumour burden and good condition, especially with conversion therapy purpose for colorectal liver-limited metastases (CRLMs). The objective was to evaluate whether pre-PTR chemotherapy could improve progression-free survival (PFS) for patients with asymptomatic synchronous unresectable CRLMs.. Patients with asymptomatic synchronous unresectable CRLMs were randomly assigned to receive pre-PTR chemotherapy (arm A) or upfront PTR (arm B). Chemotherapy regimens of mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab or mFOLFOX6 alone were chosen according to the RAS genotype. The primary end-point was PFS; secondary end-points included overall survival (OS), tumour response, disease control rate (DCR), liver metastases resection rate, surgical complications and chemotherapy toxicity.. Three hundred and twenty patients were randomly assigned to arm A (160 patients) and arm B (160 patients). Patients in arm A had significantly improved the median PFS compared with arm B (10.5 versus 9.1 months; P = 0.013). Patients in arm A also had significantly better DCR (84.4% versus 75.0%; P = 0.037). The median OS (29.4 versus 27.2 months; P = 0.058), objective response rate (ORR) (53.1% versus 45.0%; P = 0.146) and liver metastases resection rate (21.9% versus 18.1%; P = 0.402) were not significantly different. The Clavien-Dindo 3-4 complications post PTR (4.5% versus 3.8%, P = 0.759) and the incidence of grade 3/4 chemotherapy events (42.2% versus 40.4%, P = 0.744) reached no statistical significance.. For asymptomatic synchronous unresectable CRLMs, Pre-PTR chemotherapy improved the PFS compared with upfront PTR.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms

The efficacy and tolerability of hepatic arterial infusion (HAI) oxaliplatin plus systemic 5-fluorouracil and cetuximab as frontline treatment in patients with colorectal liver metastases (CRLM) are unknown.. In this multicenter, single-arm phase II study, patients with CRLM not amenable to curative-intent resection or requiring complex/major liver resection, and no prior chemotherapy for metastatic disease, received HAI oxaliplatin and intravenous 5-fluorouracil, leucovorin and cetuximab, every two weeks until disease progression, limiting toxicity or at least 3 months after complete response or curative-intent resection/ablation. The primary endpoint was overall response rate (ORR).. 35 patients, mostly with bilateral (89%), multiple CRLM (>4, 86%; >10, 46%) were enrolled in eight centers. The ORR was 88% (95% CI, 71%-96%) among evaluable patients (n = 32), and 95% (95% CI 70-100%) among the 22 wild-type RAS/BRAF evaluable patients. After a median follow-up of 8.8 years (95% CI, 8.7-not reached), median progression-free survival was 17.9 months (95% CI, 15-23) and median overall survival (OS) was 46.3 months (95% CI, 40.0-not reached). 23 of the 35 patients (66%), including 22 (79%) of the 25 patients with wild-type RAS tumor, underwent curative-intent surgical resection and/or ablation of CRLM. HAI catheter remained patent in 86% of patients, allowing for a median of eight oxaliplatin infusions (range, 1-19). Treatment toxicity was manageable, without toxic death.. HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Oxaliplatin; Treatment Outcome

Colorectal cancer (CRC) patients have a better prognosis if metastases are resectable. Initially, unresectable liver-only metastases can be converted to resectable with chemotherapy plus a targeted therapy. We assessed which of chemotherapy doublet (2-CTx) or triplet (3-CTx), combined with targeted therapy by RAS status, would be better in this setting.. PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. The primary endpoint was to increase the R0/R1 liver-resection rate from 50 to 70% with the 3-CTx.. Patients (n = 256) were mainly men with an ECOG PS of 0, and a median age of 60 years. In total, 109 patients (42.6%) had RAS-mutated tumours. After a median follow-up of 45.6 months, the R0/R1 liver-resection rate was 56.9% (95% CI: 48-66) with the 3-CTx versus 48.4% (95% CI: 39-57) with the 2-CTx (P = 0.17). Median overall survival was 43.4 months with 3-CTx versus 40 months with 2-CTx.. We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms

In patients with unresectable liver metastases from colorectal cancer (CRCLM), systemic doublet or triplet chemotherapy and targeted therapy is considered a standard first-line treatment. Hepatic arterial infusion of oxaliplatin (HAI-ox) generates a high response rate, but this still needs to be confirmed in a randomized trial. We incorporated HAI-ox in doublet or triplet + targeted therapy to validate its efficacy.. The OSCAR study is an ongoing randomized phase III trial comparing FOLFOX + targeted therapy according to RAS status, or FOLFOXIRI + bevacizumab in patients eligible for triplet therapy, with the same regimen but with HAI-ox instead of IV-ox as the first-line treatment for CRCLM.. Main eligibility criteria are colorectal cancer, unresectable liver metastasis, no extra-hepatic metastases except pulmonary nodules if ≤3 and <10 mm, ECOG performance status 0 or 1.. The primary endpoint is progression-free survival (PFS). A difference of 4 months for the median PFS in favor of HAI-ox is expected (HR = 0.73). Secondary endpoints include overall survival, overall response rate, secondary liver resection, safety, and quality of life.. This study is planned to include 348 patients to demonstrate the superiority of HAI-ox over systemic oxaliplatin in first-line CRCLM treatment (NCT02885753).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

To clarify the efficacy of perioperative chemotherapy for the patients with resectable colorectal liver metastases (CLM), we conducted a multicenter randomized phase III trial to compare surgery followed by postoperative FOLFOX regimen with perioperative FOLFOX regimen plus cetuximab in patients with KRAS wild-type resectable CLM.. Patients who had KRAS wild-type resectable CLM having one to eight liver nodules without extrahepatic disease were randomly assigned to the postoperative chemotherapy group, wherein up-front hepatectomy was performed followed by 12 cycles of postoperative modified FOLFOX6, and the perioperative chemotherapy group (experimental), wherein six cycles of preoperative modified FOLFOX6 plus cetuximab were performed followed by hepatectomy and six cycles of postoperative modified FOLFOX6 plus cetuximab. The primary endpoint was progression-free survival (PFS).. There were 37 patients in postoperative chemotherapy group and 40 patients in the perioperative chemotherapy group who were analyzed. Baseline characteristics were well-balanced between groups. The PFS and overall survival (OS) showed no significant difference (PFS, hazard ratio 1.18 [95% confidence interval 0.69-2.01], P = 0.539: OS, 1.03 [0.46-2.29], P = 0.950). In the postoperative chemotherapy group, 35.1% had a 3-year PFS, and 86.5% had a 3-year OS. Meanwhile, in the perioperative chemotherapy group, 30.0% had a 3-year PFS, and 74.4% had a 3-year OS.. There was no difference in survival found between the group of the perioperative chemotherapy plus cetuximab and that of the postoperative chemotherapy in the cohort of our study. The study was registered in the University Hospital Medical Information Network (UMIN000007787).

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Proto-Oncogene Proteins p21(ras)

The effect of bevacizumab plus mFOLFOX6 on downsizing of liver metastases for curative resection has not been well assessed for patients with advanced colorectal liver metastases (CRLMs). This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS.. Patients with advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included. Surgical indication was evaluated every 4 cycles of bevacizumab plus mFOLFOX6. Liver resection was planned if the CRLMs were resectable. The primary endpoint was R0 resection rate. The secondary endpoints included overall survival (OS), recurrence-free survival, progression-free survival, and safety.. Between 2013 and 2017, 29 patients from six centers were registered. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality occurred. During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months.. For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras)

This trial investigates the addition of panitumumab to chemotherapy with fluorouracil/folinic acid and oxaliplatin (FOLFOX) in a 2:1 randomised, controlled, open-label, phase II trial in RAS wild-type colorectal cancer patients with R0/1-resected liver metastases.. The primary endpoint was progression-free survival (PFS) two years after randomisation. The experimental arm (12 weeks of biweekly mFOLFOX6 plus panitumumab followed by 12 weeks of panitumumab alone) was considered active if the two-year PFS rate was ≥65%. Based on historical data, a two-year PFS rate of 50% was estimated in the control arm (12 weeks of biweekly FOLFOX). The trial was performed with a power of 80% and an alpha of 0.05. Secondary endpoints included overall survival (OS) and toxicity. The trial is registered with ClinicalTrials.gov, NCT01384994.. The full analysis set consists of 70 patients (pts) in the experimental arm and 36 pts in the control arm. The primary endpoint was missed with a two-year PFS of 35.7% with FOLFOX plus panitumumab and 30.6% in the control arm. In comparative analyses, trends towards improved PFS (HR 0.83; 95%CI, 0.52-1.33; P = 0.44) and OS (HR 0.70; 95% CI, 0.34-1.46; P = 0.34) were observed in favour of the panitumumab-based study arm. No new or unexpected safety signals were observed with FOLFOX plus panitumumab following liver resection.. The PARLIM trial failed to demonstrate a two-year PFS rate of 65% after resection of colorectal liver metastases. The positive trends in survival endpoints may support future trials evaluating treatment with anti-EGFR agents after resection of liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Panitumumab

The combination of lenvatinib, toripalimab and hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) suggested encouraging antitumour activity in our retrospective study. We hereby prospectively establish the efficacy, safety and predictive biomarkers of the combination therapy as a first-line treatment in patients with high-risk advanced hepatocellular carcinoma (HCC).. This phase II, single-centre, single-arm trial enrolled advanced HCC participants with high-risk. Of 51 screened participants, 36 received lenvatinib, toripalimab plus FOLFOX-HAIC. Participants received 21-day treatment cycles of lenvatinib, toripalimab, and FOLFOX-HAIC. The primary end-point was the progression-free survival (PFS) rate per RECIST at six months.. Thirty-six participants (86.1% with high-risk features) were enrolled in our study. The primary end-point was met with a PFS rate of 80.6% (95% CI, 64.0%-91.8%) at six months. The median PFS was 10.4 months (95% CI, 5.8-15.0), and the median OS was not reached at the prespecified final analysis and was 17.9 months (95% CI, 14.5-21.3) after follow-up was extended. The ORR per RECIST was 63.9%, and per mRECIST was 66.7%. The median duration of response was 14.4 months (95% CI, 8.9-19.9). The most common adverse events were thrombocytopenia, elevated aspartate aminotransferase, and hypertension, and no treatment-related death was reported. Participants with low levels of both CCL28 and BTC had unsatisfactory prognosis.. Lenvatinib, toripalimab and FOLFOX-HAIC showed safe and encouraging antitumour activity for advanced HCC with high-risk features. The levels of CCL28 and BTC might be the predictive biomarkers for the triple combination therapy.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Phenylurea Compounds; Quinolines; Retrospective Studies; Treatment Outcome

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Prognosis; Prospective Studies; Retrospective Studies; Risk Factors; Survival Rate; Weight Loss

According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available.. In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection.. This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer.. EudraCT 2019-002734-37 ; NCT04617457 .

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Fluorouracil; Germany; Humans; Irinotecan; Leucovorin; Liposomes; Liver Neoplasms; Male; Neoadjuvant Therapy; Oxaliplatin; Pancreatic Neoplasms; Progression-Free Survival; Quality of Life

The combination of conventional transarterial chemoembolization (cTACE) and systemic therapy has the potential to treat chemotherapy-refractory unresectable colorectal liver metastases (CRLMs). This study aimed to compare survival after this combined treatment versus systemic chemotherapy alone.. This single-centre RCT included patients with unresectable CRLMs that progressed after first-line treatment. Patients were randomized on a 1 : 1 basis to either systemic chemotherapy with or without cTACE, without further stratification. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall response rate, disease control rate, conversion rate to liver resection, overall survival, and adverse events.. Of 180 patients recruited, 168 were randomized. Eighty-five patients in arm A received systemic chemotherapy plus cTACE and 83 in arm B received systemic chemotherapy alone. Median PFS was longer in arm A than B (6.7 versus 3.8 months; hazard ratio (HR) 0.67, 95 per cent c.i. 0.49 to 0.91; P = 0.009), but did not translate into prolonged median overall survival (18.4 versus 14.8 months; HR = 0.92, 0.62 to 1.36; P = 0.669). Overall response rates (20 versus 22 per cent; P = 0.788) and conversion rate to liver resection (18 versus 16 per cent; P = 0.730) were no different between arms A and B. The disease control rate was higher in arm A than arm B (67 versus 51 per cent; P = 0.030). No adverse event higher than grade 3 according to the Common Terminology Criteria for Adverse Events was observed during treatment.. Systemic chemotherapy plus cTACE is a safe option as second-line treatment for unresectable colorectal liver metastases, with a modest effect on PFS. Registration number: NCT03783559 (http://www.clinicaltrials.gov).

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoembolization, Therapeutic; Colorectal Neoplasms; Combined Modality Therapy; Craniofacial Dysostosis; Female; Fluorouracil; Humans; Leucovorin; Limb Deformities, Congenital; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Progression-Free Survival; Survival Analysis; Treatment Outcome

Immune checkpoint inhibitors and chemotherapy can synergistically increase efficacy in a variety of malignancies. We conducted this phase Ib/II study to assess the safety and efficacy of anti-PD-1 antibody camrelizumab in combination with FOLFOX4 for treatment-naive advanced hepatocellular carcinoma (aHCC).. This open-label, multicenter phase Ib/II study (NCT03092895) enrolled patients with aHCC and without prior systemic treatment for treatment with camrelizumab (3 mg/kg) and FOLFOX4 every two weeks. First, six patients were enrolled, followed by an additional 28 patients after dose-limiting toxicity cases were determined to be <33% of patients. The primary endpoint was tolerability and safety of treatment.. A total of 34 aHCC patients were enrolled and received study treatment. No dose-limiting toxicity were observed in the first six patients enrolled. Twenty-nine (85.3%) of the total 34 patients had grade ≥3 treatment-related adverse events (TRAEs), with the most common ones being decreased neutrophil count (55.9%) and decreased white blood cell count (38.2%). No TRAEs-related deaths occurred. The objective response and disease control rate were 29.4% (95% CI, 15.1-47.5) and 79.4% (95% CI, 62.1-91.3), respectively. The median duration of response, progression-free survival, and overall survival was 6.9 months (range, 3.3-11.5), 7.4 months (95% CI, 3.9-9.2), and 11.7 months (95% CI, 8.2-22.0), respectively.. Camrelizumab combined with FOLFOX4 for first-line treatment of patients with aHCC showed good safety and tolerability, with promising preliminary antitumor activity.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Arginine starvation depletes the micronutrients required for DNA synthesis and interferes with both thymidylate synthetase activity and DNA repair pathways in preclinical models of hepatocellular carcinoma (HCC). Pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, potentiates the cytotoxic activity of platinum and pyrimidine antimetabolites in HCC cellular and murine models.. This was a global, multicenter, open-label, single-arm, phase 2 trial of ADI-PEG 20 and modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in patients who had HCC with Child-Pugh A cirrhosis and disease progression on ≥2 prior lines of treatment. The primary objective was the objective response rate assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary objectives were to estimate progression-free survival, overall survival, safety, and tolerability. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 36 mg/m. In total, 140 patients with advanced HCC were enrolled. The median patient age was 62 years (range, 30-85 years), 83% of patients were male, 76% were of Asian race, 56% had hepatitis B viremia, 10% had hepatitis C viremia, 100% had received ≥2 prior lines of systemic therapy, and 39% had received ≥3 prior lines of systemic therapy. The objective response rate was 9.3% (95% confidence interval [CI], 5.0%-15.4%), with a median response duration of 10.2 months (95% CI, 5.8 months to not reached). The median progression-free survival was 3.8 months (95% CI, 1.8-6.3 months), and the median overall survival was 14.5 months (95% CI, 13.6-20.9 months). The most common grade ≥3 treatment-related events were neutropenia (32.9%), white blood cell count decrease (20%), platelet count decrease (19.3%), and anemia (9.3%).. Concurrent mFOLFOX6 plus ADI-PEG 20 exhibited limited antitumor activity in patients with treatment-refractory HCC. The study was terminated early, and no further evaluation of the combination will be pursued.. Arginine is an important nutrient for hepatocellular carcinoma (HCC). The depletion of arginine with pegylated arginine deiminase (ADI-PEG 20), an arginine degrader, appeared to make chemotherapy (FOLFOX) work better in animal models of HCC and in patients with HCC on an early phase clinical trial. To formally test this hypothesis in the clinical setting, a large, global, phase 2 clinical trial was conducted of ADI-PEG 20 and FOLFOX in the treatment of patients with refractory HCC. The study showed limited activity of ADI-PEG 20 and FOLFOX in advanced HCC and was stopped early.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Hydrolases; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polyethylene Glycols

The NAnoliPOsomaL Irinotecan (NAPOLI-1) study (NCT01494506) was the largest global phase 3 study in a post-gemcitabine metastatic pancreatic adenocarcinoma (mPAC) population (N = 417). The subanalyses reported here investigated the prognostic effect of tumor characteristics and disease stage, prior treatment characteristics, baseline patient characteristics on survival outcomes in NAPOLI-1, and whether liposomal irinotecan (nal-IRI) + 5-fluorouracil/leucovorin (5-FU/LV) benefited patients with mPAC across subgroups.. Post hoc analyses were performed in the NAPOLI-1 population (4 across tumor characteristics and disease stage, 6 across prior treatment characteristics, and 4 across patient baseline characteristics). Survival outcomes were estimated by Kaplan-Meier analysis and patient safety data were evaluated.. Mortality and morbidity risk was lower on nal-IRI+5-FU/LV treatment across subgroups. Exceptions were patients who had received prior nonliposomal irinotecan and those who had undergone prior Whipple procedure (overall survival hazard ratio = 1.25 and 1.23, respectively). Decreased appetite, liver metastases, and number of measurable metastatic lesions seemed to be prognostic of survival in this population. Subgroup safety data were generally comparable with those in the overall NAPOLI-1 safety population.. A diverse population of patients with mPAC that progressed on gemcitabine-based therapy benefited from nal-IRI+5-FU/LV versus 5-FU/LV, potentially helping guide treatment decisions for challenging cases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liposomes; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

This study was aimed at evaluating the intravoxel incoherent motion (IVIM) parameter alterations of liver metastases of colorectal carcinoma (CRC) during antiangiogenic bevacizumab combination therapy.. Twenty-five patients with CRC liver metastases treated with bevacizumab in combination with FOLFOX-or-FOLFIRI protocols were enrolled in the study. MRI was performed using a 1.5-tesla scanner pre-treatment (PT) and at 3, 6, and 9 months of therapy. Routine abdominal MRI sequences and an IVIM-DWI (diffusion-weighted imaging) sequence were obtained. The IVIM-DWI sequence was executed with 16 b-values varying from 0 to 1,400 s/mm2. The mean values of apparent diffusion coefficient (ADC), true diffusion (D), pseudodiffusion (D*), and perfusion fraction (f) of each metastasis were obtained for all b-values, and the time-related changes were recorded to analyze the chronologic responses to antiangiogenic therapy. The RECIST 1.1 criteria were used for the evaluation of treatment response.. The diameters of the metastases diminished significantly at 9 months when compared with PT (p = 0.03). The D (p = 0.10) and ADC (p = 0.21) values of the metastases increased at 9 months of therapy. D* was the highest at 3 months (p =0.24); it decreased at 6 (p =0.97) and 9 months (p =0.87) of therapy. The f value had peaked at 3 months (p =0.51) and started to decrease thereafter. At 6 months, f decreased to the lowest values (p =0.12).. IVIM parameters, particularly the perfusion fraction, may quantitatively reflect the response to antiangiogenic treatment. The antiangiogenic response manifests after 3 months of therapy before the RECIST-related response.

Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Diffusion Magnetic Resonance Imaging; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Pilot Projects; Prospective Studies

Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population.. A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients.. Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels.. In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors.. VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Bone Neoplasms; Camptothecin; Cell Count; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Prognosis; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins B-raf; ras Proteins; Risk Assessment; Young Adult

To investigate the long-term outcome and entire treatment course of patients with technically unresectable CRLM who underwent conversion hepatectomy and to examine factors associated with conversion to hepatectomy.. Recurrence and survival data with long-term follow-up were analyzed in the cohort of a multi-institutional phase II trial for technically unresectable colorectal liver metastases (the BECK study).. A total of 22/12 patients with K-RAS wild-type/mutant tumors were treated with mFOLFOX6 + cetuximab/bevacizumab. The conversion R0/1 hepatectomy rate was significantly higher in left-sided primary tumors than in right-sided tumors (75.0% vs 30.0%, P = .022). The median follow-up was 72.6 months. The 5-year overall survival (OS) rate in the entire cohort was 48.1%. In patients who underwent R0/1 hepatectomy (n = 21), the 5-year RFS rate and OS rate were 19.1% and 66.3%, respectively. At the final follow-up, seven patients had no evidence of disease, five were alive with disease, and 20 had died from their original cancer. All 16 patients who achieved 5-year survival underwent conversion hepatectomy, and 11 of them underwent further resection for other recurrences (median: 2, range: 1-4).. Conversion hepatectomy achieved a similar long-term survival to the results of previous studies in initially resectable patients, although many of them experienced several post-hepatectomy recurrences. Left-sided primary was found to be the predictor for conversion hepatectomy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Genes, ras; Hepatectomy; Humans; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Prospective Studies; Survival Analysis

Whether patients with resectable colorectal liver metastases (CRLM) gain a survival benefit from perioperative chemotherapy remains controversial. The benefit of including bevacizumab in chemotherapy also remains unclear.. Seventy-six patients with CRLM were randomly assigned to either 6 cycles of FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin)/FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) with bevacizumab before and after surgery or 12 cycles after surgery. Progression-free survival (PFS) was estimated using the Kaplan-Meier method and compared by the log-rank test.. The median PFS of all patients was 37.4 months at 5.4 years follow-up, and the median overall survival (OS) was not reached. The PFS between the perioperative group and the postoperative group did not reveal a statistical difference (P = .280). The OS was significantly better in the perioperative group (hazard ratio [HR], 0.60; 95% confidence interval [CI],) 0.35-1.02; P = .049). In subgroup patients with carcinoembryonic antigens (CEA) ≥ 5 ng/mL or those with over 2 liver metastases, perioperative group had longer OS than postoperative group (CEA: HR, 0.49; 95% CI, 0.25-0.93; P = .030; number of liver metastases: HR, 0.55; 95% CI, 0.30-0.99; P = .049). The largest liver metastases size, disease-free interval, and sidedness did not affect PFS or OS. There was no difference between the 2 groups in postoperative complications with bevacizumab or adverse events during chemotherapy.. In patients with resectable CRLMs, perioperative chemotherapy had no effect on PFS, but improved OS. Patients with high CEA levels or over 2 liver metastases may benefit from perioperative chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Perioperative Period; Postoperative Complications; Progression-Free Survival; Prospective Studies; Tomography, X-Ray Computed

Programmed cell death 1 (PD-1) inhibitors have limited effect in pancreatic ductal adenocarcinoma (PDAC), underscoring the need to co-target alternative pathways. CXC chemokine receptor 4 (CXCR4) blockade promotes T cell tumor infiltration and is synergistic with anti-PD-1 therapy in PDAC mouse models. We conducted a phase IIa, open-label, two-cohort study to assess the safety, efficacy and immunobiological effects of the CXCR4 antagonist BL-8040 (motixafortide) with pembrolizumab and chemotherapy in metastatic PDAC (NCT02826486). The primary outcome was objective response rate (ORR). Secondary outcomes were overall survival (OS), disease control rate (DCR) and safety. In cohort 1, 37 patients with chemotherapy-resistant disease received BL-8040 and pembrolizumab. The DCR was 34.5% in the evaluable population (modified intention to treat, mITT; N = 29), including nine patients (31%) with stable disease and one patient (3.4%) with partial response. Median OS (mOS) was 3.3 months in the ITT population. Notably, in patients receiving study drugs as second-line therapy, the mOS was 7.5 months. BL-8040 increased CD8

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; CD8-Positive T-Lymphocytes; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Myeloid-Derived Suppressor Cells; Pancreatic Neoplasms; Peptides; Peritoneal Neoplasms; Receptors, CXCR4; Retroperitoneal Neoplasms; Survival Rate; T-Lymphocytes, Regulatory; Treatment Outcome

Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection.. In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session.. Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3).. Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal.. NCT01839877.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoembolization, Therapeutic; Colorectal Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Survival Analysis; Treatment Outcome

The effect of cetuximab plus mFOLFOX on downsizing of the tumors for curative resection has yet to be assessed for patients with advanced colorectal liver metastases (CRLMs). This study aimed to assess the oncologic benefit of cetuximab plus mFOLFOX for wild-type KRAS patients with advanced CRLMs.. In this multicenter phase 2 trial, patients with technically unresectable tumor and/or five or more CRLMs harboring wild-type KRAS were treated with mFOLFOX plus cetuximab. The patients were assessed for resectability after 4 treatments, and then every 2 months up to 12 treatments. Patients with resectable disease were offered surgery after a waiting period of 1 month. The primary end point of the study was the R0 resection rate. The secondary end points were safety, progression-free survival (PFS), and overall survival (OS). The study is registered with the University Hospital Medical Information Network-Clinical Trials Registry Clinical Trials Registry (no. C000007923).. Between 2012 and 2015, 50 patients from 13 centers were enrolled in this trial. Two patients were excluded because they had not received induction therapy. The 48 patients had a complete response rate of 0% and a partial response rate of 64.6%. For 26 R0 resections (54.2%) and 5 R1 resections (10.4%), no mortality occurred. During a median follow-up period of 31 months, the median OS for all the patients was calculated to be 41 months (95% confidence interval, 28-not reached). The 3-year OS rate was 59%.. For patients with advanced CRLMs harboring wild-type KRAS, cetuximab administered in combination with mFOLFOX yields high response rates, leading to significantly high R0 resection rates and favorable prognoses.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

To assess the effects of bevacizumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) as first-line treatment of. From October 2013 to December 2017, patients with. The intention-to-treat population comprised 241 patients. A total of 121 patients were randomly assigned to arm A and 120 to arm B. The median follow-up time was 37.0 months for all patients. The R0 resection rates for liver metastases were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with a significant difference (. For patients with initially unresectable

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; GTP Phosphohydrolases; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Membrane Proteins; Metastasectomy; Middle Aged; Organoplatinum Compounds; Progression-Free Survival; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Rate; Young Adult

The purpose of this work is to assess the heterogeneity across organs of response to treatment in metastatic colorectal patient based on longitudinal individual target lesion diameters (ILD) in comparison to sum of tumor lesion diameters (SLD). Data were from the McCAVE trial, in which 189 previously untreated patients with metastatic colorectal carcinoma (mCRC) received either bevacizumab (control, C) or vanucizumab (experimental, E), on top of standard chemotherapy. Bayesian hierarchical longitudinal non-linear mixed effect models were fitted to the data using Hamilton Monte Carlo algorithm to characterize the time dynamics of the tumor burden, and to obtain estimates of the tumor shrinkage and regrowth rates. The ILD model brought more nuanced results than to the SLD model. Besides substantial differences in tumor size at baseline (with lesions located in liver more than twice as large as the ones in lungs), it revealed a more durable response in lesions located in lymph nodes and 'other organs' compared to liver and lungs. Specifically, in lymph nodes and 'other organs', the projected time to nadir was doubled in group E (2.12 and 2.44 years respectively) compared to group C (1.07 and 1.20 years respectively). This long period of tumor shrinkage associated with a slightly larger change from baseline at nadir (- 51.4% in lymph nodes and - 62.6% in 'other organs' in the group E, compared to - 46.2% and - 46.9% in group C) resulted in a clinically meaningful difference in the tumor dynamics of patients in group E compared to the group C. The proportion of variance explained by the inter-lesion variability for each model parameter was large (ranging between 10 and 56%), reflecting the heterogeneity in tumor dynamics across organs. These findings suggest that there is value in understanding both within- and between-patient variability in tumor size's time dynamics using an appropriate modeling framework, as this information may help in pairing the right treatment with individual patient profile.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bevacizumab; Biological Variation, Individual; Biological Variation, Population; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Longitudinal Studies; Lung; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Models, Biological; Monte Carlo Method; Organoplatinum Compounds; Tumor Burden

The phase III West Japan Oncology Group (WJOG) 4407G study showed noninferiority of folinic acid, bolus/continuous fluorouracil, and irinotecan plus bevacizumab to modified folinic acid, bolus/continuous fluorouracil, and oxaliplatin 6 plus bevacizumab in progression-free survival (PFS) as first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response in patients with colorectal liver metastases (CLM) as a post hoc analysis of the WJOG4407G study.Morphologic response was assessed by comparing contrast-enhanced computed tomography (CT) images at baseline and week 8. Three blinded radiologists evaluated CT images and classified their response as optimal, incomplete, or no response according to the morphologic criteria. Response evaluation criteria in solid tumors (RECIST) response, early tumor shrinkage (ETS), and depth of response (DpR) were also evaluated.Among 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. We finally evaluated 55 of these patients. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank, P = .96). The median overall survival (OS) was 26.2 and 35.5 months, respectively (log-rank, P = .062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.Morphologic response might be neither a predictive nor a prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Predictive Value of Tests; Prognosis; Progression-Free Survival; Response Evaluation Criteria in Solid Tumors; Tomography, X-Ray Computed; Topoisomerase I Inhibitors; Treatment Outcome; Vitamin B Complex

There is no standardized assessment of symptomatic events in metastatic colorectal cancer (mCRC) despite disease symptoms that affect treatment decisions. Data from 3 first-line panitumumab in mCRC trials were retrospectively analyzed to assess whether early tumor shrinkage (ETS) and depth of response (DpR) were associated with time to occurrence of tumor-related symptoms.. Patients with RAS wild-type mCRC from PRIME, PEAK, and Study 314 were included. ETS was defined as a reduction of ≥ 30% in the sum of the longest diameters of lesions at 8 weeks. DpR was calculated as maximum percentage change in tumor size from baseline to nadir. The proportion of patients who developed symptoms (including a composite symptomatic endpoint) during study treatment was calculated. This study was registered at ClinicalTrials.gov as PRIME (NCT00364013), PEAK (NCT00819780), and Study 314 (NCT00508404).. Overall, data of 659 patients were analyzed. Onset of symptoms was delayed in patients with ETS ≥ 30% versus ETS < 30% and in patients with greater DpR. In patients with symptoms at baseline who experienced ETS ≥ 30%, overall survival was similar to that seen for patients without symptoms at baseline.. Both ETS and DpR were associated with delayed onset of symptoms in RAS wild-type mCRC patients. Treatments with high cytoreductive potential may delay symptom development.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mutation; Organoplatinum Compounds; Panitumumab; Prognosis; ras Proteins; Retrospective Studies; Survival Rate; Young Adult

This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, open-label, phase II trial in patients with untreated. The primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI [mFOLFOXIRI] plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival.. A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3%. The addition of panitumumab to mFOLFOXIRI in patients with

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Case-Control Studies; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mutation; Oxaliplatin; Panitumumab; Prognosis; ras Proteins; Survival Rate

Background This phase I/II trial evaluated toxicity and antitumor activity of everolimus plus mFOLFOX6 + bevacizumab for first-line treatment of metastatic colorectal cancer (mCRC). Methods A phase I, modified 3 + 3 Fibonacci schema determined the maximum tolerated dose (MTD) of everolimus, followed by phase II dose expansion. The phase II primary objective was progression-free survival at 6 months (PFS-6 m). Results The everolimus MTD was 10 mg daily with mFOLFOX6 + bevacizumab based on safety from phase I (n = 22). Twenty-five patients were treated in the phase II at 10 mg everolimus daily. Frequent grade 3-4 adverse events were neutropenia (64%), leukopenia (28%) and hypokalemia (26%). Grade 2 stomatitis was observed in 62% of patients. Two dose-limiting toxicities were observed with one attributed to everolimus 10 mg daily (grade 3 diarrhea, hypokalemia, and anorexia) and grade 3 coronary vasospasm attributed to fluorouracil. The objective response rate was 53% and was higher (86%) in those with PTEN deficiency. PFS-6 m was 96% (95% CI 89-99.9%) at the MTD (n = 35). The everolimus recommended phase II dose of this regimen is 7.5 mg daily due to frequent stomatitis and dose reductions. Conclusions Everolimus plus mFOLFOX-6 + bevacizumab is tolerable and demonstrated preliminary efficacy for first-line mCRC. Further studies are warranted in PTEN deficiency.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Everolimus; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Oxaliplatin; Prognosis; Survival Rate; Tissue Distribution; Young Adult

Purpose Our previous phase I trial suggested feasibility of addition of leucovorin (LV) to S-1 and gemcitabine therapy in advanced pancreatic cancer. The aim of this phase II trial was to assess the efficacy and toxicity of gemcitabine, S-1 and LV (GSL) combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naïve patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1000 mg/m2 by 30 min infusion on days 1, S-1 40 mg/m2 orally twice daily and LV 25 mg orally twice daily on days 1 to 7 every 2 weeks. Primary end point was progression free survival (PFS). Results A total of 49 patients with advanced pancreatic cancer (19 locally advanced and 30 metastatic) were enrolled. Overall response rate and disease control rate were 32.7% and 87.8%. The median PFS and overall survival (OS) were 10.8 (95% confidence interval [CI], 7.4-13.5) and 20.7 (95% CI 13.0-NA) months with 1-year survival rate of 73.4%. Major Grade 3-4 toxicities were neutropenia (22.4%) and stomatitis (14.3%). No toxicity related death was observed. Conclusions In this single center, phase II trial, gemcitabine, S-1 and LV combination therapy was tolerable and can potentially be a treatment option for advanced pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Drug Combinations; Female; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxonic Acid; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Survival Rate; Tegafur

First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC.. ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Oxaliplatin; Prognosis; Survival Rate; Young Adult

This study aimed to explore the correlation between survival and tumor calcification in patients with metastatic colorectal cancer who received cetuximab combined with chemotherapy. The study was a single-center retrospective analysis that enrolled 111 patients who had received therapy between April 2011 and October 2016. Tumor calcification and treatment efficacy were evaluated independently by radiologists on the basis of computed tomography scans. Clinical characteristics and follow-up data were collected from electronic medical records. Correlations between tumor calcification and clinical characteristics, tumor response rate, and patient survival were analyzed. Among the 111 enrolled patients, 27 had tumor calcification [27/111 (24.3%)]. The median progression-free survival was significantly longer for patients with tumor calcification than for those without calcification (9.3 vs. 6.2 months, P=0.022). Patients with tumor calcification also had a higher objective response rate (55.6 vs. 31%, P=0.021) and better overall survival (21.9 vs. 16.5 months, P=0.084). The correlation between calcification features and prognosis showed that patients with an increasing number of calcifications after treatment had a significantly longer median overall survival (22.9 vs. 9.1 months, P=0.033). Simultaneously, new liver metastases and multiple calcifications also showed a trend toward better overall survival. There were also no significant correlations between clinical characteristics (sex, age, gene mutation, primary tumor location, pathological type, blood test result) and survival (Supplementary Table 1, Supplemental digital content 1, http://links.lww.com/ACD/A280). Tumor calcification is associated with a better treatment outcome and is a potential prognostic marker.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Calcinosis; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

Akt activation is common in gastric/gastroesophageal junction cancer (GC/GEJC) and is associated with chemotherapy resistance. Treatment with ipatasertib, a pan-Akt inhibitor, may potentiate the efficacy of chemotherapy in GC/GEJC.. In this randomised, double-blind, placebo-controlled, multicentre, phase II trial, patients with locally advanced or metastatic GC/GEJC not amenable to curative therapy were randomised 1:1 to receive ipatasertib or placebo, plus mFOLFOX6 (modified regimen of leucovorin, bolus and infusional 5-fluorouracil [5-FU], and oxaliplatin). The co-primary end-point was progression-free survival (PFS) in the intent-to-treat (ITT) population and in phosphatase and tensin homolog (PTEN)-low patients. Secondary end-points included PFS in patients with PI3K/Akt pathway-activated tumours; overall survival, investigator-assessed objective response rate and duration of response in the ITT population; and safety assessments.. In 153 enrolled patients, the median PFS (ITT) was 6.6 months (90% confidence interval [CI], 5.7-7.5) with ipatasertib/mFOLFOX6 versus 7.5 months (90% CI, 6.2-8.1) with placebo/mFOLFOX6 (hazard ratio, 1.12; 90% CI, 0.81-1.55; P = 0.56). No statistically significant PFS benefit was observed in biomarker-selected patient subgroups (PTEN-low and PI3K/Akt pathway-activated tumours) with ipatasertib/mFOLFOX6 versus placebo/mFOLFOX6. Other secondary end-points did not favour the ipatasertib/mFOLFOX6 treatment arm. The percentages of patients with ≥1 adverse event (AE, 100% versus 98%) and grade ≥3 AEs (79% versus 74%) were similar between arms. Higher rates of AEs leading to treatment withdrawal (16% versus 6%) and serious AEs were reported in the ipatasertib arm (54% versus 43%). Thirty-nine and 29 deaths occurred in the ipatasertib and placebo arms, respectively.. Ipatasertib/mFOLFOX6 compared with placebo/mFOLFOX6 did not improve PFS in unselected or biomarker-selected patients. No unexpected safety concerns were observed.. ClinicalTrials.gov (NCT01896531).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Esophagogastric Junction; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Organoplatinum Compounds; Piperazines; Progression-Free Survival; Proto-Oncogene Proteins c-akt; Pyrimidines; Stomach Neoplasms

The TRICC0808 trial is a phase II multi-institutional trial that investigated the efficacy of preoperative mFOLFOX6 + bevacizumab (BV) therapy for liver-only metastasis that is unsuitable for upfront resection. The R0 resection rate in the efficacy analysis has been reported to be 44.4%, and the final analysis for survival was conducted (data fixation on February 16, 2015).. Six cycles of mFOLFOX6 + BV therapy were applied to patients with liver-only metastases, which were > 5 cm in diameter or more than four tumors (H2 and H3), and hepatectomy was performed if possible. Primary and secondary endpoints were the R0 hepatectomy rate and overall survival (OS), respectively.. Of 46 patients registered, OS was analyzed for 45 patients in whom the 3-year OS rate from the starting date of chemotherapy was 44.0% with a 33.6-month median survival time (MST). The 3-year OS rate of 31 patients with hepatectomy, including resection after an additional chemotherapy, was 61.3% with a 43.1-month MST, which was significantly better than 0% of the 3-year OS rate with a 21.0-month MST of 14 patients without hepatectomy (p value < 0.0001). In 24 patients who underwent hepatectomy after six cycles of protocol chemotherapy, the 3-year relapse-free survival rate was 8.3%, with a 36.8-month MST.. This final analysis of the TRICC0808 trial revealed a better long-term survival in patients with hepatectomy after mFOLFOX6 + BV therapy, although most examined patients eventually developed recurrence. Thus, hepatectomy after chemotherapy might improve the survival in patients with advanced liver metastases, although cure remains difficult.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Preoperative Care; Survival Rate

Liposomal irinotecan (nal-IRI) plus 5-fluorouracil and leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. This approval was based on significantly improved median overall survival compared with 5-FU/LV alone (6.1 vs 4.2 months; hazard ratio [HR], 0.67) in the global phase 3 NAPOLI-1 trial. Here, we report the final survival analysis and baseline characteristics associated with long-term survivors (survival of ≥1 year) in the NAPOLI-1 trial.. Patients with mPDAC were randomised to receive nal-IRI + 5-FU/LV (n = 117), nal-IRI (n = 151), or 5-FU/LV (n = 149) for the first 4 weeks of 6-week cycles. Baseline characteristics and efficacy in the overall population were compared with those in patients who survived ≥1 year. Through 16th November 2015, 382 overall survival events had occurred.. The overall survival advantage for nal-IRI+5-FU/LV vs 5-FU/LV was maintained from the original nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1) analysis (6.2 vs 4.2 months, respectively; HR, 0.75; 95% confidence interval: 0.57-0.99). Median progression-free survival, objective response rate and disease control rate also favoured nal-IRI+5-FU/LV therapy. Estimated one-year overall survival rates were 26% with nal-IRI+5-FU/LV and 16% with 5-FU/LV. Baseline characteristics associated with long-term survival in the nal-IRI+5-FU/LV arm were Karnofsky performance status ≥90, age ≤65 years, lower CA19-9 levels, neutrophil-to-lymphocyte ratio ≤5 and no liver metastases. No new safety concerns were detected.. The survival benefits of nal-IRI+5-FU/LV versus 5-FU/LV were maintained over an extended follow-up, and prognostic markers of survival ≥1 year were identified.. NCT01494506.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Karnofsky Performance Status; Leucovorin; Liposomes; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Progression-Free Survival; Proportional Hazards Models

Among patients with hepatocellular carcinoma (HCC), 85% of patients have an advanced disease stage at diagnosis and curative therapies cannot be performed. Prognosis has been quite poor as until recently there was no proven effective chemotherapy. Our group found that all-trans-retinoic acid (ATRA) could improve the efficacy of platinum in HCC in vivo and in vitro, thus we wish to validate the efficiency of ATRA in clinical practice.. This is a double-blinded, 1:1 randomized, controlled, multicenter clinical trial. Three hundred and sixty-eight patients with HCC and extrahepatic metastases will receive palliative chemotherapy at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University and Fujian Provincial Cancer Hospital. Subjects will be randomly assigned to one of the two arms, either ATRA + oxaliplatin + 5-fluorouracil/leucovorin (FOLFOX4) or FOLFOX4 alone. ATRA 20 mg will be given orally three times/day for 3 days prior to the initiation of FOLFOX4. ATRA will be discontinued at the end of FOLFOX4.. Overall survival rate is the primary endpoint. Secondary endpoints are time to progression according to the modified response evaluation criteria in solid tumors (mRECIST) criteria, acute and chronic adverse events, and quality of life.. Chinese Clinical Trial Registry, ChiCTR-IIR-17012916 . Registered on 9 October 2017.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Disease Progression; Double-Blind Method; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Multicenter Studies as Topic; Organoplatinum Compounds; Palliative Care; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors; Tretinoin

Sorafenib is the first-line treatment for hepatocellular carcinoma with portal vein invasion; however, it has shown unsatisfactory survival benefit. Sorafenib plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin (FOLFOX) has shown promising results for these patients in a previous phase 2 study.. To investigate the efficacy and safety of sorafenib plus HAIC compared with sorafenib for hepatocellular carcinoma with portal vein invasion.. This randomized, open-label clinical trial enrolled 818 screened patients. Of the 818 participants, 247 with hepatocellular carcinoma and portal vein invasion were randomly assigned (1:1) via a computer-generated sequence to receive sorafenib plus HAIC or sorafenib. This trial was conducted at 5 hospitals in China and enrolled patients from April 1, 2016, to October 10, 2017, with a follow-up period of 10 months.. Randomization to receive 400 mg sorafenib twice daily (sorafenib group) or 400 mg sorafenib twice daily plus HAIC (SoraHAIC group) (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 on day 1, and fluorouracil infusion 2400 mg/m2 for 46 hours, every 3 weeks).. The primary endpoint was overall survival by intention-to-treat analysis. Safety was assessed in patients who received at least 1 dose of study treatment.. For 247 patients (median age, 49 years; range, 18-75 years; 223 men and 24 women), median overall survival was 13.37 months (95% CI, 10.27-16.46) in the SoraHAIC group vs 7.13 months (95% CI, 6.28-7.98) in the sorafenib group (hazard ratio [HR], 0.35; 95% CI, 0.26-0.48; P < .001). The SoraHAIC group showed a higher response rate than the sorafenib group (51 [40.8%] vs 3 [2.46%]; P < .001), and a longer median progression-free survival (7.03 [95% CI, 6.05-8.02] vs 2.6 [95% CI, 2.15-3.05] months; P < .001). Grade 3/4 adverse events that were more frequent in the SoraHAIC group than in the sorafenib group included neutropenia (12 [9.68%] vs 3 [2.48%]), thrombocytopenia (16 [12.9%] vs 6 [4.96%]), and vomiting (8 [6.45%] vs 1 [0.83%]).. Sorafenib plus HAIC of FOLFOX improved overall survival and had acceptable toxic effects compared with sorafenib in patients with hepatocellular carcinoma and portal vein invasion.. ClinicalTrials.gov identifier: NCT02774187.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Portal Vein; Protein Kinase Inhibitors; Sorafenib; Treatment Outcome; Young Adult

Epidemiologic and preclinical data suggest isoflavones have anticancer activity in colorectal malignancy prevention and treatment. This is the first clinical trial assessing safety and tolerability of Genistein in combination with chemotherapy in metastatic colorectal cancer.. Patients who had histologically confirmed metastatic colorectal cancer and had not received previous treatment were eligible to enroll. Subjects were treated with FOLFOX or FOLFOX-Bevacizumab as per the investigator choice. Genistein was administered orally for 7 days every 2 weeks, beginning 4 days prior to chemotherapy and continuing through days 1-3 of infusional chemotherapy. Primary endpoint was safety and secondary endpoints included cycle 6 response rate, best overall response rate (BOR), and median progression-free survival (PFS).. Thirteen patients received chemotherapy with Genistein in this trial. The most common adverse events related to Genistein alone were mild and included headaches, nausea, and hot flashes. One subject was observed to have grade 3 hypertension. No increase in chemotherapy-related adverse events was observed when Genistein was added. BOR and median PFS were 61.5% and 11.5 months, respectively.. We observed that adding Genistein to FOLFOX or FOLFOX-Bevacizumab was safe and tolerable. Efficacy results are notable and warrant verification in larger clinical trials.. The study was registered at ClinicalTrials.gov Identifier: NCT01985763.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Genistein; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxaliplatin; Peritoneal Neoplasms; Pilot Projects; Prognosis; Survival Rate

FOLFIRI/aflibercept is approved as a second-line treatment in metastatic colorectal cancer (mCRC) but there are limited data for its use as a first-line treatment.. To investigate the activity and safety of first-line FOLFIRI/aflibercept in mCRC, as well as to prospectively evaluate biomarkers of early response to treatment.. MINOAS was a phase II trial that aimed to evaluate the activity and toxicity of first-line FOLFIRI/aflibercept in mCRC. The primary endpoint was objective response rate (ORR). The secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and the evaluation of CEACAM-positive circulating tumor cells (CTC) and diffusion-weighted (DW)-MRI as biomarkers.. Thirty-one patients were enrolled and 259 chemotherapy cycles were administered. At the time of the preplanned interim analysis, all patients had discontinued treatment and the ORR was 61.3%, crossing the activity threshold for trial discontinuation. Median PFS was 8.4 months (95% CI 7.8-9.0). Median OS had not been reached. There was one toxic death due to sepsis; grade 3/4 adverse events included neutropenia (n = 5), diarrhea (n = 6), hypertension (n = 4), asthenia (n = 3), proteinuria (n = 1), and bowel perforation (n = 1). Retaining CTC-negative status predicted better OS compared to continuous detection of CTCs (p = 0.015). Early decrease of the apparent diffusion coefficient (ADC) in DW-MRI was associated with an objective response.. The activity and safety of first-line FOLFIRI/aflibercept merit further evaluation in randomized studies. CLINICALTRIALS.. NCT02624726.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Rate

Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET).. The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS).. Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively.. Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions.. This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Efficacy of treatments for colorectal liver metastases after failure of first-line chemotherapy is limited. The aim of this study was to prospectively evaluate the feasibility, tolerability, and pharmacokinetics of selective transarterial chemoembolization (TACE) with irinotecan-loaded 40 μm microspheres combined with systemic FOLFIRI for colorectal liver metastases refractory to oxaliplatin regimen.. The dose escalation study was conducted in three patient groups with different amounts of irinotecan loaded (50, 75 and 100 mg per mL-microspheres). Selective catheterization was performed to embolize subsegments or segments of located tumors using TACE navigation system. FOLFIRI was administrated 7 days after TACE. Plasma concentration was measured before and time points after administration.. Nine patients successfully underwent a total of 22 TACE procedures. Dose-limiting toxicity did not appear at any level. The overall response rate was 55.6%. The median progression free and overall survival were 8.1 and 18.2 months, respectively. The AUC and C. Selective TACE using 40 μm irinotecan-loaded microspheres combined with systemic FOLFIRI was feasible and safe even when a high dose of irinotecan was loaded. Irinotecan-loaded microspheres resulted in a higher plasma concentration and AUC of SN-38 than treatment with FOLFIRI. Further large scale trials to evaluate the efficacy are mandatory.. University Hospital Medical Information Network (UMIN) Clinical Trials Registry, Registration number; UMIN000015367 ; Registered date; 08,10,2014.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoembolization, Therapeutic; Cohort Studies; Colorectal Neoplasms; Drug Dosage Calculations; Feasibility Studies; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Prospective Studies; Survival Analysis

Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study.. The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS).. From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention.. Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Deoxyuridine; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Survival Rate; Treatment Outcome

Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways. Preclinical data indicates that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in arginine auxotrophs.. This is a single-center, open-label, phase 1 trial of ADI-PEG 20 and modified FOLFOX6 (mFOLFOX6) in treatment-refractory hepatocellular carcinoma (HCC) and other advanced gastrointestinal tumors. A 3 + 3 dose escalation design was employed to assess safety, tolerability, and determine the recommended phase 2 dose (RP2D) of ADI-PEG 20. A RP2D expansion cohort for patients with HCC was employed to define the objective response rate (ORR). Secondary objectives were to estimate progression-free survival (PFS), overall survival (OS), and to explore pharmacodynamics and immunogenicity. Eligible patients were treated with mFOLFOX6 intravenously biweekly at standard doses and ADI-PEG-20 intramuscularly weekly at 18 (Cohort 1) or 36 mg/m. Twenty-seven patients enrolled-23 with advanced HCC and 4 with other gastrointestinal tumors. No dose-limiting toxicities were observed in cohort 1 or 2. The RP2D for ADI-PEG 20 was 36 mg/m. Concurrent mFOLFOX6 plus ADI-PEG-20 intramuscularly at 36 mg/m

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Hydrolases; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Polyethylene Glycols; Progression-Free Survival

The efficacy and safety of the FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin) regimen combined with aflibercept has not been studied in the first-line management of patients with metastatic colorectal cancer (mCRC).. In the context of a prospective single-arm trial (NCT02129257), patients with mCRC received standard doses of a maximum of 12 cycles of FOLFIRI combined with aflibercept (4 mg/kg body weight delivered intravenously) every 2 weeks, followed by aflibercept maintenance. Endpoints were 12-month progression-free survival rate, efficacy, and toxicity.. Seventy-three fit patients were enrolled onto the study between 2014 and 2016. Median relative dose intensities administered were 0.80 for irinotecan and 1.0 for aflibercept. The most common grade 3/4 adverse events were neutropenia (13 patients, 18%), febrile neutropenia (3 patients, 4%), diarrhea (11 patients, 15%), hypertension (19 patients, 26%), proteinuria (8 patients, 11%), infections (8 patients, 11%), and mucositis (6 patients, 8%), with no toxic deaths. The objective response rate was 46.6%, significantly associated with the presence of right-sided primary, synchronous metastases, and a relapse-free interval of < 12 months (odds ratio = 3.00, 2.92, and 3.75 respectively, P ≤ .05). Intermediate infiltration by stromal core lymphocytes correlated with progression-free survival (hazard ratio = 0.40, [95% confidence interval (CI), 0.19-0.83], P = .014). At a median follow-up of 24.5 months, 12-month progression-free survival rate was 21.9% (median overall survival 20.9 months [95% CI, 16.6-29], median progression-free survival 8.4 months [95% CI, 7.4-9.3]).. The FOLFIRI + aflibercept regimen is active and tolerable; however, it failed to improve historical benchmarks of efficacy in chemonaive patients with mCRC. Preliminary data hint that this regimen has cytoreductive activity in disease with adverse biology.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Prognosis; Prospective Studies; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Survival Rate; Young Adult

After curative-intent surgery for colorectal liver metastases (CRLM), liver recurrence occurs in more than 60% of patients, despite the administration of perioperative or adjuvant chemotherapy. This risk is even higher after resection of more than three CRLM. As CRLM are mostly supplied by arterial blood flow, hepatic arterial infusion (HAI) of chemotherapeutic agents after resection of CRLM is an attractive approach. Oxaliplatin-based HAI chemotherapy, in association with systemic fluoropyrimidines, has been shown to be safe and highly active in patients with CRLM. In a retrospective series of 98 patients at high risk of hepatic recurrence (≥4 resected CRLM), adjuvant HAI oxaliplatin combined with systemic chemotherapy was feasible and significantly improved disease-free survival compared to adjuvant, 'modern' systemic chemotherapy alone.. This study is designed as a multicentre, randomized, phase II/III trial. The first step is a non-comparative randomized phase II trial (power, 95%; one-sided alpha risk, 10%). Patients will be randomly assigned in a 1:1 ratio to adjuvant systemic FOLFOX (control arm) or adjuvant HAI oxaliplatin plus systemic LV5FU2 (experimental arm). A total 114 patients will need to be included. The main objective of this trial is to evaluate the potential survival benefit of adjuvant HAI with oxaliplatin after resection of at least 4 CRLM (primary endpoint: 18-month hepatic recurrence-free survival rate). We also aim to assess the feasibility of delivering at least 4 cycles of HAI (or i.v.) oxaliplatin after surgical treatment of at least 4 CRLM, the toxicity (NCI-CTC v4.0) of adjuvant HAI plus systemic chemotherapy, including HAI catheter-related complications, compared to systemic chemotherapy alone, and the efficacy of adjuvant HAI on hepatic and extra-hepatic recurrence-free (survival and overall survival).. If 18-month hepatic recurrence-free survival is greater than 50% in the experimental arm, the study will be pursued in phase III, for which the primary endpoint will be 3-year recurrence-free survival rate. Patients randomized in the phase II will be included in the phase III, with an additional number of 106 patients.. ClinicalTrials.gov, NCT02494973 . Trial registration date: July 10, 2015.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Disease-Free Survival; Feasibility Studies; Female; Fluorouracil; France; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Multicenter Studies as Topic; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

This randomized phase III trial compared hepatic arterial infusion (HAI) chemotherapy with 5-fluorouracil (5-FU) followed by uracil/tegafur (UFT) and leucovorin (LV) versus UFT/LV alone for patients with curatively resected liver metastases from colorectal cancer (CRC).. The study was designed to include 280 patients to be randomized to receive either HAI with 5-FU followed by UFT/LV (Arm A) or UFT/LV alone (Arm B) to assess whether HAI chemotherapy improved disease-free survival (DFS).. Forty-four patients were randomized. Three-year DFS was relatively worse in the experimental arm although this difference was not statistically significant (43.5% in Arm A vs. 58% in Arm B; hazard ratio [HR], 1.304; P = 0.534). The experimental arm also tended to have a worse 3-year overall survival rate (80.2% in Arm A vs. 85.2% in Arm B; HR, 2.255; P = 0.192). There was no significant difference in the frequency of Grade 3 or higher toxicities between the two arms.. Although this study was limited by a small sample size after early study termination, our analysis found that HAI with 5-FU followed by UFT/LV did not improve the DFS of patients with curatively resected liver metastases from CRC compared with UFT/LV alone. The future studies are necessary to evaluate the survival benefit of HAI in combination with newer systemic chemotherapeutic agents for patients with resectable liver metastases from CRC.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Tegafur

The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting.. Chemotherapy-naïve patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0-1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%.. Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3-97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3-43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8-12.9) and 33.4 m (95% CI, 22.6-38.2), respectively.. Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step.. Clinicaltrials.gov, NCT01674309.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fatigue; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Diseases; Hematologic Diseases; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Oxaliplatin; Paresthesia; Progression-Free Survival; Rectal Neoplasms; Remission Induction; Tomography, X-Ray Computed; Treatment Outcome

We have previously shown that refractory neuroendocrine tumors can respond to moderate doses of chemoradiotherapy. We completed a dose-escalation phase I/II trial combining hepatic arterial (HA) chemotherapy, chemoembolization, and dose-escalated whole liver radiotherapy to determine the maximum safe dose of radiation that could be delivered and to make a preliminary assessment of response.. From 2002 to 2009, 19 patients with symptomatic neuroendocrine liver metastases who failed somatostatin analog therapy were enrolled. HA fluorodeoxyuridine, leucovorin, and streptozotocin were delivered, as concurrent whole liver radiotherapy was dose escalated from 24 to 32 Gy in 2 Gy fractions, with a target rate of dose-limiting grade ≥3 radiation-induced liver disease of 10%. Eight weeks later, for patients without grade ≥3 liver or grade ≥4 any toxicity, a 72-hour infusion of HA fluorodeoxyuridine and leucovorin was given, followed by transarterial chemoembolization.. Eleven patients completed the entire protocol and received 24 to 32 Gy. No patients developed radiation-induced liver disease; 7 had grade 3 to 4 transiently increased liver function tests, and 4 had other grade 4 toxicities. Three patients (14%) had partial response, 16 (84%) stable disease. Median freedom from local progression and overall survival were 35.3 and 54.6 months, respectively.. Thirty-two in 2 Gy daily fractions can be delivered safely when combined with HA chemotherapy and subsequent transarterial chemoembolization. However, although objective responses were observed, this combination was not significantly better than our prior approaches. Further treatment intensification strategies, including individualized dose escalation for radiation-tolerant livers, and improved radiosensitization should be investigated, along with improved systemic therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Neuroendocrine; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Floxuridine; Follow-Up Studies; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis; Radiotherapy Dosage; Streptozocin; Survival Rate

Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.. In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.. At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.. This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction.. To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection.. The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013.. Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT.. The primary end point was overall survival.. In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients.. Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials.. clinicaltrials.gov identifier: NCT00849615.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Docetaxel; Esophagogastric Junction; Fluorouracil; Gastrectomy; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prospective Studies; Stomach Neoplasms; Survival Rate; Taxoids; Young Adult

RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear.. Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR).. Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively.. In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Exons; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Treatment Outcome

In first-line wild-type (WT)-Kirsten rat sarcoma viral oncogene homologue (KRAS) metastatic colorectal cancer (mCRC), panitumumab (Pmab) improves outcomes when added to FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, 5-fluorouracil, and irinotecan]. However no trial has directly compared these combinations.. Multicentre, open-label study in untreated patients ≥ 18 years with (WT)-KRAS mCRC and multiple or unresectable liver-limited disease (LLD) randomised to either Pmab-FOLFOX4 or Pmab-FOLFIRI. The primary end-point was objective response rate (ORR). Secondary end-points included liver metastases resection rate (R0 + R1), progression-free survival (PFS), overall survival (OS), adverse events and perioperative safety. Exploratory end-points were: response by RAS status, early tumour shrinkage (ETS) and depth of response (DpR) in WT-RAS patients.. Data on 77 patients were analysed (38 Pmab-FOLFOX4; 39 Pmab-FOLFIRI; WT-RAS: 27/26, respectively). ORR was 74% with Pmab-FOLFOX4 and 67% with Pmab-FOLFIRI (WT-RAS: 78%/73%). Out of the above, 45% and 59% underwent surgical resection, respectively (WT-RAS: 37%/69%). The R0-R1 resection rate was 34%/46% (WT-RAS:26%/54%). Median PFS was 13/14 months (hazard ratio [HR] Pmab-FOLFIRI versus Pmab-FOLFOX4: 0.9; 95% confidence interval: [0.6-1.5]; WT-RAS:13/15; HR: 0.7 [0.4-1.3]). Median OS was 37/41 months (HR:1.0 [0.6-1.8]; WT-RAS: 39/49; HR:0.9 [0.4-1.9]). In WT-RAS patients with confirmed response, median DpR was 71%/66%, and 65%/77% of patients showed ETS ≥ 30%/ ≥ 20% at week 8, without significant differences between arms; these patients had longer median PFS and OS and higher resectability rates. Surgery was associated with longer survival. Perioperative and overall safety were similar, except for higher grade 3/4 neutropenia (40%/10%; p = 0.003) and neuropathy (13%/0%; p = 0.025) in the Pmab-FOLFOX4 arm.. In patients with WT-KRAS mCRC and LLD, both first-line Pmab-FOLFOX4 and Pmab-FOLFIRI resulted in high ORR and ETS, allowing potentially curative resection. No significant differences in efficacy were observed between the two regimens. (clinicaltrials.gov:NCT00885885).

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Panitumumab; Spain; Survival Analysis

Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM.. A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS).. Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively.. Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Cetuximab; Colorectal Neoplasms; Female; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate

Although liver resection combined with preoperative chemotherapy is expected to improve outcomes of patients with resectable colorectal liver metastasis (CRLM), there is as yet insufficient clinical evidence supporting the efficacy of preoperative systemic chemotherapy. The aim of this phase II study was to assess the feasibility and efficacy of preoperative FOLFOX systemic chemotherapy for patients with initially resectable CRLM.. A prospective multi-institutional phase II study was conducted to evaluate the feasibility and efficacy of preoperative chemotherapy for resectable CRLM (ClinicalTrials.gov identifier number NCT00594529). Patients were scheduled to receive 6 cycles of mFOLFOX6 therapy before liver surgery. The primary endpoint was the macroscopic curative resection rate.. A total of 30 patients were included in this study. Two patients who were diagnosed with hepatocellular and intrahepatic cholangiocellular carcinoma based on pathology were excluded from the analysis. More than half of the patients (57 %) had solitary liver metastasis. The completion rate of preoperative chemotherapy was 64.3 % and the response rate was 53.6 %. Two patients were unable to proceed to liver resections due to disease progression and severe postoperative complications following primary tumor resection. Macroscopic curative resection was obtained in 89.3 % of eligible patients. Postoperative mortality and severe complication (≥Gr. 3) rates were 0 and 11 %, respectively. The 3-year overall and progression-free survival rates were 81.9 and 47.4 %, respectively.. Our phase II study demonstrated the feasibility of liver resection combined with preoperative mFOLFOX6 therapy in patients with initially resectable CRLM. Further study is warranted to address the oncological effects of preoperative chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Feasibility Studies; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; Young Adult

Hepatic arterial infusion (HAI) was evaluated for different drugs to treat hepatic metastasis from colorectal cancer (CRC). Combination treatment with 5-fluorouracil (5-FU), leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) is effective for CRC. A phase II study was conducted to evaluate concomitant HAI administration of oxaliplatin and intravenous leucovorin, 5-FU and irinotecan (FOLFIRI) for patients with inoperable liver metastasis, which had chemotherapy with oxaliplatin (OX) 85 mg/m(2) HAI plus systemic intravenous chemotherapy [leucovorin 200 mg/m(2), 5-FU 2400 mg/m(2) and irinotecan (IRI) 160 mg/m(2) in 48 hours]. We treated 24 patients. Neutropaenia was the most frequent toxicity. The main HAI-related toxicity was pain. Two patients (8%) obtained complete response and 17 patients (70%) partial response, giving an objective response rate of 78%. Median follow-up was 22.8 months, and median overall and disease-free survival times were 29 and 20 months, respectively. Therefore, OX HAI and intravenous FOLFIRI is feasible and effective in patients with metastatic CRC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intralesional; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons.. Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics.. In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy.. Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Cooperative Behavior; Female; Fluorouracil; Humans; Interprofessional Relations; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Patient Selection; Single-Blind Method; Tomography, X-Ray Computed

To evaluate the efficacy and safety of upfront mFOLFOX6 followed by short-course radiotherapy (SCRT) and surgery in patients with locally advanced rectal cancer and liver-only metastases.. This single-arm phase II study involved 32 patients. mFOLFOX6 was administered for four cycles followed by SCRT and another four cycles of mFOLFOX6. Surgery was performed 4-6 weeks after the last chemotherapy cycle. The primary endpoint was complete (R0) resection rate. Secondary endpoints were response rate, progression-free survival (PFS), overall survival (OS), and complication rates.. Surgical resection of the rectum and liver was performed in 25 patients (78%) and R0 resection was achieved in 20 patients (63%). Local tumor downstaging was observed in 54% of patients. Median OS and PFS were 38 and 9 months, respectively. One patient discontinued treatment due to toxicity and no treatment-related deaths occurred. Patients who progressed after 4 cycles of mFOLFOX6 were less likely to receive resection.. This regimen was safe and effective in inducing local tumor response and achieving R0 resection in this patient population.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Disease-Free Survival; Dose Fractionation, Radiation; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Rectal Neoplasms; Survival Analysis; Treatment Outcome

The purpose of this study was to assess the efficacy and tolerance of induction chemotherapy combining LV5FU2 with increased doses of irinotecan adapted to UGT1A1 genotyping and cetuximab in untreated potentially resectable liver metastases of colorectal cancer.. Twenty-six patients, PS 0-1, with class II hepatic metastases received chemotherapy combining irinotecan 260 mg/m(2) on day 1 for UGT1A1 6/6 and 6/7 genotypes and 220 mg/m(2) for UGT1A1 7/7 genotypes, with leucovorin on day 1, 5FU 400 mg/m(2) bolus on day 1 and continuous 5FU infusion for 46 h, and cetuximab on day 1 (day 1 = day 14). Primary prevention with lenograstim (day 5-9) was given to UGT1A1 6/7 and 7/7 genotypes. The primary endpoint was the response rate (RECIST1.1), and the secondary endpoints were tolerance (NCI-CTC criteria) and R0 resection rate.. The average number of cycles per patient was 6 (±1.9). The UGT1A1 genotype was 6/6 in 34.6 %, 6/7 in 53.9 %, and 7/7 in 11.5 % of patients. At 6 cycles, 18 patients (69.2 %) presented a partial response, 5 patients (19.2 %) had stable disease, 2 patients (7.7 %) died independently of chemotherapy, and 1 patient (3.9 %) refused the treatment after 3 cycles. Four patients received 2 more cycles and the cumulative response rate at 8 cycles was 76.9 % (20/26). There was no progression. Among assessable patients (n = 23), the overall response rate was 82.6 % and 21 patients (80.7 %) had a metastasis resection. The most frequent grade 3-4 toxicities were neutropenia (31 %), diarrhea (20.8 %), and anorexia (16.4 %). There were no deaths due to toxicity.. High-dose FOLFIRI combined with cetuximab yielded high response rates and enabled complete resection of class II hepatic metastases in most patients. It seemed to be well-tolerated among healthy selected patients thanks to irinotecan dose adaptation according to UGT1A1 pharmacogenomics status. This intensified chemotherapy regimen needs to be confirmed in a randomized, phase III study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis; Survival Rate

FOLFOXIRI plus bevacizumab is a valid option as upfront treatment for metastatic colorectal cancer (mCRC) patients. While several trials investigated the effect of combining bevacizumab with different chemotherapy regimens, including fluoropyrimidines monotherapy and oxaliplatin- or irinotecan-containing doublets, no randomized comparison assessing the impact of the addition of bevacizumab to FOLFOXIRI is available.. A total of 122 mCRC patients received first-line FOLFOXIRI in the phase III trial by the GONO (FOLFOXIRI group) and 252 patients received first-line FOLFOXIRI plus bevacizumab in the TRIBE trial (FOLFOXIRI plus bevacizumab group). A propensity score-adjusted method was adopted to provide an estimation of the benefit from the addition of bevacizumab to FOLFOXIRI in terms of survival and activity parameters.. Patients in the FOLFOXIRI group had more frequently Eastern Cooperative Oncology Group performance status of one or two, high Köhne score, metachronous and liver-limited disease, had previously received adjuvant treatments and had their primary tumors resected. The median progression-free survival (PFS) was 12.3 months in the FOLFOXIRI plus bevacizumab group compared with 10.0 months in the FOLFOXIRI group {propensity score-adjusted hazard ratio (HR) 0.74 [95% confidence interval (CI) 0.59-0.94], P = 0.013}. This association was significant also in the multivariable model (P = 0.024). The median OS was 29.8 months in the FOLFOXIRI plus bevacizumab group compared with 23.6 months in the FOLFOXIRI group [propensity score-adjusted HR: 0.72 (95% CI 0.56-0.93), P = 0.014]. At the multivariable model, the addition of bevacizumab was still associated with significantly longer OS (P = 0.030). No significant differences in RECIST response rate (RR) [65.1% versus 55.7%; propensity score-adjusted odds ratio (OR): 1.29 (95% CI 0.81-2.05), P = 0.280], early RR [62.7% versus 57.8%; OR: 1.14 (95% CI 0.68-1.93), P = 0.619] and median depth of response (42.2% versus 53.8%, P = 0.259) were reported.. Though in the absence of a randomized comparison, the addition of bevacizumab to FOLFOXIRI provides significant benefit in PFS and OS, thus supporting the use of FOLFOXIRI plus bevacizumab as upfront treatment for mCRC patients.. NCT01219920 and NCT00719797.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis.. Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate.. Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found.. KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC.. Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined.. In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [(18)F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS.. In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Prospective Studies; Survival Rate

The addition of cetuximab (CTX) to perioperative chemotherapy (CT) for operable colorectal liver metastases resulted in a shorter progression-free survival. Details of disease progression are described to further inform the primary study outcome.. A total of 257 KRAS wild-type patients were randomised to CT alone or CT with CTX. Data regarding sites and treatment of progressive disease were obtained for the 109 (CT n=48, CT and CTX n=61) patients with progressive disease at the cut-off date for analysis of November 2012.. The liver was the most frequent site of progression (CT 67% (32/48); CT and CTX 66% (40/61)). A higher proportion of patients in the CT and group had multiple sites of progressive disease (CT 8%, 4/48; CT and CTX 23%, 14/61 P=0.04). Further treatment for progressive disease is known for 84 patients of whom 69 received further CT, most frequently irinotecan based. Twenty-two patients, 11 in each arm, received CTX as a further line agent.. Both the distribution of progressive disease and further treatment are as expected for such a cohort. The pattern of disease progression seen is consistent with failure of systemic micrometastatic disease control rather than failure of local disease control following liver surgery.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

The high recurrence rate after surgery for colorectal cancer liver metastasis (CLM) remains a crucial problem. The aim of this trial was to evaluate the efficacy of adjuvant therapy with uracil-tegafur and leucovorin (UFT/LV).. In the multicenter, open-label, phase III trial, patients undergoing curative resection of CLM were randomly assigned in a 1:1 ratio to either the UFT/LV group or surgery alone group. The UFT/LV group orally received 5 cycles of adjuvant UFT/LV (UFT 300mg/m2 and LV 75mg/day for 28 days followed by a 7-day rest per cycle). The primary endpoint was recurrence-free survival (RFS). Secondary endpoints included overall survival (OS).. Between February 2004 and December 2010, 180 patients (90 in each group) were enrolled into the study. Of these, 3 patients (2 in the UFT/LV group and 1 in the surgery alone group) were excluded from the efficacy analysis. Median follow-up was 4.76 (range, 0.15-9.84) years. The RFS rate at 3 years was higher in the UFT/LV group (38.6%, n = 88) than in the surgery alone group (32.3%, n = 89). The median RFS in the UFT/LV and surgery alone groups were 1.45 years and 0.70 years, respectively. UFT/LV significantly prolonged the RFS compared with surgery alone with the hazard ratio of 0.56 (95% confidence interval, 0.38-0.83; P = 0.003). The hazard ratio for death of the UFT/LV group against the surgery alone group was not significant (0.80; 95% confidence interval, 0.48-1.35; P = 0.409).. Adjuvant therapy with UFT/LV effectively prolongs RFS after hepatic resection for CLM and can be recommended as an alternative choice.. UMIN Clinical Trials Registry C000000013.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Tegafur; Treatment Outcome; Uracil

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Deoxycytidine; Evidence-Based Medicine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaloacetates; Practice Patterns, Physicians'; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; United Kingdom

A phase II clinical trial was conducted on colorectal cancer patients with only liver metastases (focal diameter exceeds 5 cm or the number of liver metastases is ≥5; H2·H3) to evaluate the liver resection rate and safety after 6 cycles of mFOLFOX6+bevacizumab (BV) therapy.. mFOLFOX6+BV therapy was applied for 6 cycles to the patients with H2·H3 liver only metastasis. Hepatectomy was considered after the sixth cycle as a rule, and was performed if possible. The primary endpoint was the curative hepatectomy rate (R0 resection rate).. Forty-six patients were registered and 45 patients were included in the efficacy analysis. Of the 19 patients rated as unresectable before therapy, 18 completed 6 cycles of mFOLFOX6+BV therapy and subsequently underwent hepatectomy (16 were R0-resected). Of the 26 initially unresectable patients, 6 underwent hepatectomy (4 were RO-resected). The overall R0 resection rate was 44.4% (20/45). Chemotherapy-associated grade 3 or higher adverse events included neutrophil decreased (17.4%) and leukocyte decreased (8.7%), fatigue (6.5%) etc. Only hypertension (6.5%) and venous thromboembolism (2.2%) were BV-associated grade 3 or higher adverse events. Among the 25 patients who underwent hepatectomy, intraoperative/postoperative complications included grade 3 wound infections (2 cases), biloma, delayed wound healing and intraperitoneal abscess (each 1 case).. In colorectal cancer patients with liver-only metastases, mFOLFOX6+ BV therapy yielded a high hepatectomy rate and a high percentage of initially unresectable and subsequently resectable cases. The chemotherapy associated adverse events and hepatectomy complications were both within acceptable ranges.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis

For patients with initially unresectable liver metastases from colorectal cancer, chemotherapy can downsize metastases and facilitate secondary resection. We assessed the efficacy of bevacizumab plus modified FOLFOX-6 (5-fluorouracil/folinic acid, oxaliplatin) or FOLFOXIRI (5-fluorouracil/folinic acid, oxaliplatin, irinotecan) in this setting.. OLIVIA was a multinational open-label phase II study conducted at 16 centres in Austria, France, Spain, and the UK. Patients with unresectable liver metastases were randomised to bevacizumab (5 mg/kg) plus mFOLFOX-6 [oxaliplatin 85 mg/m(2), folinic acid 400 mg/m(2), 5-fluorouracil 400 mg/m(2) (bolus) then 2400 mg/m(2) (46-h infusion)] or FOLFOXIRI [oxaliplatin 85 mg/m(2), irinotecan 165 mg/m(2), folinic acid 200 mg/m(2), 5-fluorouracil 3200 mg/m(2) (46-h infusion)] every 2 weeks. Unresectability was defined as ≥1 of the following criteria: no possibility of upfront R0/R1 resection of all lesions; <30% residual liver volume after resection; metastases in contact with major vessels of the remnant liver. Resectability was evaluated by multidisciplinary review. The primary end point was overall resection rate (R0/R1/R2). Efficacy end points were analysed by intention-to-treat analysis.. In patients assigned to bevacizumab-FOLFOXIRI (n = 41) or bevacizumab-mFOLFOX-6 (n = 39), the overall resection rate was 61% [95% confidence interval (CI) 45% to 76%] and 49% (95% CI 32% to 65%), respectively (difference 12%; 95% CI -11% to 36%). R0 resection rates were 49% and 23%, respectively. Overall tumour response rates were 81% (95% CI 65% to 91%) with bevacizumab-FOLFOXIRI and 62% (95% CI 45% to 77%) with bevacizumab-mFOLFOX-6. Median progression-free survival (PFS) was 18·6 (95% CI 12.9-22.3) months and 11·5 (95% CI 9.6-13.6) months, respectively. The most common grade 3-5 adverse events were neutropenia (bevacizumab-FOLFOXIRI, 50%; bevacizumab-mFOLFOX-6, 35%) and diarrhoea (30% and 14%, respectively).. Bevacizumab-FOLFOXIRI was associated with higher response and resection rates and prolonged PFS versus bevacizumab-mFOLFOX-6 in patients with initially unresectable liver metastases from colorectal cancer. Toxicity was increased but manageable with bevacizumab-FOLFOXIRI.. NCT00778102.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy.. In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%.. The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient.. Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy.. ClinicalTrials.gov, number NCT00544700.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; Young Adult

This updated analysis of the CECOG/CORE 1.2.002 study investigated the association between clinical outcome and RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients treated with FOLFOX4 plus cetuximab.. Available DNA samples from CECOG/CORE 1.2.002 study patients with KRAS exon 2 wild type (wt) (at codons 12 and 13) tumors were screened for mutations at other loci in the KRAS and NRAS (RAS) coding regions by Sanger sequencing, and for BRAF codon 600 mutations by Sanger sequencing and pyrosequencing. Clinical outcome was compared among different mutation subgroups.. Of 152 KRAS wt mCRC patients, 148 were evaluable for RAS and BRAF mutation status. Eleven RAS mutations were detected in 10 patients' tumors (7%). BRAF mutations were detected in 14 patients' tumors (9%). RAS and BRAF tumor mutations were mutually exclusive. Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.. These findings support those from recent studies that RAS and BRAF mutations are associated with poor outcome in patients receiving an epidermal growth factor receptor-targeted monoclonal antibody in combination with oxaliplatin-based chemotherapy. Furthermore, mutation testing should not only include RAS codons 12 and 13 but should also be extended to the entire coding regions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Codon; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; GTP Phosphohydrolases; Humans; Leucovorin; Liver Neoplasms; Male; Membrane Proteins; Middle Aged; Mutation; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Survival Rate

Multidrug regimens are active against advanced colorectal cancer (ACRC). However, the increased toxicity requires the use of biomarkers to select the patients who will derive the most benefit. We assessed circulating tumor cells (CTCs) as a prognostic biomarker in patients treated with a 4-drug regimen.. A single-arm phase II trial (Erbitux Study of CPT11, Oxaliplatin, UFToral Targeted-therapy [eSCOUT]) was undertaken in patients with previously untreated KRAS wild-type ACRC using a regimen of irinotecan, oxaliplatin, and tegafur-uracil with leucovorin and cetuximab. Baseline CTCs were enumerated using CellSearch. The endpoints were an objective response rate (ORR) and overall survival (OS). We modeled our results and compared them with those modeled for the capecitabine, oxaliplatin, bevacizumab +/- cetuximab (CAIRO2) trial, stratifying patients a priori into low (< 3) and high (≥ 3) CTC groups.. For 48 eligible patients, the best ORR from the 4-drug regimen was 71%, with a disease control rate of 98%. The median OS for patients with a high and low CTC count was 18.7 and 22.3 months (log-rank test, P = .038), respectively. In our modeled data, for patients with a low CTC count, no differences were found between the median OS in the eSCOUT trial and that in the CAIRO2 trial (22.2 vs. 22.0 months). However, for the high CTC group, a clinically relevant improvement was seen in median OS (eSCOUT vs. CAIRO2, 18.7 vs. 13.7 months; P = .001).. These data are hypothesis generating-for patients with ACRC, stratification by CTC count can identify those who might benefit the most from an intensive 4-drug regimen, avoiding high-toxicity regimens in low CTC groups. This hypothesis warrants validation in a phase III biomarker-driven trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate

The need for low toxicity adjuncts to standard care chemotherapy in inoperable colorectal cancer, with potential to improve outcomes and decrease the side-effect burden, is well recognised. Addition of the low toxicity diet-derived agent, curcumin (the active ingredient of turmeric), to standard oxaliplatin-based therapy has shown promise in numerous pre-clinical studies.. This study is the first to combine daily oral curcumin with standard care FOLFOX-based (5-fluorouracil, folinic acid and oxaliplatin) chemotherapy in colorectal cancer patients with inoperable liver metastases: the CUFOX trial. CUFOX comprises a Phase 1 dose-escalation study (3 + 3 + 3 design) to determine an acceptable target dose of curcumin with which to safely proceed to a Phase IIa open-labelled randomised controlled trial. Thirty three participants with histological or cytological confirmation of inoperable colorectal cancer will then be randomised to oxaliplatin-based chemotherapy with the addition of daily oral curcumin at the target dose determined in Phase I, or to standard care oxaliplatin-based chemotherapy alone (recruiting at a ratio of 2:1).. Primary outcome measures will be the determination of a target dose which is both safe and tolerable for long-term administration to individuals in receipt of first-line oxaliplatin-based chemotherapy for inoperable colorectal cancer. Secondary outcome measures will include observation of any changes in neuropathic side-effects of chemotherapy, improvement to progression-free or overall survival and identification of putative efficacy biomarkers in plasma. The results will be disseminated via presentation at national and international conferences, via publication in appropriate peer-reviewed journals and via the Cancer Research UK/Department of Health Experimental Cancer Medicine Centre Network. This trial has full ethical and institutional approval, and commenced recruitment in February 2012.. ClinicalTrials.gov ( NCT01490996 , registered 7(th) December 2011), European Drug Regulating Authorities (EudraCT 2011-002289-19, registered 13(th) May 2011), UKCRN ID#10672.

Topics: Administration, Oral; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Clinical Protocols; Colorectal Neoplasms; Curcumin; Disease Progression; Disease-Free Survival; Drug Administration Schedule; England; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Research Design; Time Factors; Treatment Outcome

The current study aimed to evaluate the short-term efficacy and safety of endostar plus irinotecan/calcium folinate/5-fluorouracil (FOLFIRI) in treatment of advanced colorectal cancer (CRC).. Forty patients with advanced CRC were enrolled in this study and randomly assigned to two groups. The control group (n = 18) and tested group (n = 22) were received FOLFIRI alone and FOLFIRI plus endostar, respectively. The end points were overall response rate, progression-free survival (PFS) and toxicity.. A total of 38 patients (17 in control group and 21 in tested group) completed two cycles of treatment and were deemed assessable for response. Patients treated with FOLFIRI plus endostar experienced a obviously higher overall response rate (42.9%) compared with patients who received FOLFIRI alone (29.4%) and a statistically significant improvement in median PFS (14.5 vs. 11.0  months). The toxicity of FOLFIRI/endostar was comparative to that of FOLFIRI with regard to gastrointestinal reactions, haematologic toxicity, peripheral neuropathy and cholinergic syndrome. Cardiovascular adverse reactions including electrocardiogram abnormality and hypertension, which might be ascribed to endostar treatment, were reversible and manageable.. The addition of endostar to FOLFIRI resulted in a higher overall response rate and longer PFS and did not increase unacceptable adverse responses in patients with advanced CRC. Future randomised controlled clinical trials with a larger group of patients are warranted to further investigate the value of FOLFIRI plus endostar in CRC treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Endostatins; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Prognosis; Recombinant Proteins; Survival Rate

Patients with colorectal liver metastasis (CRLM) might be down-staged by chemotherapy from an initially unresectable stage to a resectable stage. Because the tumor response to preoperative chemotherapy has been correlated with resection rate, the improved efficacy from the concept that only the patients without K-ras mutations receive an anti-EGFR antibody might be expected to increase the conversion rate. The purpose of this study is to evaluate the conversion rate from unresectable CRLM to complete resection.. We conducted a multi-institutional phase II trial for unresectable CRLM. Patients received mFOLFOX6 with either bevacizumab (bev) or cetuximab (cet) based on K-ras status (UMIN000004310). Planned treatment was for six cycles during which tumors were assessed for resectability every three cycles. Patients whose disease was unresectable after six cycles switched their chemotherapy regimen from mFOLFOX6 to FOLFIRI. The primary endpoint was R0 resection rate.. Thirty-five patients with unresectable CRLM were enrolled. A total of 22/12 patients with K-ras wild-type/mutant (wt/mt) were treated with mFOLFOX6 plus cet/bev, respectively. The overall response rate was 64.7% (wt/mt; 77.3%/41.7%, P = 0.04). In 20 patients (58.8%), hepatectomy was performed according to protocol treatment, and the conversion rate was 72.7%/33.3% in wt/mt patients, respectively (P = 0.03). Finally, 23 patients (67.6%) underwent hepatectomy, and the conversion rate was 77.2%/50.0% in wt/mt patients (P = 0.09). The overall R0 resection rate was 47.1% (wt/mt; 50.0%/41.7%, P = 0.36).. This prospective study showed that combined chemotherapy based on K-ras status can facilitate conversion to resection in patients with unresectable CRLM.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Genes, ras; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Prospective Studies

Colorectal cancer patients with unresectable liver-only metastases may be cured after downsizing of metastases by neoadjuvant systemic therapy. However, the optimal neoadjuvant induction regimen has not been defined, and the lack of consensus on criteria for (un)resectability complicates the interpretation of published results.. CAIRO5 is a multicentre, randomised, phase 3 clinical study. Colorectal cancer patients with initially unresectable liver-only metastases are eligible, and will not be selected for potential resectability. The (un)resectability status is prospectively assessed by a central panel consisting of at least one radiologist and three liver surgeons, according to predefined criteria. Tumours of included patients will be tested for RAS mutation status. Patients with RAS wild type tumours will be treated with doublet chemotherapy (FOLFOX or FOLFIRI) and randomised between the addition of either bevacizumab or panitumumab, and patients with RAS mutant tumours will be randomised between doublet chemotherapy (FOLFOX or FOLFIRI) plus bevacizumab or triple chemotherapy (FOLFOXIRI) plus bevacizumab. Radiological evaluation to assess conversion to resectability will be performed by the central panel, at an interval of two months. The primary study endpoint is median progression-free survival. Secondary endpoints are the R0/1 resection rate, median overall survival, response rate, toxicity, pathological response of resected lesions, postoperative morbidity, and correlation of baseline and follow-up evaluation with respect to outcomes by the central panel.. CAIRO5 is a prospective multicentre trial that investigates the optimal systemic induction therapy for patients with initially unresectable, liver-only colorectal cancer metastases.. CAIRO 5 is registered at European Clinical Trials Database (EudraCT) (2013-005435-24). CAIRO 5 is registered at ClinicalTrials.gov: NCT02162563 , June 10, 2014.

Topics: Adult; Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Panitumumab; Treatment Outcome

In vitro and pre-clinical studies have suggested that addition of the diet-derived agent curcumin may provide a suitable adjunct to enhance efficacy of chemotherapy in models of colorectal cancer. However, the majority of evidence for this currently derives from established cell lines. Here, we utilised patient-derived colorectal liver metastases (CRLM) to assess whether curcumin may provide added benefit over 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) in cancer stem cell (CSC) models. Combination of curcumin with FOLFOX chemotherapy was then assessed clinically in a phase I dose escalation study. Curcumin alone and in combination significantly reduced spheroid number in CRLM CSC models, and decreased the number of cells with high aldehyde dehydrogenase activity (ALDH(high)/CD133(-)). Addition of curcumin to oxaliplatin/5-FU enhanced anti-proliferative and pro-apoptotic effects in a proportion of patient-derived explants, whilst reducing expression of stem cell-associated markers ALDH and CD133. The phase I dose escalation study revealed curcumin to be a safe and tolerable adjunct to FOLFOX chemotherapy in patients with CRLM (n = 12) at doses up to 2 grams daily. Curcumin may provide added benefit in subsets of patients when administered with FOLFOX, and is a well-tolerated chemotherapy adjunct.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Colorectal Neoplasms; Curcumin; Dose-Response Relationship, Drug; Fluorouracil; Heterografts; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells; Organoplatinum Compounds; Oxaliplatin; Spheroids, Cellular

Second-line treatment with chemotherapy and anti-epidermal growth factor receptor or anti-vascular endothelial growth factor antibodies improves outcomes in patients with wild type Kirsten rat sarcoma viral oncogene homolog (KRAS) metastatic colorectal cancer (mCRC). The choice of biological agent in second-line mCRC remains unclear. In this randomized, phase II estimation trial, we compared FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) in combination with panitumumab or bevacizumab in patients with disease progression during oxaliplatin-based chemotherapy and bevacizumab.. One hundred eighty-two patients were randomized to FOLFIRI with panitumumab or bevacizumab. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), and safety.. PFS was similar between arms, with a hazard ratio (HR) of 1.01 (95% confidence interval [CI], 0.68-1.50; P = .97). Median PFS was 7.7 months (95% CI, 5.7-11.8) in the panitumumab arm and 9.2 months (95% CI, 7.8-10.6) in the bevacizumab arm. OS was also similar between arms, with an HR of 1.06 (95% CI, 0.75-1.49; P = .75). Median OS was 18.0 months (95% CI, 13.5-21.7) in the panitumumab arm and 21.4 months (95% CI, 16.5-24.6) in the bevacizumab arm. ORR was 32% (95% CI, 23%-43%) in the panitumumab arm and 19% (95% CI, 11%-29%) in the bevacizumab arm. Skin disorders, diarrhea, hypomagnesemia, hypokalemia, dehydration, and hypotension were more frequent in the panitumumab arm. Neutropenia was more frequent in the bevacizumab-containing arm.. Panitumumab or bevacizumab with FOLFIRI as second-line treatment had efficacy similar in patients whose disease progressed during oxaliplatin-based chemotherapy with bevacizumab, with expected toxicities. The development of more accurate biomarkers might help caregivers and patients to better choose between therapies for individual patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Salvage Therapy; Survival Rate

Reports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis.. Patients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival.. The intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months).. The simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Delivery Systems; Fluorouracil; Hepatic Artery; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

The current study aimed at improvement of treatment effects for patients with resectable metastases of colorectal cancer in the liver with a poor prognosis. Overall 437 patients were enrolled with metastatic colorectal cancer in the liver exhibiting at least one adverse factor of long-term prognosis: multiple metastases, bilobar liver metastases, large metastases, the presence of extrahepatic metastases, etc. Combined treatment was performed for 339 (78%) patients: combined treatment with adjuvant systemic chemotherapy (163 patients), combined treatment with perioperative systemic chemotherapy (54 patients), or combined treatment of perioperative regional chemotherapy (122 patients). Surgical treatment was performed in 66 (15%) patients. The remaining group of 32 (7%) patients with resectable metastases who received only systemic chemotherapy was considered separately. All liver resections were extensive due to the widespread metastases. The complication rate stood at 56%. Mortality among operated patients was 4%. Postoperative mortality and complications as well as the intraoperative blood loss were not statistically different in two groups. Adding bevacizumab to preoperative chemotherapy did not increase blood loss. After combined treatment with adjuvant chemotherapy a 5-year survival was 26 ± 4% that significantly outperforming a 5-year survival rate after surgery (17 ± 5%), after just drug treatment a 5-year survival has not been reached, and also after combined treatment with perioperative systemic chemotherapy (13 ± 5%) and not statistically significant exceeded a 5-year survival after combined treatment with perioperative regional chemotherapy (20 ±5%). Thus our study demonstrates the benefits of combined treatment with adjuvant systemic chemotherapy for resectable metastases of colorectal cancer in the liver with a poor prognosis. For initially unresectable metastases with extrahepatic manifestations of the disease treatment should be begun with systemic chemotherapy. To liver resection in the latter cases there are resorted only after the transfer of patients in operable condition.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Blood Loss, Surgical; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Prognosis; Risk Assessment; Risk Factors; Survival Analysis; Treatment Outcome

To investigate whether the immune response in colorectal liver metastases is related to progression free survival (PFS) and if this may be influenced by systemic therapy.. A retrospective central collection of tumour tissue was organised for the European Organisation for Research and Treatment of Cancer (EORTC) study 40983, where patients with colorectal liver metastases were treated by either resection alone or resection with perioperative FOLFOX. Immunostaining on whole slides was performed to recognise T-lymphocytes (CD3+, CD4+, CD8+), B-lymphocytes (CD20+), macrophages (CD68+) and mast cells (CD117+) inside the tumour, at the tumour border (TNI) and in normal liver tissue surrounding the tumour (0.5-2mm from the TNI). Immunological response was compared between treatment arms and correlated to PFS.. Tumour tissue and immune response profiles were available for 82 resected patients, 38 in the perioperative chemotherapy arm and 44 in the surgery alone arm. Baseline patient and disease characteristics were similar between the treatment arms. In response to chemotherapy, we observed increased CD3+ lymphocyte and mast cell counts inside the tumour (p<0.01), lower CD4+ lymphocytes in the normal liver tissue (p=0.02) and lower macrophage counts in normal tissue (p<0.01) and at the TNI (p=0.02). High number of CD3+ lymphocyte and mast cells, and high T-cell score were correlated with tumour regression grade (TRG). Prolonged PFS correlated with the presence of mast cells in the tumour (9.8 versus 16.5 months, Hazard ratio (HR) 0.54 p=0.03), higher CD3+ lymphocyte count at the TNI (10.8 versus 22.8 months, HR 0.57, p=0.03) and T-cell score >2 (10.8 versus 38.6 months, HR 0.51, p=0.04).. Our analyses in the context of a randomised study suggest that chemotherapy influences immune cell profiles, independent of patient characteristics. Immune responses of lymphocytes and mast cells were associated with pathological response to chemotherapy and to increased PFS. High CD3+ lymphocytes at the tumour front and intratumoural mast cells appear to be prognostic for patients with colorectal liver metastases.

Topics: Adult; Aged; Antigens, CD; Antigens, CD20; Antigens, Differentiation, Myelomonocytic; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; CD3 Complex; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Immune System; Leucovorin; Liver Neoplasms; Macrophages; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; T-Lymphocytes; Treatment Outcome

To compare the efficacy and safety of chemoembolization alone or chemoembolization combined with hepatic arterial infusion chemotherapy (HAIC), including oxaliplatin (OXA), 5-fluorouracil (5-FU) and folinic acid (CF), in inoperable hepatocellular carcinoma (HCC) without distant metastasis.. Eighty-four inoperable HCC patients were enrolled. Thirty-nine patients underwent chemoembolization alone, and the other 45 patients underwent chemoembolization + HAIC (OXA/5-FU/CF) treatment non-randomly. The progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and adverse reactions were compared between the two groups.. A significant difference in the ORR was observed between the chemoembolization alone and chemoembolization + HAIC groups. There was no statistically significant difference in DCR between the two groups. The median PFS (mPFS) showed a significant difference between the two groups. For patients with BCLC stage A/B disease, with or without vessel invasion, the chemoembolization + HAIC group showed better mPFS when compared to chemoembolization alone, but no significant difference was found in patients with BCLC stage C disease. The parameter of pain (grade III-IV) in the chemoembolization + HAIC group was increased statistically.. Chemoembolization combined with HAIC with OXA/5-FU/CF may be safe and more effective than chemoembolization alone for inoperable HCC patients without distant metastasis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chi-Square Distribution; China; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

The study 20050181 demonstrated significant improvements in progression-free survival (PFS), objective response, and a nonsignificant trend toward increased overall survival (OS) with panitumumab-FOLFIRI versus FOLFIRI alone for second-line wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Updated long-term data from a prespecified descriptive analysis are reported.. Patients receiving one prior mCRC treatment were randomly assigned (1:1) to panitumumab (6.0 mg/kg)-FOLFIRI versus FOLFIRI every 2 weeks. Co-primary end points (PFS and OS) were prospectively analyzed by tumor KRAS status.. One thousand one hundred and eighty-six patients were randomly assigned. In patients with WT KRAS tumors, panitumumab-FOLFIRI significantly improved PFS versus FOLFIRI [median 6.7 versus 4.9 months; hazard ratio (HR) 0.82 [95% confidence interval (CI) 0.69, 0.97]; P = 0.023]. A trend toward longer OS was observed (median 14.5 versus 12.5 months; HR 0.92 [95% CI 0.78, 1.10]; P = 0.37). Response rates improved from 10% to 36% (P < 0.0001). From post hoc analyses in patients receiving prior oxaliplatin-bevacizumab, panitumumab-FOLFIRI improved PFS (median 6.4 versus 3.7 months; HR 0.58 [95% CI 0.37, 0.90]; P = 0.014). PFS and OS appeared longer for worst-grade skin toxicity of 2-4, versus 0-1 or FOLFIRI. Safety results were as previously reported and consistent with the known toxicities with anti-epidermal growth factor receptor therapy.. These data confirm the primary efficacy and safety findings of this trial and support panitumumab-FOLFIRI as a second-line treatment of WT KRAS mCRC.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Panitumumab; Quality of Life; Skin Diseases; Treatment Outcome

To report the results of a phase II trial combining celecoxib and preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer.. Patients with clinical stage II or III rectal cancer were treated with radiotherapy of 44 Gy in 22 fractions. Concurrent chemotherapy consisted of oral tegafur-uracil and folinate on days 1-30 and 38-65. Celecoxib (400 mg/day) given from days 1 to 65. Surgery was done on day 70. The expression of cyclooxygenase 2 (COX-2) in tumor tissues was evaluated microscopically as a prognostic factor.. From 2008 to 2011, 53 patients completed CRT+ celecoxib therapy and 47 received radical surgery. Grade 3 diarrhea developed in 5 (9%). Grade 4 anemia was seen in 2 (4%). Pathological complete response (pCR) was seen in 6 (13%). T or N downstaging found in 38 (81%). Sphincter preservation was achieved in 77% of low-positioned tumors. Patients with tumors expressing high-level COX-2 after CRT + celecoxib treatment had inferior pelvic control (P = 0.01), disease-free survival (P = 0.04), and overall survival (P = 0.03) than those with low-level expression.. Celecoxib can be safely combined with preoperative CRT for rectal cancer. More intensified adjuvant therapy may be considered for tumors expressing high-level COX-2 after CRT and surgery.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Chemoradiotherapy, Adjuvant; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease-Free Survival; Dose Fractionation, Radiation; Female; Humans; Immunohistochemistry; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Prognosis; Pyrazoles; Rectal Neoplasms; Rectum; Sulfonamides; Tegafur; Uracil

This is a multicenter phase II study to assess the efficacy and toxicity of FOLFIRI treatment agents in full and the influence of UGT1A1*28 polymorphism in Japanese patients with advanced/metastatic colorectal cancer (mCRC).. Fifty patients with mCRC participated in this study. Treatment consisted of FOLFIRI (irinotecan; 150 mg/m(2)) as second-line chemotherapy; 34 patients consented to the evaluation of UGT1A1 genotype.. The overall response rate was 12% for all 50 evaluable patients; 31 patients (62.0%) had stable disease, and only in 12 (24.0%) did disease progress. The median progression-free survival was 5.8 months. The tolerance treatment was acceptable, with only 15 out of 50 patients (30%) experiencing grade 3/4 neutropenia, and grade 4 thrombocytopenia was observed in only one case. Grade 3 non-hematological adverse reactions included stomatitis in three, diarrhea in one, and a clinically insignificant increase in serum alkaline phosphatases in one patient, respectively. There was no definite relation between the UGT1A1*28 polymorphism and toxicity.. Standard FOLFIRI regimen can be administered to Japanese patients. The results showed good tolerability and efficacy for second-line FOLFIRI, provided that evaluation of UGT1A1 polymorphism is properly implemented before the start of the chemotherapy.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Glucuronosyltransferase; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Polymorphism, Genetic; Prognosis; Promoter Regions, Genetic; Prospective Studies; Survival Rate

Initially, unresectable colorectal liver metastases can be resected after response to chemotherapy. While cetuximab has been shown to increase response and resection rates, the survival outcome for this conversion strategy needs further evaluation.. Patients with technically unresectable and/or ≥5 liver metastases were treated with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated with regard to resectability every 2 months. Tumour response and secondary resection data have been reported previously. A final analysis of overall survival (OS) and progression-free survival (PFS) was carried out in December 2012.. Between December 2004 and March 2008, 56 patients were randomised to arm A, 55 to arm B. The median OS was 35.7 [95% confidence interval (CI) 27.2-44.2] months [arm A: 35.8 (95% CI 28.1-43.6), arm B: 29.0 (95% CI 16.0-41.9) months, HR 1.03 (95% CI 0.66-1.61), P = 0.9]. The median PFS was 10.8 (95% CI 9.3-12.2) months [arm A: 11.2 (95% CI 7.2-15.3), arm B: 10.5 (95% CI 8.9-12.2) months, HR 1.18 (95% CI 0.79-1.74), P = 0.4]. Patients who underwent R0 resection (n = 36) achieved a better median OS [53.9 (95% CI 35.9-71.9) months] than those who did not [21.9 (95% CI 17.1-26.7) months, P < 0.001]. The median disease-free survival for R0 resected patients was 9.9 (95% CI 5.8-14.0) months, and the 5-year OS rate was 46.2% (95% CI 29.5% to 62.9%).. This study confirms a favourable long-term survival for patients with initially sub-optimal or unresectable colorectal liver metastases who respond to conversion therapy and undergo secondary resection. Both FOLFOX/FOLFIRI plus cetuximab, appear to be appropriate regimens for 'conversion' treatment in patients with K-RAS codon 12/13/61 wild-type tumours. Thus, liver surgery can be considered curative or alternatively as an additional 'line of therapy' in those patients who are not cured.. NCT00153998, www.clinicaltrials.gov.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Proportional Hazards Models; Treatment Outcome

The use of adjuvant systemic chemotherapy for resectable liver metastases from colorectal cancer (CRC) is controversial because no trial demonstrated its benefit. We conducted the phase III trial to evaluate UFT/leucovorin (LV) for colorectal liver metastases (CRLM). The primary endpoint has not been available until 2014, we first report the feasibility and safety data of UFT/LV arm. In this multicenter trial, patients who underwent curative resection of liver metastases from colorectal cancer were randomly assigned to receive surgery alone or surgery followed by adjuvant chemotherapy with UFT/LV. The primary endpoint was relapse-free survival. Secondary endpoints included overall survival and safety. A total of 180 patients were enrolled, 90 were randomly assigned to receive UFT/LV therapy. Eighty two of whom were included in safety analyses. In the UFT/LV group, the completion rate of UFT/LV was 54.9%, the relative dose intensity was 70.8% and grade 3 or higher adverse events occurred in 12.2% of the patients. Elevated bilirubin levels, decreased hemoglobin levels, elevated alanine aminotransferase levels, diarrhea, anorexia were common. Most other adverse events were grade 2 or lower and tolerable. In conclusions, UFT/LV is a safe regimen for postoperative adjuvant chemotherapy in patients who have undergone resection of liver metastases from colorectal cancer. Further studies are warranted to improve completion rate, but UFT/LV is found to be a promising treatment in this setting.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Hepatectomy; Humans; Japan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Tegafur; Time Factors; Treatment Outcome; Uracil

To evaluate panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated wild-type (WT) KRAS exon 2 (codons 12 and 13) metastatic colorectal cancer (mCRC). A prespecified secondary objective was to assess treatment effects in an extended RAS analysis that included exons 2, 3, and 4 of KRAS and NRAS.. Patients with WT KRAS exon 2 tumors were randomly assigned at a one-to-one ratio to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6. The primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and safety.. Of 285 randomly assigned patients, 278 received treatment. In the WT KRAS exon 2 intent-to-treat group, PFS was similar between arms (hazard ratio [HR], 0.87; 95% CI, 0.65 to 1.17; P = .353). Median OS was 34.2 and 24.3 months in the panitumumab and bevacizumab arms, respectively (HR, 0.62; 95% CI, 0.44 to 0.89; P = .009). In the WT RAS subgroup (WT exons 2, 3, and 4 of KRAS and NRAS), PFS favored the panitumumab arm (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). Median OS was 41.3 and 28.9 months (HR, 0.63; 95% CI, 0.39 to 1.02; P = .058) in the panitumumab and bevacizumab arms, respectively. Treatment discontinuation rates because of adverse events were similar between arms.. PFS was similar and OS was improved with panitumumab relative to bevacizumab when combined with mFOLFOX6 in patients with WT KRAS exon 2 tumors. Patients with WT RAS tumors seemed to experience more clinical benefit with anti-epidermal growth factor receptor therapy.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Exons; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Organoplatinum Compounds; Panitumumab; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Rate; Young Adult

The aim of this study was the evaluation of pharmacokinetic parameters, biomarkers, clinical outcome, and imaging parameters in metastatic colorectal cancer (mCRC) patients treated with FOLFIRI plus sunitinib.. mCRC patients with liver metastases were treated with FOLFIRI and sunitinib as 1st line therapy. At protocol-defined time points, multicontrast magnetic resonance imaging (MRI)measurements, computed tomography (CT) scans, pharmacokinetics (PK), and biomarker analyses were performed during the first and second treatment cycle. Thereafter, patients were treated until tumor progression, investigator’s decision due to toxicity, or patient withdrawal.. 28 patients were screened, 26 were included, and 23 received at least one study medication. Full safety analysis was performed in 23 patients. Full PK and biomarker analyses were performed in 21 patients. Strong responses in tumor size reduction forced a change from the original imaging timing scheme. This unforeseen change in the timing scheme resulted in subgroups too small for meaningful statistical analysis of most imaging parameters. Thus, only a descriptive analysis of the MRI data was possible. In 21/22 patients, MRI showeda decrease of the liver metastases. Best response was partial remission (PR) in 8/17 patients. Plasma concentrations of sVEGFR-2 and sVEGFR-3 decreased in all patients. The majority of the patients developed some kind of toxicity not always deducible to FOLFIRI or sunitinib.. Due to the observed side effect profile, FOLFIRI plus sunitinib 37.5 mg per day cannot be recommended for previously untreated mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Indoles; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Pyrroles; Sunitinib; Tomography, X-Ray Computed; Treatment Outcome; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3

Colorectal cancer (CRC) is the second most common malignancy in Europe and a leading cause of cancer-related death. Almost 50% of patients with CRC develop liver metastases, which heralds a poor prognosis unless metastases can be downsized to surgical resection or ablation. The FOXFIRE trial examines the hypothesis that combining radiosensitising chemotherapy (OxMdG: oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-Spheres®; Sirtex Medical Limited, North Sydney, Australia) as a first-line treatment for liver-dominant metastatic CRC will improve clinical outcomes when compared to OxMdG chemotherapy alone.. FOXFIRE is an open-label, multicentre, randomised controlled trial of OxMdG with or without the addition of SIRT (1:1 randomisation). Eligible adult patients have histologically confirmed colorectal adenocarcinoma, liver metastases measurable on computed tomography scan and untreatable by either surgical resection or local ablation, and they may have limited extra-hepatic disease, defined as ≤5 nodules in the lung and/or one other metastatic site which is amenable to future definitive treatment. Eligible patients may have received adjuvant chemotherapy following resection of the primary tumour, but are not permitted to have previously received chemotherapy for metastatic disease, and must have a life expectancy of ≥3 months and a WHO performance status of 0-1. The primary outcome is overall survival. Secondary outcomes include progression free survival (PFS), liver-specific PFS, patient-reported outcomes, safety, response rate, resection rate and cost-effectiveness. FOXFIRE shares a combined statistical analysis plan with an international sister trial called SIRFLOX.. This trial is establishing a network of SIRT centres and 'feeder' chemotherapy-only centres to standardise the delivery of SIRT across the whole of the UK and to provide greater equity of access to this highly specialised liver-directed therapy. The FOXFIRE trial will establish the potential role of adding SIRT to first-line chemotherapy for unresectable liver metastatic colorectal cancer, and the impact on current treatment paradigms for metastatic CRC.. ISRCTN83867919.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Radiation-Sensitizing Agents; Radiotherapy; Yttrium Radioisotopes

The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.. In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0-1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.. From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.. The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.. http://www.clinicaltrials.gov: NCT00422773.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Maximum Tolerated Dose; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

A prospective randomized trial was conducted to compare the impact of systemic chemotherapy versus multi-modality therapy (complete cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC), and systemic chemotherapy) on overall survival (OS) in patients with gastric carcinomatosis.. Patients with measurable metastatic gastric adenocarcinoma involving the peritoneum, and resectable to "no evidence of disease" were randomized to gastrectomy, metastasectomy, HIPEC, and systemic FOLFOXIRI (GYMS arm) or FOLFOXIRI alone (SA arm).. Seventeen patients were enrolled (16 evaluable); 7 of 9 patients in the multi-modality GYMS arm achieved complete cytoreduction (CCR0). Median OS was 11.3 months in the GYMS arm and 4.3 months in the SA arm. Four patients in the GYMS arm survived >12 months, 2 patients close to 2 years at last follow-up, and 1 patient more than 4 years, with 2 of these patients still alive. No patient in the SA arm lived beyond 11 months. All patients surviving beyond 12 months in the surgery arm achieved complete cytoreduction and had an initial Peritoneal Cancer Index (PCI) of ≤ 15.. Maximal cytoreductive surgery combined with regional (HIPEC) and systemic chemotherapy in selected patients with gastric carcinomatosis and limited disease burden can achieve prolonged survival.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Cancer, Regional Perfusion; Female; Fluorouracil; Gastrectomy; Humans; Hyperthermia, Induced; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Peritoneal Neoplasms; Peritoneum; Prospective Studies; Stomach Neoplasms

Patients (pts) with metastatic rectal cancer and symptomatic primary, require local and systemic control. Chemotherapy used during chemoradiotherapy (CRT) is adequate for radiosensitisation, but suboptimal for systemic control. The aim of this phase II study was to assess tolerability, local/systemic benefits, of a novel regimen delivering interdigitating intensive chemotherapy with radical CRT.. Eligible pts had untreated synchronous symptomatic primary/metastatic rectal cancer. A total of 12 weeks of treatment with split-course pelvic CRT (total 50.4 Gy with concurrent oxaliplatin and 5-FU infusion) alternating with FOLFOX chemotherapy. All pts staged with CT, MRI and FDG-PET pre and post treatment.. Twenty-six pts were treated. Rectal primary MRI stage: T3 81% and T4 15%. Liver metastases in 81%. Twenty-four pts (92%) completed the 12-week regimen. All patients received planned RT dose, and for both agents over 88% of patients achieved a relative dose intensity of >75%. Grade 3 toxicities: neutropenia 23%, diarrhoea 15%, and radiation skin reaction 12%. Grade 4 toxicity: neutropenia 15%. FDG-PET metabolic response rate for rectal primary 96%, and for metastatic disease 60%.. Delivery of interdigitating chemotherapy with radical CRT was feasible to treat both primary and metastatic rectal cancer. High completion and response rates were encouraging.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Cohort Studies; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pelvic Neoplasms; Prognosis; Radiotherapy Dosage; Rectal Neoplasms; Survival Rate

To determine the maximum tolerated dose (MTD) and preliminary efficacy of concurrent hepatic arterial infusion (HAI) of floxuridine (FUDR) and systemic modified oxaliplatin, 5-fluorouracil and leucovorin (m-FOLFOX6) in Chinese patients with unresectable hepatic metastases from colorectal cancer.. Thirty-five patients with unresectable liver metastases with or without extrahepatic disease were treated with concurrent HAI and systemic m-FOLFOX6. HAI FUDR was delivered in a 14-day infusion with escalating dose levels, and each cycle was repeated every 4 weeks.. The MTD for FUDR was 0.12 mg/kg/day when combined with systemic m-FOLFOX6. The dose-limited toxicities were neutropenia (8.6 %), alanine aminotransferase/aspartate aminotransferase elevation (5.7 %) and diarrhea (11.4 %). The overall response rate was 68.6 % for hepatic metastases and 14.3 % for extrahepatic metastases. The median progression-free survival and overall survival were 8.23 and 25 months, respectively.. The recommended dose of FUDR was 0.12 mg/kg/day when combined with systemic m-FOLFOX6. This combination achieved a high response rate in hepatic disease and a high control rate in extrahepatic disease. Further study is needed to assess the potential additional value of HAI therapy in converting patients with hepatic metastases to candidates for resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; China; Colorectal Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Treatment Outcome; Young Adult

The EACH study assessed the efficacy of oxaliplatin, 5-fluorouracil, and leucovorin (the FOLFOX4 regimen) compared with doxorubicin alone in terms of overall survival (OS), progression-free survival (PFS), and safety in patients with advanced hepatocellular carcinoma (HCC). We present the results of this study in Chinese patients.. In a multicenter, open-label, randomized, phase III study (NCT00471965), 371 patients (279 patients from the People's Republic of China) were randomized 1:1 to receive either FOLFOX4 or doxorubicin until disease progression, intolerable toxicity, death, or surgical resection.. Baseline characteristics of the Chinese patients enrolled in the study were similar for the 2 treatment groups and in comparison with the whole EACH cohort. Median OS at the prespecified time point of treatment was 5.7 months with FOLFOX4 and 4.3 months with doxorubicin (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.55-0.98; p = .03). At the end of the follow-up period, median OS was 5.9 months with FOLFOX4 and 4.3 months with doxorubicin (HR: 0.75; 95% CI: 0.58-0.98; p = .03). Median PFS was 2.4 months and 1.7 months in the FOLFOX4 and doxorubicin groups, respectively (HR: 0.55; 95% CI: 0.45-0.78; p = .0002). The response rate (RR) and disease control rate (DCR) were significantly higher in the FOLFOX4 group than in the doxorubicin group (RR: 8.6% vs. 1.4%, p = .006; DCR: 47.1% vs. 26.6%, p = .0004). Hematological toxicity was more frequently reported in the FOLFOX4 group.. For Chinese HCC patients enrolled in the EACH study, FOLFOX4 significantly improved the RR and DCR and prolonged survival compared with doxorubicin. Systemic chemotherapy with oxaliplatin-based regimens may play an important role in the treatment of Chinese patients with advanced HCC.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma, Hepatocellular; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Survival Analysis; Treatment Outcome

A fluoropyrimidine plus irinotecan or oxaliplatin, combined with bevacizumab (a monoclonal antibody against vascular endothelial growth factor), is standard first-line treatment for metastatic colorectal cancer. Before the introduction of bevacizumab, chemotherapy with fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) showed superior efficacy as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI). In a phase 2 study, FOLFOXIRI plus bevacizumab showed promising activity and an acceptable rate of adverse effects.. We randomly assigned 508 patients with untreated metastatic colorectal cancer to receive either FOLFIRI plus bevacizumab (control group) or FOLFOXIRI plus bevacizumab (experimental group). Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression. The primary end point was progression-free survival.. The median progression-free survival was 12.1 months in the experimental group, as compared with 9.7 months in the control group (hazard ratio for progression, 0.75; 95% confidence interval [CI], 0.62 to 0.90; P=0.003). The objective response rate was 65% in the experimental group and 53% in the control group (P=0.006). Overall survival was longer, but not significantly so, in the experimental group (31.0 vs. 25.8 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 1.00; P=0.054). The incidences of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia were significantly higher in the experimental group.. FOLFOXIRI plus bevacizumab, as compared with FOLFIRI plus bevacizumab, improved the outcome in patients with metastatic colorectal cancer and increased the incidence of some adverse events. (Funded by the Gruppo Oncologico Nord Ovest and others; ClinicalTrials.gov number, NCT00719797.).

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

In colorectal cancer (CRC), unresectable liver metastases are linked to poor prognosis. Systemic chemotherapy with regimens such as FOLFOX (combination of infusional 5-fluorouracil, leucovorin and oxaliplatin) is the standard first-line treatment. The SIRFLOX trial was designed to assess the efficacy and safety of combining FOLFOX-based chemotherapy with Selective Internal Radiation Therapy (SIRT or radioembolisation) using yttrium-90 resin microspheres (SIR-SpheresR; Sirtex Medical Limited, North Sydney, Australia).. SIRFLOX is a randomised, multicentre trial of mFOLFOX6 chemotherapy+/-SIRT as first-line treatment of patients with liver-only or liver-predominant metastatic CRC (mCRC). The trial aims to recruit adult chemotherapy-naive patients with proven liver metastases with or without limited extra-hepatic disease, a life expectancy of >=3 months and a WHO performance status of 0-1. Patients will be randomised to receive either mFOLFOX6 or SIRT+mFOLFOX6 (with a reduced dose of oxaliplatin in cycles 1-3 following SIRT). Patients in both arms can receive bevacizumab at investigator discretion. Protocol chemotherapy will continue until there is unacceptable toxicity, evidence of tumour progression, complete surgical resection or ablation of cancerous lesions, or the patient requests an end to treatment. The primary endpoint of the SIRFLOX trial is progression-free survival (PFS). Secondary endpoints include: PFS in the liver; tumour response rate (liver and any site); site of tumour progression; health-related quality of life; toxicity and safety; liver resection rate; and overall survival. Assuming an increase in the median PFS from 9.4 months to 12.5 months with the addition of SIRT to mFOLFOX6, recruiting >=450 patients will be sufficient for 80% power and 95% confidence.. The SIRFLOX trial will establish the potential role of SIRT+standard systemic chemotherapy in the first-line management of mCRC with non-resectable liver metastases.. SIRFLOX ClinicalTrials.gov identifier: NCT00724503. Registered 25 July 2008.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Microspheres; Organoplatinum Compounds; Yttrium Radioisotopes

Targeted agents presently available for mutant KRAS metastatic colorectal cancer (mCRC) are bevacizumab and aflibercept. We evaluated the efficacy and safety of conatumumab (an agonistic monoclonal antibody against human death receptor 5) and ganitumab (a monoclonal antibody against the type 1 insulin-like growth factor receptor) combined with standard FOLFIRI chemotherapy as a second-line treatment in patients with mutant KRAS mCRC.. Patients with mutant KRAS metastatic adenocarcinoma of the colon or rectum refractory to fluoropyrimidine- and oxaliplatin-based chemotherapy were randomized 1 : 1 : 1 to receive intravenous FOLFIRI plus conatumumab 10 mg/kg (Arm A), ganitumab 12 mg/kg (Arm B), or placebo (Arm C) Q2W. The primary end point was progression-free survival (PFS).. In total, 155 patients were randomized. Median PFS in Arms A, B, and C was 6.5 months (HR, 0.69; P = 0.147), 4.5 months (HR, 1.01; P = 0.998), and 4.6 months, respectively; median overall survival was 12.3 months (HR, 0.89; P = 0.650), 12.4 months (HR, 1.27; P = 0.357), and 12.0 months; and objective response rate was 14%, 8%, and 2%. The most common grade ≥3 adverse events in Arms A/B/C included neutropenia (30%/25%/18%) and diarrhea (18%/2%/10%).. Conatumumab, but not ganitumab, plus FOLFIRI was associated with a trend toward improved PFS. Both combinations had acceptable toxicity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Genotype; Humans; Insulin-Like Growth Factor Binding Proteins; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Receptors, IgG; Treatment Outcome

This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer (mCRC).. Patients were randomized to sorafenib (400 mg b.i.d.) or placebo, combined with mFOLFOX6 (oxaliplatin 85 mg/m(2); levo-leucovorin 200 mg/m(2); fluorouracil 400 mg/m(2) bolus and 2400 mg/m(2) continuous infusion) every 14 days. Primary endpoint was progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power (two-sided α = 0.20) to detect an HR = 0.65.. Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR = 0.88; 95% CI, 0.64-1.23; P = 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival showed no difference between treatment arms by KRAS or BRAF status (mutant and wild type). The most common grade 3/4 adverse events in the sorafenib and placebo arms were neutropenia (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand-foot skin reaction (20% vs. 0%). Treatment discontinuation because of adverse events was 9% and 6%, respectively. Generally, dose intensity (duration and cumulative doses) was lower in the sorafenib arm than in the placebo arm.. This study did not detect a PFS benefit with the addition of sorafenib to first-line mFOLFOX6 for mCRC. KRAS and BRAF status did not seem to impact treatment outcomes but the subgroups were small. These results do not support further development of sorafenib in combination with mFOLFOX6 in molecularly unselected patients with mCRC.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neutropenia; Niacinamide; Organoplatinum Compounds; Oxaliplatin; Phenylurea Compounds; Sorafenib; Treatment Outcome

Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. The aim of this study was to assess the feasibility and activity of bevacizumab plus FOLFIRI in this setting.. Patients aged 18-75 years, PS 0-1, with resectable liver-confined metastases from CRC were eligible. They received bevacizumab 5 mg kg(-1) followed by irinotecan 180 mg m(-)(2), leucovorin 200 mg m(-)(2), 5-fluorouracil 400 mg m(-)(2) bolus and 5-fluorouracil 2400 mg m(-)(2) 46-h infusion, biweekly, for 7 cycles. Bevacizumab was stopped at cycle 6. A single-stage, single-arm phase 2 study design was applied with 1-year progression-free rate as the primary end point, and 39 patients required.. From October 2007 to December 2009, 39 patients were enrolled in a single institution. Objective response rate was 66.7% (95% exact CI: 49.8-80.9). Of these, 37 patients (94.9%) underwent surgery, with a R0 rate of 84.6%. Five patients had a pathological complete remission (14%). Out of 37 patients, 16 (43.2%) had at least one surgical complication (most frequently biloma). At 1 year of follow-up, 24 patients were alive and free from disease progression (61.6%, 95% CI: 44.6-76.6). Median PFS and OS were 14 (95% CI: 11-24) and 38 (95% CI: 28-NA) months, respectively.. Preoperative treatment of patients with resectable liver metastases from CRC with bevacizumab plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Survival Rate

This randomized phase II study investigated first-line chemotherapy plus cetuximab administered every second week in KRAS wild-type metastatic colorectal cancer.. Patients received FOLFOX4 plus either standard weekly cetuximab (arm 1) or cetuximab (500 mg/m(2)) every second week (arm 2), until disease progression or unacceptable toxicity. Primary end point was the objective response rate (ORR). Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety were also investigated. The study was not powered to establish non-inferiority, but aimed at the estimation of treatment differences.. Of 152 randomized eligible patients, 75 were treated in arm 1 and 77 in arm 2; ORRs [53% versus 62%, odds ratio 1.40, 95% confidence interval (CI) 0.74-2.66], PFS [median 9.5 versus 9.2 months, hazard ratio (HR) 0.92, 95% CI 0.63-1.34], OS (median 25.8 versus 23.0 months, HR 0.86, 95% CI 0.56-1.30) and DCR (87%) were comparable. HRs adjusted for baseline factors were 1.01 and 0.99 for PFS and OS, respectively. Frequencies of grade 3/4 adverse events in arms 1 versus 2 were similar: most common were neutropenia (28% versus 34%) and rash (15% versus 17%).. Activity and safety of FOLFOX4 plus either cetuximab administered weekly or every second week were similar.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Genotype; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

To assess the effects of cetuximab plus chemotherapy as first-line treatment for unresectable colorectal liver metastases (CLMs).. After resection of their primary tumors, patients with KRAS wild-type synchronous nonresectable liver-limited metastases from colorectal cancer were randomly assigned to receive chemotherapy (FOLFIRI [fluorouracil, leucovorin, and irinotecan] or mFOLFOX6 [modified fluorouracil, leucovorin, and oxaliplatin]) plus cetuximab (arm A) or chemotherapy alone (arm B). The primary end point was the rate of patients converted to resection for liver metastases. Secondary end points included tumor response and survival.. The intent-to-treat population comprised 138 patients; 70 patients were randomly assigned to arm A and 68 to arm B. After a median of 25.0 months of follow-up, the 3-year overall survival (OS) rate and median survival time (MST) for all patients were 30% and 24.4 months, respectively. The R0 resection rates for liver metastases were 25.7% (18 of 70 patients) in arm A and 7.4% (five of 68 patients) in arm B, which were significantly different (P < .01). Patients in arm A had improved objective response rates (57.1% v 29.4%; P < .01), increased 3-year OS rate (41% v 18%; P = .013) and prolonged MST (30.9 v 21.0 months; P = .013) compared with those in arm B. In addition, in arm A, patients who had resection of liver metastases had a significantly improved MST (46.4 v 25.7 months; P < .01) compared with those who did not undergo surgery.. For patients with initially unresectable KRAS wild-type CLMs, cetuximab combined with chemotherapy improved the resectability of liver metastases and improved response rates and survival compared with chemotherapy alone.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Cetuximab; China; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Research Design; Treatment Outcome

Despite median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit, and these patients are candidates for second-line treatment.. The objective of this study is to evaluate the efficacy and safety of oxaliplatin plus 5-fluorouracil and folinic acid in patients with gemcitabine-pretreated advanced pancreatic cancer.. Thirty patients with advanced pancreatic cancer who were pretreated with gemcitabine received oxaliplatin (85 mg/m(2)) on days 1 and 15 followed by leucovorin (20 mg/m(2)) and 5-fluorouracil (500 mg/m(2)) on days 1, 8, and 15. The cycle was repeated every 3 weeks.. The majority of patients (80 %) had locally advanced disease. Median age was 63 years, and 60 % were males. The liver was the most common site of metastasis. Partial response was observed in 2 patients (6.7 %) and stable disease in 6 patients (20 %), while 12 patients progressed (40 %). Improved performance status was reported in 10 patients (33.3 %). The median duration of response was 13 weeks, and median overall survival was 22 weeks. There was no grade 4 toxicity apart from grade 4 neutropenia in 6.6 % of patients. Neutropenia (46.5 %) and neuropathy (43.2 %) were the most common toxicities, while hand-foot syndrome was the least frequent one (20 %). There were no treatment-related deaths. The 6-month survival rate was 30 %.. This regimen is feasible and active with an acceptable toxicity; however, further investigation in phase III trial is needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prognosis; Survival Rate

Liver resection may offer the only chance of cure in patients with colorectal cancer with liver metastases. In the unresectable cases, neoadjuvant chemotherapy could render curability if resectability could be achieved.. Newly diagnosed K-RAS wild-type colorectal cancer patients with unresectable liver-only metastases were treated with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) plus cetuximab every 2 weeks for a maximum of 12 cycles. Clinical response was evaluated every 6 weeks, and surgery was performed at the physician's discretion in patients with sufficient tumor shrinkage, followed by chemotherapy with the same regimen, to complete a total of 12 cycles. The primary endpoint was an overall R0 resection rate.. Between July 2008 and December 2009, 73 patients were registered from 11 Korean centers. Among 53 (73 %) patients who showed at least partial response, surgery with curative intent was attempted in 36 (49 %) patients. Intention-to-treat analysis revealed a R0 resection rate of 27 % (20/73) including 8 patients whose unresectable liver metastases were successfully treated with radiofrequency ablation (RFA). The most common grade 3 and 4 toxicity was neutropenia (50/462 cycles, 10.7 %). Median time to progression (TTP) was 9.8 months (range 0.5-31.8) in all patients, but we observed TTP of 14.1 months (range 1.3 to -30.8) in patients who received R0 resection and RFA + R0 resection.. Neoadjuvant chemotherapy with FOLFOX6 plus cetuximab showed high response rates and increased the resectability in colorectal patients with non-resectable liver-only metastases.

Topics: Ablation Techniques; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Intention to Treat Analysis; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neutropenia; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Severity of Illness Index; Tumor Burden

Continuous treatment with FOLFOX therapy is associated with peripheral nerve toxicity, and to improve this inconvenient side effect various methods of administration are being investigated. A regimen of intermittent oxaliplatin administration by continuous infusion therapy, i.e., modified FOLFOX7 (mFOLFOX7) + bevacizumab, was designed with the goal of alleviating severe peripheral nerve disorders and hematological toxicity. A phase II clinical study was conducted to evaluate the efficacy and safety of this regimen.. Previously untreated patients were assigned to mFOLFOX7 (oxaliplatin 85 mg/m(2), levofolinate [l-LV] 200 mg/m(2), 5-fluorouracil [5-FU] 2400 mg/m(2)) + bevacizumab (5 mg/kg) administered every 2 weeks for 8 cycles, maintenance without oxaliplatin for 8 cycles, and reintroduction of mFOLFOX7 + bevacizumab for 8 cycles or until disease progression. Progression free survival (PFS) following the first dose (PFS 1) and following reintroduction of oxaliplatin (PFS 2) were used as indices for assessing the efficacy of intermittent administration.. Fifty-two patients were enrolled, with median age of 64 years (range, 36-74). Median PFS 1 was 11.8 months (95 % confidence interval [CI], 9.5 to 13.7), median time to treatment failure was 10.3 months (95 % CI, 5.6 to 12.1), percentage of patients with neutropenia of grade 3 or higher was 7.8 %, and percentage with peripheral nerve disorders was 3.9 %. Response rate was 50 %, and 84.4 % of patients who started modified simplified LV5FU2 + bevacizumab were reintroduced to oxaliplatin.. By excluding 5-FU bolus administration and administering bevacizumab continuously the mFOLFOX7 + bevacizumab regimen with preplanned withdrawal of oxaliplatin showed high tolerability and prevented severe peripheral neuropathy and neutropenia without reducing efficacy.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Peritoneal Neoplasms; Treatment Outcome

Hepatic arterial infusion (HAI) of chemotherapy requires the implantation of a transcatheter application system which is traditionally performed by surgery. This procedure, but particularly the adjacent drug application via pump or port is often hampered by specific complications and device failure. Interventionally implanted port catheter systems (IIPCS) facilitate the commencement of HAI without need for laparatomy, and are associated with favorable complication rates. We here present an evaluation of the most important technical endpoints associated with the use of IIPCS for HAI in patients with primary liver cancers.. 70 patients (pts) with hepatocellular (HCC, n=33) and biliary tract cancer (BTC, n=37) were enrolled into a phase II -study. Of those, n=43 had recurrent disease and n=31 suffered from liver-predominant UICC-stage IVb. All pts were provided with IIPCSs before being treated with biweekly, intraarterial chemotherapy (oxaliplatin, 5-Flourouracil, folinic acid). The primary objective of the trial was defined as evaluation of device-related complications and port duration.. Implantation of port catheters was successful in all patients. Mean treatment duration was 5.8 months, and median duration of port patency was not reached. Disease-progression was the most common reason for treatment discontinuation (44 pts., 63%), followed by chemotherapy-related toxicity (12 pts., 17%), and irreversible device failure (5 pts., 7%). A total of 28 port complications occurred in 21 pts (30%). No unexpected complications were observed.. HAI via interventionally implanted port catheters can be safely applied to patients with primary liver tumors far advanced or/and pretreated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Catheterization; Catheters; Cholangiocarcinoma; Disease Progression; Equipment Failure; Female; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Withholding Treatment

To determine whether FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) administered as palliative chemotherapy to patients with advanced hepatocellular carcinoma (HCC) provides a survival benefit and efficacy versus doxorubicin.. This multicenter, open-label, randomized, phase III study in mainland China, Taiwan, Korea, and Thailand involved 371 patients age 18 to 75 years who had locally advanced or metastatic HCC and were ineligible for curative resection or local treatment. They were randomly assigned at a ratio of one to one to receive either FOLFOX4 (n = 184) or doxorubicin (n = 187). The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR) by RECIST (version 1.0), and safety.. At the prespecified final analysis, median OS was 6.40 months with FOLFOX4 (95% CI, 5.30 to 7.03) and 4.97 months with doxorubicin (95% CI, 4.23 to 6.03; P = .07; hazard ratio [HR], 0.80; 95% CI, 0.63 to 1.02). Median PFS was 2.93 months with FOLFOX4 (95% CI, 2.43 to 3.53), and 1.77 months with doxorubicin (95% CI, 1.63 to 2.30; P < .001; HR, 0.62; 95% CI, 0.49 to 0.79). RR was 8.15% with FOLFOX4 and 2.67% with doxorubicin (P = .02). On continued follow-up, the trend toward increased OS with FOLFOX4 was maintained (P = .04; HR, 0.79; 95% CI, 0.63 to 0.99). Toxicity was consistent with previous experiences with FOLFOX4; proportions of grade 3 to 4 adverse events were similar between treatments.. Although the study did not meet its primary end point, the trend toward improved OS with FOLFOX4, along with increased PFS and RR, suggests that this regimen may confer some benefit to Asian patients, but an OS benefit cannot be concluded from these data.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Doxorubicin; Female; Fluorouracil; Follow-Up Studies; Humans; International Agencies; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Prospective Studies; Survival Rate; Young Adult

There was conducted an assessment of the effectiveness of a combination of systemic and regional modes of chemotherapy versus systemic chemoinfusion in treatment of 70 patients with unresectable metastases of colorectal cancer in the liver after extrahepatic progression of a disease. The use of combined therapy statistically significantly increased overall survival more than doubled as compared to a group of systemic chemotherapy (median 10 vs. 4.5 months, p = 0.002) as well as the time before intrahepatic progression (median 5.9 vs. 3.5 months, p = 0.01). In addition, there was a trend toward a greater frequency of objective responses in the combination therapy group 18% in comparison with 9.7% in the systemic chemotherapy group (p = 0.49) but the difference was not statistically significant and it needed further study on more clinical material.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Disease Progression; Doxorubicin; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Organoplatinum Compounds; Quinazolines; Thiophenes; Treatment Outcome

The purpose of this multicenter phase II study was to evaluate the efficacy and safety of a combination of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) plus bevacizumab as first-line chemotherapy in Japanese patients with metastatic colorectal cancer.. Patients with metastatic colorectal cancer were eligible for enrollment. On day 1 of a 14-day cycle, patients received bevacizumab 5 mg/kg, irinotecan 150 mg/m², and L-leucovorin 200 mg/m² as an intravenous infusion, followed by 5-FU 400 mg/m² as an intravenous bolus and then 5-FU 2,400 mg/m² as an 46-h intravenous infusion. This treatment cycle was repeated. The primary endpoint was progression-free survival (PFS).. We enrolled 40 patients, but one withdrew consent before starting treatment. The remaining 39 patients received a total of 509 cycles of FOLFIRI plus bevacizumab (median 11 per patient; range 1-30). The median PFS was 11.5 months, the median overall survival (OS) was 22.0 months, and the 1-year OS rate was 81.8 %. All 39 patients had adverse events. Grade 3 or 4 neutropenia and stomatitis occurred in 21 (53.9 %) and 4 (10.3 %) patients, respectively.. Our results suggest that FOLFIRI plus bevacizumab is a clinically effective regimen with a manageable toxicity profile as first-line chemotherapy in patients with metastatic colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Incidence; Japan; Leucovorin; Leukopenia; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Stomatitis; Survival Analysis

Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up.. This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18-80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m(2), folinic acid 200 mg/m(2) (DL form) or 100 mg/m(2) (L form) on days 1-2 plus bolus, and fluorouracil 400 mg/m(2) (bolus) and 600 mg/m(2) (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients.. Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6-9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68-1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0-83·4) in the perioperative chemotherapy group and 54·3 months (41·9-79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6-58·3) in the perioperative chemotherapy group versus 47·8% (40·3-55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment.. We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients.. Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Europe; Female; Fluorouracil; Hepatectomy; Hong Kong; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Time Factors; Treatment Outcome

Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients.. We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline.. Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002).. As front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.

Topics: Adult; Aged; Aged, 80 and over; Angiopoietin-2; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Middle Aged; Treatment Outcome

Neoadjuvant chemotherapy for unresectable colorectal liver metastases can reduce tumor size, which sometimes leads to curative resection. The aim of the present study was to identify and describe patients with initially unresectable liver-only metastases from colorectal cancer who obtained sufficient chemotherapeutic benefit that eventually lead to the removal of the metastatic diseases in the liver.. A phase II multicenter cooperative study was conducted in 38 medical institutions using modified FOLFOX6 (mFOLFOX6) as neoadjuvant chemotherapy from January 2008 to June 2009. Patients with liver-only metastases from colorectal cancer that was deemed not optimally resectable by liver surgeons received mFOLFOX6 as preoperative neoadjuvant chemotherapy for 6-8 cycles. Patients were reassessed for resectability after 6 cycles of mFOLFOX6. Surgery was carried out 3-6 weeks after chemotherapy. The primary endpoint was the rate of macroscopic curative surgery including liver resection.. 36 patients (23 male/13 female, ECOG performance status 0-1) were enrolled. The median age of the patients was 62.5 years; 78% (28 patients) had 5 or more metastatic tumors, and 50% (18 patients) had metastatic tumors over 5 cm diameter. The mFOLFOX6 regimen was safety administered resulting in 18 partial responses (50%), 12 stable disease, and 4 progressive disease. There was no grade 3/4 neurotoxicity. Fourteen patients (38.9%) underwent surgery (R0: 13; R1: 1). Of these, thirteen patients (36.1%) underwent R0 surgery.. Our data suggest that mFOLFOX6 has a high response rate in patients with liver-only metastases from colorectal cancer, allowing for R0 resection of liver metastases in a proportion of patients initially not judged to be optimally resectable.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Humans; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Survival Rate

Selective internal radiation therapy (SIRT) with yttrium-90 (Y) microspheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio for treatment of colorectal cancer liver metastases. The aim of this study was to investigate the objective responses obtained by Y microsphere treatment when combined with contemporary chemotherapy in the front-line (first or second line) setting in patients with CRCLM.. This study used an in vivo comparison between the right and left liver lobes; systemic chemotherapy was supplied to both liver lobes by virtue of systemic administration, whereas SIRT was administered selectively to the target liver lobe only. Response to treatment was evaluated by serial fludeoxyglucose positron emission tomography computed tomography performed at 4 weeks, 2 to 4 months, and 6 to 8 months. Standard uptake value, anatomic volume, functional tumor volume, and total lesion glycolysis (TLG) calculations were obtained at each time point.. A decrease in TLG on fludeoxyglucose positron emission tomography computed tomography imaging was seen in 19 of the 20 patients. The mean decrease in TLG values in the tumors receiving chemo-SIRT and chemo-only treatment were 86.26%±18.57% and 31.74%±80.99% (P<0.01), 93.13%±11.81% and 40.80%±73.32% (P=0.01), and 90.55%±19.75% and 54.91%±38.55% (P<0.01) at 4 weeks, 2 to 4 months, 6 to 8 months posttreatment, respectively. Functional and anatomic tumor volume changes were in concordance with the TLG changes.. The study demonstrated that, under near identical conditions in terms of patient and tumor characteristics, the chemo-SIRT combination produced superior objective responses compared with chemo-only treatment in a front-line treatment setting in patients with colorectal cancer liver metastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Brachytherapy; Camptothecin; Chemoradiotherapy; Colorectal Neoplasms; Female; Fluorodeoxyglucose F18; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; Tomography, X-Ray Computed; Yttrium Radioisotopes

We conducted a retrospective cohort study to compare 2 different chemotherapy regimens for advanced biliary tract cancer (BTC).. Records of patients consecutively treated in our institution for advanced BTC from 2001 to 2006 were retrieved. Chemotherapy treatment with FOLFOX-4 regimen was routinely offered as first option; gemcitabine (GEM) as single agent was proposed as an alternative option to patients who refused central venous catheter implantation. Toxicity, overall response rate, progression-free survival (PFS), and overall survival (OS) obtained with the 2 treatments were evaluated.. Twenty-two patients were treated with FOLFOX-4, whereas 18 patients received GEM. In the FOLFOX-4 group, the overall response rate was 13.6% (95% confidence interval [CI], 4.7-33.3), with 1 complete response and 2 partial responses, and 54.5% (95% CI, 34.7-73.1) of disease control rate (complete response+partial response+stable disease). Median OS was 14.1 months (95% CI, 9.1-18.8) and median PFS 5.44 months (95% CI, 3.2-6.3). In the GEM group, we observed no objective response, whereas 27.7% (95% CI, 12.5-50.9) obtained disease control. Median OS was 8.3 months (95% CI, 4.7-12.9) and median PFS 3.9 months (95% CI, 2.2-5.4). Toxicity, mainly hematological, was acceptable for both treatments. On a multivariable Cox model including a propensity score, only the performance status and chemotherapy regimen were confirmed as strong predictors of OS, with an hazard ratio of 0.49 (95% CI, 0.24-0.99) in favor of FOLFOX-4.. The combination chemotherapy with oxaliplatin and 5-fluorouracil is well tolerated and seems to provide prolonged survival than GEM alone in advanced BTC treatment, but further randomized trials are warranted.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Bone Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Retrospective Studies; Survival Rate; Young Adult

Two identical randomized controlled trials designed to optimize adjuvant treatment of colon cancer (CC) (n =855) and rectal cancer (RC) (n = 796) were performed. Long-term evaluation confirmed that the addition of folinic acid (FA) to 5-fluorouracil (5-FU) improved 7-year overall survival (OS) in CC but not in RC and revealed different patterns of recurrence in patients with CC and those with RC.. Our aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU).. We separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon-alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation.. Median follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5-FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5-61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525).. FA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Immunologic Factors; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Peritoneal Neoplasms; Prognosis; Prospective Studies; Rectal Neoplasms; Survival Rate

To report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol.. A fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m(2), 65 mg/m(2), and 80 mg/m(2). In phase II, tumor response, toxicity, and survival times were assessed.. The study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m(2). In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval [CI], 4.06-13.5 mo) and 21.1 months (95% CI, 8.37-33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%).. This study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m(2) mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.

Topics: Absorbable Implants; Aged; Antineoplastic Combined Chemotherapy Protocols; Catheterization, Peripheral; Chemoembolization, Therapeutic; Cisplatin; Colorectal Neoplasms; Drug Combinations; Embolization, Therapeutic; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Organoplatinum Compounds; Powders; Radiography; Starch; Treatment Failure; Treatment Outcome

Recently, analysis of tumor antigens using micro-arrays has revealed upregulation of cancer-testis antigens RNF43 and TOMM34 and vascular endothelial growth factor receptors VEGFR1 and VEGFR2 in colorectal cancer. A phase I clinical trial of peptide vaccine therapy together with oral anticancer drugs was conducted to treat advanced colorectal cancer using synthesized peptides of these tumor antigens in order to confirm the safety, immunogenicity and activity of this treatment. The subjects were patients with a human leukocyte antigen (HLA) type of A2402 who had inoperable colorectal cancer but had failed to respond to or were unable to undergo standard chemotherapy. Four peptides (RNF43, TOMM34, VEGFR1 and VEGFR2) were emulsified with incomplete Freund's adjuvant (Montanide), and the resulting solution was administered subcutaneously once a week. Patients received the oral anticancer drug tegafur-uracil plus leucovorin for four weeks continuously as part of one course followed by one week of rest. The primary endpoint of the trial was observation of adverse events as determined by the NCI-CTCAE criteria, and the secondary endpoints were the size of the tumor and the number of cytotoxic T lymphocytes (CTLs) in the peripheral blood after treatment. Vaccine therapy was administered 148 times to 10 patients from July 2008 to December 2009. The adverse events were grade 1 redness and induration, a grade 2 skin ulcer at the vaccination site and grade 1 pyrexia. All patients tolerated treatment. Tumor imaging revealed that after 1 course of treatment 1 patient had partial response (PR), 7 had stable disease (SD) and 2 had progressive disease. A CTL assay of 10 patients revealed an increase in peptide-specific CTLs in patients with PR and SD, and the clinical responses of those patients were observed. Kaplan‑Meier analysis indicated that patients who had a strong CTL reaction had a tendency to have longer progression‑free survival and overall survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Humans; Immunotherapy, Active; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; T-Lymphocytes, Cytotoxic; Tegafur; Treatment Outcome; Uracil; Vaccines, Subunit

This phase 2 study evaluated trebananib (AMG 386), an investigational peptide-Fc fusion protein that neutralises the interaction between angiopoietins-1/2 and the Tie2 receptor, plus FOLFIRI as second-line treatment for patients with metastatic colorectal cancer.. Patients had adenocarcinoma of the colon or rectum with progression within 6 months of receiving only one prior fluoropyrimidine/oxaliplatin-based chemotherapy regimen for metastatic disease. All patients received FOLFIRI and were randomised 2:1 to also receive intravenous trebananib 10 mg kg(-1) once weekly (QW) (Arm A) or placebo QW (Arm B). The primary end point was investigator-assessed progression-free survival (PFS).. One hundred and forty-four patients were randomised (Arms A/B, n=95/49). Median PFS in Arms A and B was 3.5 and 5.2 months (hazard ratio (HR) 1.23; 95% CI, 0.81-1.86; P=0.33) and median overall survival (OS) was 11.9 and 8.8 months, respectively (HR 0.90; 95% CI; 0.53-1.54; P=0.70). Objective response rate (ORR) was 14% and 0% in Arms A and B, respectively. Incidence of grade ≥3 adverse events was similar between treatment arms (Arm A, 61%; Arm B, 65%) and included pulmonary embolism (1%/4%), deep vein thrombosis (5%/2%), and hypertension (1%/0%).. Administration of trebananib plus FOLFIRI did not prolong PFS compared with placebo plus FOLFIRI. Toxicities were manageable and consistent with those known for FOLFIRI and trebananib.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Double-Blind Method; Female; Fluorouracil; Humans; International Agencies; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis; Recombinant Fusion Proteins; Salvage Therapy; Survival Rate; Young Adult

The aim of this phase II study was to investigate the efficacy and safety of oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic breast cancer (MBC) patients heavily pretreated with anthracyclines, taxanes, vinorelbine, gemcitabine, and capecitabine. Sixty-two women who had received at least 3 above-mentioned drug classes were treated with oxaliplatin 85 mg/m(2) as a 2-h infusion on day 1, LV 200 mg/m(2) as a 2-h infusion followed by bolus 5-FU 400 mg/m(2) on day 1, and a continuous infusion of 5-FU 1,200 mg/m(2) for 44 h. The median patient age was 52 years with a median of two involved organs, and the metastases were mostly in the lung (53.2%), lymph nodes (51.6%), and liver (45.2%). Patients had a median of three prior chemotherapy regimens. Forty-five patients (72.6%) had prior exposure to all 5 classes of drugs. Based on an intention-to-treat analysis, 60 patients were assessable for responses and 11 patients achieved a partial response (PR), giving an overall response rate (ORR) of 18.3%. Twenty-one (35%) patients had stable disease (SD), and of these, 8 achieved long SD (13.3%). The median progression-free survival (PFS) was 3 months, and the median overall survival (OS) was 10 months. Toxicity was mild to moderate with grade 3 or 4 neutropenia, thrombocytopenia, and neuropathy occurring in 14 (22.6%), 9 (14.5%), and 3 (4.8%) patients, respectively. The study demonstrated that the combination of oxaliplatin plus 5-FU/LV was a well-tolerated salvage regimen with moderate activity in patients with heavily pretreated MBC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Salvage Therapy; Survival Rate; Young Adult

Patients with multiple liver metastases from colorectal cancer are at high risk of recurrence after resection. Hepatic artery infusion (HAI) alternating with systemic therapy after surgical resection may improve survival after surgery.. Patients with liver-only metastases from colorectal cancer amenable to resection/cryoablation were eligible. Previous adjuvant chemotherapy for a completely resected primary tumor was allowed. Alternating courses of HAI and systemic therapy included floxuridine (FUDR) by HAI. Systemic chemotherapy consisted of bolus leucovorin (LV) plus 5-fluorouracil (5-FU).. Forty-nine patients had complete resection of their liver metastases, with 44% having more than 4 hepatic metastases and 78% having bilobar disease. Thirty-six patients had HAI FUDR alternating with systemic therapy. Patients received a median of 3.5 cycles (range, 1-4) and 3 cycles (range, 0-6) of therapy with HAI FUDR and systemic therapy, respectively. At the time of final analysis the estimated median disease-free survival and hepatic disease-free survival was 1.2 years (95% confidence interval [CI], 0.9-2.1) and 1.8 years (95% CI, 1.8-not available), respectively. Eleven patients (31%) were alive at this writing. All surviving patients had a minimum of 5.5 years of follow-up.. This trial of adjuvant chemotherapy in patients who underwent complete resection with unfavorable characteristics demonstrates apparent improvement in outcome compared with historical series treated with surgery alone. However the results of this trial and other randomized trials of HAI do not appear to support its use at this time because of the development of more effective systemic options.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Cryosurgery; Female; Floxuridine; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Metastasectomy; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Survival Rate; Treatment Outcome

Bevacizumab (BV) is an antivascular endothelial growth factor antibody. When administered with other chemotherapeutic drugs, BV-combined regimens prolong survival of colorectal cancer patients. We conducted a phase II trial to confirm the pharmacokinetic parameters from 3-Tesla dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as surrogate biomarkers of BV + FOLFIRI regimen efficacy in colorectal cancer with liver metastases. DCE-MRI was performed before treatment, on the seventh day after first treatment and every 8 weeks thereafter using a 3-Tesla MRI system. DCE-MRI parameters-area under the contrast concentration versus time curve at 90 and 180 s (AUC90 and AUC180, respectively) after contrast injection, and volume transfer constant of contrast agents (K(trans) and K(ep) ) were calculated from liver metastases. Fifty-eight liver metastases were analyzed. Univariate analysis revealed that a decrease in K(trans) ratios (ΔK(trans) ), K(ep) ratios (ΔK(ep) ), AUC90 ratios (ΔAUC90) and AUC180 ratios (ΔAUC180) correlated with higher response (all p < 0.0001) and longer time to progression (TTP) (ΔK(trans) : p = 0.001; ΔK(ep) : p = 0.004; ΔAUC90: p = 0.006; ΔAUC180: p < 0.0001). Multivariate analysis showed that ΔAUC180 was correlated with higher response (p = 0.009), and ΔK(trans) and ΔAUC180 were correlated with longer TTP (ΔK(trans) : p = 0.001; ΔAUC180: p = 0.024). ΔK(trans) and ΔAUC180 are pharmacodynamic biomarkers of the blood perfusion of BV + FOLFIRI. Our data suggest that ΔK(trans) and ΔK(ep) can predict response to chemotherapy at 1 week. Changes in 3-Tesla DCE-MRI parameters confirmed the potential of these biomarkers of blood perfusion as surrogate predictors of response and TTP.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Contrast Media; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Treatment Outcome

This prospective phase II study assessed the efficacy and safety of bevacizumab plus chemotherapy regimens commonly used in the second-line treatment of metastatic colorectal cancer (mCRC).. Patients with mCRC who progressed or relapsed after first-line oxaliplatin-based or irinotecan-based treatment received bevacizumab 2.5 mg/kg/week plus chemotherapy until disease progression. The primary endpoint was disease-control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.. Fifty-three patients (66% men; median age, 62 years old) received second-line bevacizumab plus folinic acid, fluorouracil, and irinotecan (FOLFIRI; 57%), folinic acid, fluorouracil, oxaliplatin (FOLFOX; 26%), irinotecan (15%), or capecitabine plus irinotecan (XELIRI; 2%). The DCR was 87% (95% CI, 77%-97%); ORR was 32% (95% CI, 19%-46%). Median PFS was 6.5 months (95% CI, 5.8-7.8 months) and median OS 19.3 months, (95% CI, 14.2-25.1 months).The most frequent grade 3/4 adverse events included neutropenia (21%), diarrhea (15%), asthenia, and vomiting (9% each). Five patients (9%) had grade 3/4 targeted toxicities: grade 3 hypertension (n = 2), grade 3 venous thromboembolism (n = 2), and grade 4 arterial thromboembolism (n = 1). None of these events led to death during the study.. Bevacizumab plus standard second-line chemotherapy is highly active in patients with mCRC and has an acceptable safety profile.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Salvage Therapy; Survival Rate; Treatment Outcome

To determine whether the change in tumor diameters at the first follow-up computed tomography (CT) examination after baseline examination (first change) correlates with outcome in patients with metastatic colorectal cancer (mCRC) treated with combination chemotherapy.. The first change was analyzed in a multicenter randomized phase III trial (Nordic VI, N = 567) comparing first-line irinotecan with either bolus or infused 5-fluorouracil. Cox proportional hazards multiple regression model and Kaplan-Meier survival analyses after correction for guarantee-time bias were carried out to evaluate correlations between first change, objective response according to RECIST 1.0, progression-free survival (PFS), and overall survival (OS).. The hazard ratios for PFS and OS decreased along with first change. A decrease between 10% and <30%, albeit RECIST does not regard this as a partial response, was a positive prognostic factor for PFS and OS. Patients who had new lesions or unequivocal progression of nonmeasurable lesions had a worse prognosis than those with only an increase in size of >20%.. The change in tumor size at the first follow-up CT is strongly prognostic for PFS and OS in mCRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Proportional Hazards Models; Treatment Outcome; Tumor Burden

In EORTC study 40983, perioperative FOLFOX increased progression-free survival (PFS) compared with surgery alone for patients with initially 1 to 4 resectable liver metastases from colorectal cancer (CRC). We conducted an exploratory retrospective analysis to identify baseline factors possibly predictive for a benefit of perioperative FOLFOX on PFS.. The analysis was based on 237 events from 342 eligible patients. Cox proportional hazards regression models with a significance level of 0.1 were used to build up univariate and multivariate models.. After adjustment for identified prognostic factors, moderately (5.1-30 ng/mL) and highly (>30 ng/mL) elevated carcinoembryonic antigen (CEA) serum levels were both predictive for the benefit of perioperative chemotherapy (interaction P = 0.07; hazard ratio [HR] = 0.58 and HR = 0.52 for treatment benefit). For patients with moderately or highly elevated CEA (>5 ng/mL), the 3-year PFS was 35% with perioperative chemotherapy compared to 20% with surgery alone. Performance status (PS) 0 and BMI lower than 30 were also predictive for the benefit of perioperative chemotherapy (interaction P = 0.04 and P = 0.02). However, the number of patients with PS 1 and BMI 30 or higher were limited. The benefit of perioperative therapy was not influenced by the number of metastatic lesions (1 vs 2-4, interaction HR = 0.98).. Perioperative FOLFOX seems to benefit in particular patients with resectable liver metastases from CRC when CEA is elevated and when PS is unaffected, regardless of the number of metastatic lesions.ClinicalTrials.gov number NCT00006479.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Perioperative Care; Prognosis; Retrospective Studies

This study aims to investigate the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) on liver metastases of Stage III colorectal cancer patients after curative resection.. We randomly assigned 287 Stage III colorectal cancer patients after curative resection between 2002 and 2008 to receive 2 cycles of HAIC plus 4 cycles of systemic chemotherapy (combined therapy) or 6 cycles of systemic chemotherapy alone (monotherapy). Both the HAIC and systemic chemotherapy regimen consisted of a 2-hour infusion of Oxaliplatin (85mg/m2) on day 1 followed by folinic acid 200mg/m2 as a 2-hour infusion on days 2 and 3 and by 5-fluorouracil 2400mg/m2 as a 48-hour infusion on days 2 and 3. The treatment repeated every 4 weeks. The disease-free survival, overall survival and liver metastases-free survival were compared.. There was no significant difference in adverse effects between two groups. Significant differences were found in 3-year disease-free survival (Combined therapy, 75.00%; Monotherapy, 63.27%; p=0.0035), overall survival (Combined therapy, 84.29%; Monotherapy, 65.31%; p=0.0006) and liver metastases-free survival (Combined therapy, 80.00%; Monotherapy, 69.39%; p=0.0451).. HAIC effectively and safely prevents metachronous liver metastases and improves the prognosis of patients with Stage III colorectal cancer after curative resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

To evaluate the feasibility of 3D perfusion CT for predicting early treatment response in patients with liver metastasis from colorectal cancer.. Seventeen patients with colon cancer and liver metastasis were prospectively enroled to undergo perfusion CT and 18F-FDG-PET/CT before and after one-cycle of chemotherapy. Two radiologists and three nuclear medicine physicians measured various perfusion CT and PET/CT parameters, respectively from the largest hepatic metastasis. Baseline values and reduction rates of the parameters were compared between responders and nonresponders. Spearman correlation test was used to correlate perfusion CT and PET/CT parameters, using RECIST criteria as reference standard.. Nine patients responded to treatment, eight patients were nonresponders. Baseline SUVmean30 on PET/CT, reduction rates of 30% metabolic volume and 30% lesion glycolysis (LG30) on PET/CT and blood flow (BF) and flow extraction product (FEP) on perfusion CT after chemotherapy were significantly different between responders and nonresponders (P=0.008-0.046). Reduction rates of BF (correlation coefficient=0.630) and FEP (correlation coefficient=0.578) significantly correlated with that of LG30 on PET/CT (P<0.05).. CT perfusion parameters including BF and FEP may be used as early predictors of tumor response in patients with liver metastasis from colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Early Detection of Cancer; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Imaging, Three-Dimensional; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multimodal Imaging; Organoplatinum Compounds; Perfusion Imaging; Pilot Projects; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, X-Ray Computed

The primary objective of this study is to evaluate the safety, tolerance, and pharmacokinetic profile of liver-directed therapy with drug-eluting beads irinotecan (DEBIRI) in combination with systemic modified FOLFOX in the treatment of unresectable liver metastases in chemotherapy-naive patients with colorectal cancer.. DEBIRI, loaded with 100 mg irinotecan (100-300 μm beads), was administered via hepatic artery during the off week of FOLFOX therapy. Primary endpoints were safety, tolerance, systemic dose-limiting toxicities, and pharmacokinetics of systemic irinotecan and its active metabolite SN-38 at each infusion at 1-, 4-, and 24-h post-DEBIRI. Secondary endpoints were response rate and survival.. The ten patients have undergone at least 12 cycles of FOLFOX in combination with at least two DEBIRI bead treatments during the patients' off week. Pharmacokinetic data has demonstrated minimal detectable levels of irinotecan (18.6, 21, and 18.6 ng/ml) and SN-38 (1.06, 1.47, and 1.55 ng/ml) after the first, second, and third DEBIRI treatments, respectively. Currently, there has been only one severe device-related adverse event, a grade 3 hypertensive episode that required 1 day of observation in the hospital. The initial 9- and 12-month response rates have been 100 % (2 CR, 8 PR). Four (40 %) patients were successfully downstaged to resection and/or ablation with a median overall survival of 15.2 months.. Concomitant DEBIRI and FOLFOX±bevacizumab is safe, with a minimal adverse event rate, no dose-limiting toxicities, and enhanced overall response rate.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Delivery Systems; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prospective Studies; Survival Analysis; Treatment Outcome

The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and (18)F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions.. A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUV(max)) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (K(trans)) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index.. Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in K(trans) (P=0.019). In the group of radiological responders, the median baseline SUV(max) was 3.77 (IQR: 2.88-5.60) compared with 7.20 (IQR: 4.67-8.73) in nonresponders (P=0.021). A higher follow-up SUV(max) was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016).. High relative decrease in K(trans), low follow-up SUV(max) and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Neoadjuvant Therapy; Organoplatinum Compounds; Positron-Emission Tomography; Tomography, X-Ray Computed

More than half of patients with colorectal cancer will develop metastatic disease either evident at the time of initial diagnosis or during their course of disease. Besides multidisciplinary management further treatment intensification is warranted to improve the still limited prognosis.. In these two multi-centre, randomized phase II trials, conducted in Germany, 380 patients with R0-resectable colorectal liver metastases (PERIMAX) and with unresectable, metastatic colorectal cancer (CHARTA) will be recruited. Patients previously untreated for metastatic disease with either synchronous or metachronous metastases are randomly assigned in a 1:1 ratio to resection of colorectal liver metastases followed by postoperative FOLFOX for 6 months or perioperative FOLFOXIRI and bevacizumab for 3 months pre- and postoperative and resection (PERIMAX), or to induction chemotherapy with FOLFOX and bevacizumab +/- irinotecan for a maximum of 6 months followed by maintenance treatment with fluoropyrimidine and bevacizumab. The primary objective of these trials is to evaluate the feasibility and efficacy of FOLFOXIRI and bevacizumab in metastatic colorectal cancer. Primary endpoint is failure free survival rate at 18 months in the PERIMAX trial and progression free survival rate at 9 months in CHARTA. Secondary objectives include efficacy, safety and tolerability.. The CHARTA and PERIMAX trials are designed to evaluate the benefits and limitations of a highly active four-drug regimen in distinct treatment situations of metastatic CRC. Eligible patients are classified into resectable liver metastases to be randomized to perioperative treatment with FOLFOXIRI and bevacizumab or postoperative FOLFOX in the PERIMAX, or unresectable metastatic CRC to be randomized between FOLFOX and bevacizumab with or without irinotecan, stratified for clinical groups according to disease and patients' characteristics in the CHARTA trial.. Clinical trial identifier CHARTA: NCT01321957, PERIMAX: NCT01540435.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Multicenter Studies as Topic; Organoplatinum Compounds; Randomized Controlled Trials as Topic

The aim of this study was to evaluate the therapeutic efficacy and safety of hepatic arterial infusion (HAI) with irinotecan, oxaliplatin, and floxuridine as a firstline treatment in patients with unresectable liver metastases of colorectal cancer (CRC).. Individual patients were treated with irinotecan (120 mg/m(2)), oxaliplatin (100 mg/m(2)), and floxuridine (500 mg/m(2)) via tumorsupplying arteries. Intravenous leucovorin (200 mg/day) and floxuridine (300 mg/m(2)/day) were given on days 1-3 after the procedure. The therapeutic courses were repeated every 4-8 weeks. Tumor responses, overall survival, and the time to tumor progression were observed.. 204 cumulative cycles of chemotherapy were performed for 31 patients (median 7.0). 19 patients achieved a partial response; in 10 patients the disease stabilized, and in 2 patients the disease progressed, producing an overall response rate of 61.3%. The median survival time was 24.8 months, and the median time to tumor progression was 10.1 months. Frequencies of grade 3-4 neutropenia, diarrhea, elevation of serum bilirubin, elevation of serum transaminases, and vomiting were 6.5, 9.7, 3.2, 19.4, and 90.3%, respectively.. This triplecombination chemotherapy as firstline treatment through HAI was well tolerated and effective in patients with unresectable liver metastases of CRC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Floxuridine; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

We investigated the efficacy and safety of oral Uracil/tegafur (UFT) with leucovorin and mitomycin C (MMC) as third-line treatment for patients with extensively pretreated metastatic colorectal cancer (mCRC). This was a multicenter, prospective phase II study. Patients received MMC 7 mg/m² on day 1 and UFT 300 mg/m² with leucovorin 90 mg, both divided into three daily doses, on days 1-28 every 5 weeks. All patients had failed prior treatment with irinotecan, oxaliplatin, fluoropyrimidine, bevacizumab, and cetuximab. The primary endpoint was tumor control rate evaluated after 2 cycles. Twenty-one patients were included: median age was 66 years (41.1-87.8 years). Tumor control rate was observed in 26.7% of the 15 patients evaluable for response. Median overall survival was 6.4 months. Grade 3 adverse events were asthenia, anorexia, and vomiting. In patients with mCRC who have progressed after as many as two prior therapies, the combination of UFT/leucovorin and MMC is safe and may produce a short stabilization of disease in approximately 25% of patients.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Colorectal Neoplasms; Drug Combinations; Drug Monitoring; Female; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Grading; Salvage Therapy; Survival Analysis; Tegafur; Tumor Burden; Uracil

We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC).. Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0-1 were included in the trial.. Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70%; 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1-13.4) and the overall median survival time was 30.3 months (95% CI: 18.8-41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient.. The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Cetuximab; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Pilot Projects; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases.. Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140 mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300 mg/m² per day) and LV (75 mg/body per day) on days 1-7 of each cycle, and with HAI 5-FU (2,000 mg/week) on days 8-14 of each cycle.. Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140 mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2 months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection.. Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Survival Rate; Tegafur; Treatment Outcome; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Indoles; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Pyrroles; Sunitinib

The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).. The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.. Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.. These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cetuximab; Colorectal Neoplasms; DNA, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Oxaliplatin; Polymerase Chain Reaction; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Rate; Treatment Outcome; Young Adult

In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS).. In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment.. From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001).. FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Positron-Emission Tomography; Tomography, X-Ray Computed

We report updated overall survival (OS) data from study NO16966, which compared capecitabine plus oxaliplatin (XELOX) vs 5-fluorouracil/folinic acid plus oxaliplatin (FOLFOX4) as first-line therapy in metastatic colorectal cancer.. NO16966 was a randomised, two-arm, non-inferiority, phase III comparison of XELOX vs FOLFOX4, which was subsequently amended to a 2 × 2 factorial design with further randomisation to bevacizumab or placebo. A planned follow-up exploratory analysis of OS was performed.. The intent-to-treat (ITT) population comprised 2034 patients (two-arm portion, n=634; 2 × 2 factorial portion, n=1400). For the whole NO16966 study population, median OS was 19.8 months in the pooled XELOX/XELOX-placebo/XELOX-bevacizumab arms vs 19.5 months in the pooled FOLFOX4/FOLFOX4-placebo/FOLFOX4-bevacizumab arms (hazard ratio 0.95 (97.5% CI 0.85-1.06)). In the pooled XELOX/XELOX-placebo arms, median OS was 19.0 vs 18.9 months in the pooled FOLFOX4/FOLFOX4-placebo arms (hazard ratio 0.95 (97.5% CI 0.83-1.09)). FOLFOX4 was associated with more grade 3/4 neutropenia/granulocytopenia and febrile neutropenia than XELOX, and XELOX with more grade 3 diarrhoea and grade 3 hand-foot syndrome than FOLFOX4.. Updated survival data from study NO16966 show that XELOX is similar to FOLFOX4, confirming the primary analysis of progression-free survival. XELOX can be considered as a routine first-line treatment option for patients with metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaloacetates; Survival Rate; Treatment Outcome; Young Adult

Neoadjuvant systemic therapy may induce steatosis or sinusoid obstruction syndrome in the liver. The aim of this study was to investigate the influence of systemic therapy with irinotecan, oxaliplatin and cetuximab on conspicuity of liver metastases on computed tomography (CT). CT scans of 48 patients with initial unresectable colorectal liver metastases which were treated in a Europe-wide, opened, randomized phase II trial receiving oxaliplatin or irinotecan combined with folinic acid and cetuximab were analysed. The density of the metastases and the liver parenchyma before and after systemic therapy were analysed by region-of-interest technique and the tumour-to-liver difference (dHU TLD). The mean density of liver parenchyma and liver metastases did not vary significantly before and after neoadjuvant therapy on plain (56.3 ± 8.1 HU, 54.8 ± 13.5 HU) and arterial enhanced CT (76.0 ± 15.7 HU, 70.5 ± 20.4 HU). There was a significant reduction (105.6 ± 17.3 HU, 93.3 ± 18.2 HU) in the density of liver parenchyma on portal venous scans after systemic therapy (p < 0.0001) and a reduction of dHU TLD, consecutively. In patients with colorectal liver metastases, neoadjuvant chemotherapy may have a toxic impact on liver parenchyma resulting in reduced tumour-to-liver contrast in contrast-enhanced CT. This may lead to underestimation of real lesion size.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Radiographic Image Enhancement; Retrospective Studies; Tomography, X-Ray Computed

This study was conducted to evaluate the efficacy and safety of combination chemotherapy with biweekly paclitaxel plus infusional 5-fluorouracil (5-FU) and leucovorin as first-line treatment for patients with advanced gastric cancer.. Eligible patients with histologically confirmed advanced or metastatic gastric cancer were enrolled. The chemotherapeutic regimen consisted of paclitaxel (100 mg/m(2) on day 1) as a 3-hour intravenous infusion, followed sequentially by leucovorin (400 mg/m(2) on day 1) as a 2-hour intravenous infusion, bolus 5-FU (400 mg/m(2) on day 1), and then continuous infusion 5-FU (3000 mg/m(2) on day 1) over 46 hours. Cycles were repeated every 2 weeks.. Sixty patients were enrolled (median age, 52.5 years old). Of these, 65% patients had Eastern Cooperative Oncology Group performance status of grade 2. A median of 8 cycles was administered (range, 4-12). Fifty-five patients were evaluable for response. Two patients achieved a complete response and 28 patients achieved a partial response, producing an overall response rate of 50% by intent-to-treat analysis. The median duration of response was 6.4 months (95% CI, 5.14-7.60 months). Median progression-free survival and median overall survival were 7.7 months (95% CI, 6.5-8.9 months) and 14.3 months (95% CI, 9.4-19.1 months), respectively. Hematologic toxicity was mild; grade 3 neutropenia was noted in only 6.7% of patients. Alopecia was the most common nonhematologic toxicity in 51 patients (71.4%). Grade 3 alopecia occurred in 11 patients (18.3%).. Combination chemotherapy of biweekly paclitaxel followed sequentially by infusion leucovorin, bolus 5-FU, and continuous infusion 5-FU over 46 hours is effective and well tolerated in patients with advanced gastric cancer, especially in patients with poor performance status who cannot tolerate aggressive chemotherapy regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Peritoneal Neoplasms; Skin Neoplasms; Stomach Neoplasms; Survival Rate; Time Factors; Treatment Outcome

The purpose of this study was to evaluate the efficacy of postoperative adjuvant chemotherapy with FOLFOX regimen on the outcome after LT for HCC patients who did not meet the Milan criteria. Ninety-five consecutive HCC patients with liver cirrhosis undergoing LT were enrolled. Fifty-eight who did not meet the Milan criteria were randomized to open-label treatment with or without adjuvant chemotherapy after LT (n = 29/group). The FOLFOX chemotherapy protocol comprised 3-week cycles of oxaliplatin 100 mg/m(2) on day 1, leucovorin (calcium folinate, CF) 200 mg/m(2) on day 1 followed by 3-day, and 5-fluorouracil (5-FU) 2000 mg/m(2) as a 48-h continuous infusion, for up to six courses in the 1st year after transplantation. Median survival was extended by 4.57 months by combination chemotherapy. The 1- and 3-year survival rates were 89.7% and 79.3% with chemotherapy versus 69.0% and 62.1% without chemotherapy. The cumulative 1-year survival was significantly increased by chemotherapy (log-rank test, P = 0.043). The 6-month tumor-free survival rate was 24.1% higher with chemotherapy than without. The recurrence rate after LT was significantly different between the two groups at 6 months (P = 0.036), but not at 3 years (P = 0.102). The chemotherapy regimen was generally well tolerated. Post-LT adjuvant chemotherapy with oxaliplatin/5-FU/CF could not prevent tumor recurrence post-LT but may contribute to improve the survival of HCC patients who do not meet the Milan criteria. These results should be verified in a larger sample with a longer follow-up period.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prospective Studies; Survival Rate; Treatment Outcome

Efficacy of the-state-of-the-art modalities of systemic and regional chemo-infusion with oxalyplatin (FOLFOX) and irinotecan (FOLFIRI) (162) was compared. Objective response to the former was 40.8%, to the latter--11.9% (p = 0.0002); survival before intrasplenic relapse--9 and 5 months, respectively, (p = 0.0005); overall survival before relapse (median 7 and 4 months, respectively, (p = 0.01). The rate of survival before intrasplenic relapse in the systemic chemo-infusion group was significantly higher (median 10.5 vs. 8.1 months, respectively, (p = 0.03). No significant differences in overall survival were reported (median 15 vs. 13 months, respectively, in the latter group (p = 0.72).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Recurrence; Splenic Neoplasms; Treatment Outcome

Neoadjuvant chemotherapy for unresectable colorectal liver metastases can downsize tumours for curative resection. We assessed the effectiveness of cetuximab combined with chemotherapy in this setting.. Between Dec 2, 2004, and March 27, 2008, 114 patients were enrolled from 17 centres in Germany and Austria; three patients receiving FOLFOX6 alone were excluded from the analysis. Patients with non-resectable liver metastases (technically non-resectable or > or =5 metastases) were randomly assigned to receive cetuximab with either FOLFOX6 (oxaliplatin, fluorouracil, and folinic acid; group A) or FOLFIRI (irinotecan, fluorouracil, and folinic acid; group B). Randomisation was not blinded, and was stratified by technical resectability and number of metastases, use of PET staging, and EGFR expression status. They were assessed for response every 8 weeks by CT or MRI. A local multidisciplinary team reassessed resectability after 16 weeks, and then every 2 months up to 2 years. Patients with resectable disease were offered liver surgery within 4-6 weeks of the last treatment cycle. The primary endpoint was tumour response assessed by Response Evaluation Criteria In Solid Tumours (RECIST), analysed by modified intention to treat. A retrospective, blinded surgical review of patients with radiological images at both baseline and during treatment was done to assess objectively any changes in resectability. The study is registered with ClinicalTrials.gov, number NCT00153998.. 56 patients were randomly assigned to group A and 55 to group B. One patient in each group were excluded from the analysis of the primary endpoint because they discontinued treatment before first full dose, one patient in group B was excluded because of early pulmonary embolism. A confirmed partial or complete response was noted in 36 (68%) of 53 patients in group A, and 30 (57%) of 53 patients in group B (difference 11%, 95% CI -8 to 30; odds ratio [OR] 1.62, 0.74-3.59; p=0.23). The most frequent grade 3 and 4 toxicities were skin toxicity (15 of 54 patients in group A, and 22 of 55 patients in group B), and neutropenia (13 of 54 patients in group A and 12 of 55 patients in group B). R0 resection was done in 20 (38%) of 53 patients in group A and 16 (30%) of 53 of patients in group B. In a retrospective analysis of response by KRAS status, a partial or complete response was noted in 47 (70%) of 67 patients with KRAS wild-type tumours versus 11 (41%) of 27 patients with KRAS-mutated tumours (OR 3.42, 1.35-8.66; p=0.0080). According to the retrospective review, resectability rates increased from 32% (22 of 68 patients) at baseline to 60% (41 of 68) after chemotherapy (p<0.0001).. Chemotherapy with cetuximab yields high response rates compared with historical controls, and leads to significantly increased resectability.. Merck-Serono, Sanofi-Aventis, and Pfizer.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Austria; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Germany; Hepatectomy; Humans; Leucovorin; Linear Models; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Neoadjuvant Therapy; Odds Ratio; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Risk Assessment; Time Factors; Tomography, Spiral Computed; Treatment Outcome

In 2003 Wein et al. published data after a short median follow up (23 months). Here we report on the long-term results.. The patients (n=20) received a neoadjuvant treatment regimen comprising biweekly 85 mg/m2 oxaliplatin (L-OHP) (2h-infusion, d 1, 15, 29 qd 57) and 500 mg/m2 calcium folinic acid (FA) (1-2h-infusion, d 1, 8, 15, 22, 29, 36 qd 57) followed by 2600 mg/m2 5-Fluorouracil (5-FU) (24h-infusion, d 1, 8, 15, 22, 29, 36 qd 57). Two cycles of chemotherapy were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted.. After neoadjuvant therapy, imaging procedures revealed complete remission in 2 patients (10%) and partial remission in 18 patients (90%). Diarrhea (Common Toxicity Criteria toxicity grade 3) was observed in 6 patients (30%) as main symptom of toxicity, followed by vomiting in 3 patients (15%). Higher grade sensomotoric neuropathy did not present. The curative resectability rate (R0) was 80%. In 9 out of 18 patients (50%) undergoing surgical intervention minor postoperative complications occurred. No postoperative mortality was observed. Over a median follow up of 45,5 months the median survival of all patients is 3.0 years and the 5-year overall survival rate is 40%. The 5-year disease-free survival rate is 25%.. Neoadjuvant treatment with 5-FU combined with FA and L-OHP proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Patient Compliance; Time Factors

Patients who undergo hepatic surgery for initially resectable liver metastases from colorectal cancer have a 70% risk of relapse. a recent phase III randomized trial has failed to demonstrate an improvement in disease-free survival with the addition of irinotecan to 5-fluorouracil and folinic acid as adjuvant treatment for patients with radically resected colorectal cancer with liver metastases.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Confidence Intervals; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Vitamin B Complex

Liver metastases in patients with cancer are associated with poor survival. The authors of this report conducted a phase 1 study of hepatic arterial infusion (HAI) oxaliplatin combination therapy in patients with advanced cancer and liver metastases.. Treatment consisted of escalating doses of HAI oxaliplatin 60 mg/m(2) to 175 mg/m(2) and intra-arterial heparin 3000 IU (Day 1); leucovorin 200 mg/m(2) intravenously (iv) and 5-fluorouracil 300 mg/m(2) bolus plus 600 mg/m(2) iv (Days 1 and 2); and bevacizumab 10 mg/kg iv (Day 3). A conventional "3 + 3" design was used.. Fifty-seven patients were treated, including 30 women and 27 men. The median age was 57 years, and the patients had received a median of 3 prior therapies (range, 1-7 prior therapies). The most common cancer was colorectal (n = 29). Overall, 204 cycles were administered (median per patient, 2 cycles; range, 1-17 cycles). The maximum tolerated dose (MTD) of HAI oxaliplatin was 140 mg/m(2). Dose-limiting toxicities were grade 4 thrombocytopenia (n = 1) and grade 4 hypokalemia (n = 1) at 150 mg/m(2) (n = 5). Thirty-three patients (58%) had no toxicity greater than grade 1. The most common toxicities were thrombocytopenia (n = 19), fatigue (n = 15), nausea/vomiting (n = 6), constipation (n = 6), and diarrhea (n = 4). Of 55 patients who were evaluable for response (according to Response Evaluation Criteria in Solid Tumors), 4 patients (7%) had a partial response (PR), and 32 patients (58%) had stable disease (SD), including 15 patients (48%) who had SD for >/=4 months. Of 28 patients with colorectal cancer, 3 patients (11%) had a PR, and 9 patients (32%) had SD for >/=4 months.. HAI oxaliplatin combined with systemic 5-fluorouracil, leucovorin, and bevacizumab had antitumor activity in patients with advanced cancer and liver metastases, and the current results indicated that this combination warrants further study. Cancer 2010. (c) 2010 American Cancer Society.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Child; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Young Adult

To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC).. Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1.. Modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 350 mg, and 5-fluorouracil 400 mg/m² bolus; 2.4 g/m² infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m² on day 1, then 250 mg/m² on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles.. With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005-June 2008.. Median age was 55 years (29-78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2-62). The ORR was 55% (95% confidence interval [CI], 36-73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3-15.2 months); median overall survival was 25.7 months (95% CI, 15.4-27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%).. In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab's role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Disease Progression; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

This phase I study was conducted to determine the maximum tolerated dose (MTD) of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX4) in patients with advanced colorectal cancer (CRC). Bevacizumab was later included as standard of care at the MTD.. Patients received FOLFOX4 with escalating doses of erlotinib: dose level (DL) 1, 50 mg; DL 2, 100 mg; and DL 3, 150 mg once daily continuously. Bevacizumab 5 mg/kg days 1 and 15 was added at the MTD upon Food and Drug Administration approval. Correlative studies included pharmacokinetics, pharmacodynamics was assessed in paired skin biopsies, and fluorodeoxyglucose positron emission tomography scans.. Fifteen patients received 60 cycles (120 FOLFOX treatments). Two dose-limiting toxicities (DLTs) were seen at DL 3: intolerable grade 2 rash (Common Terminology Criteria for Adverse Events version 2) lasting > 1 week, and grade 4 neutropenia. Dose level 2 was expanded to 6 more patients, this time adding bevacizumab, and 1 DLT of grade 3 mucositis occurred. As expected, the primary toxicities were cytopenias, diarrhea, rash, and fatigue. There were 2 occurrences of pneumatosis. One patient experienced an unrelated grade 4 myocardial infarction before starting chemotherapy. No pharmacokinetic drug interactions were observed. The Response Evaluation Criteria in Solid Tumors response rate was 11 of 14 (78%), median progression-free survival was 9.5 months, and median overall survival was 30 months. Three patients are currently alive > 3 years, with 1 having no evidence of disease.. The MTD of erlotinib with FOLFOX4 with or without bevacizumab is 100 mg daily. The regimen appeared to increase toxicity but showed activity in patients with CRC.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Erlotinib Hydrochloride; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Quinazolines; Survival Rate; Tissue Distribution; Treatment Outcome

In a recent randomized study, we demonstrated that XELOX (oxaliplatin + oral capecitabine) was well tolerated and not inferior in terms of efficacy to the infusional FOLFOX-6 regimen in first-line treatment of metastatic colorectal cancer (mCRC). The objective of this additional analysis was to compare the cost of XELOX and FOLFOX-6.. This cost-minimisation study took into account costs related to drug acquisition, hospital care for chemotherapy administration and for serious adverse event management. Hospital care costs were based on French 'diagnosis-related group' tariffs. Drug acquisition costs were drawn from French official sources. Analysis was performed from the French health insurance perspective.. Baseline characteristics of the 282 patients included (143 XELOX, 139 FOLFOX-6) were well balanced. Patients reported less and shorter hospitalisations (day and overnight hospital care) with XELOX: 6.4 ± 2.2 hospitalisations versus 9.7 ± 3.1 (p < 0.001); 11.4 ± 10.6 days versus 17.7 ± 11.8 (p < 0.001). Mean disease management cost per patient was significantly lower with XELOX (EUR 12,918 ± 5,075 vs. EUR 17,229 ± 8,665, p < 0.001).. In the perspective of our analysis, taking into account hospitalisation and drug acquisition costs, the treatment of mCRC patients with XELOX in comparison to FOLFOX-6 significantly decreased the costs, as well as the mean overall hospitalisation length of stay.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Cost of Illness; Costs and Cost Analysis; Deoxycytidine; Female; Fluorouracil; Health Care Costs; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaloacetates; Prospective Studies; Survival Rate; Treatment Outcome

FOLFOX-4 and FOLFIRI are considered equivalent in terms of activity and efficacy as first-line chemotherapy in metastatic colorectal cancer (mCRC). The monoclonal antibody (mAb) cetuximab showed intrinsic activity as a single agent in mCRC and was approved in combination with CPT-11 for patients who failed previous CPT-11-based treatment. The purpose of this phase II study was to evaluate the activity and safety of FOLFOX-4 plus cetuximab in untreated mCRC patients.. Untreated patients with measurable metastatic disease and expressing epidermal growth factor receptor (EGFR) received cetuximab at a loading dose of 400 mg/m(2), followed by weekly doses of 250 mg/m(2), in combination with the FOLFOX-4 regimen every 2 weeks for a maximum of 12 cycles, after which a maintenance program using cetuximab alone was allowed for a maximum of 6 months.. Eighty-two unselected patients were screened; 70 were EGFR+ and entered the trial. Of the 67 assessable patients, the objective response rate was 64.2% (95% CI: 52.5-75.5%) and the tumor growth control rate was 94% (95% CI: 88-99%). All the objective responses except 1 were confirmed. In the group of patients with initially unresectable liver disease alone, 7/33 (21%) were resected. The median time to progression (TTP) and overall survival (OS) were 10.0 and 22.0 months, respectively. The treatment was well tolerated, with no treatment-related deaths, while 24.2% of the patients were affected by cutaneous toxicity of grade >2. Mutational analysis of the KRAS and BRAF genes was retrospectively performed on 35 of the 69 patients treated with cetuximab (51%). KRAS was mutated in 13 out of the 35 cases (37%), whereas no mutations were detected in the BRAF gene. A trend toward an association between KRAS mutations and objective response to treatment (p = 0.07) was demonstrated. Analysis of survival showed that patients harboring KRAS mutations had a trend toward worst TTP (p = 0.14) confirmed by age- and sex-adjusted Cox multivariate regression (hazard ratio, HR = 0.62; 95% CI: 0.36-1.06; p = 0.08). Indeed, KRAS mutations were significantly associated with worst OS in both unadjusted analysis (p = 0.047; log rank test) and age- and sex-adjusted Cox multivariate regression (HR = 0.458; 95% CI: 0.248-0.847; p = 0.01).. These results suggest that the combination of FOLFOX-4 plus cetuximab is very active and obtains long TTP with an acceptable toxicity profile. Indeed, our results are in line with recent findings from phase II and phase III randomized studies providing strong evidence that the efficacy of anti-EGFR mAb is confined to patients with wild-type KRAS mCRC. Investigation of other predictive biomarkers may be useful to further define the responder population.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

We have previously reported that intra-arterial chemotherapy prolongs the survival of patients with advanced HCC (aHCC); however, whether the response to intra-arterial chemotherapy depends on the etiology of underlying liver cirrhosis (LC) is still unknown.. The aim of this study was to assess any influences of the etiology of LC on the response to combined intra-arterial chemotherapy for aHCC.. A total of 53 adult Japanese LC patients (46 men and 7 women) with aHCC were treated with combined intra-arterial chemotherapy between 2002 and 2007 at our hospital. All of the patients had a Japan Integrated Staging (JIS) score of 3 or 4. Their tumors were inoperable according to computed tomography findings. Combined intra-arterial chemotherapy was administered via the proper hepatic artery every 5 days for 4 weeks and the chemotherapy regimen was continued for as long as possible.. There were 15 patients with HBV infection (B-LC group), 29 patients with HCV infection (C-LC group), and nine patients with alcoholic cirrhosis (A-LC group). The percentage of patients with a complete or partial response after 4 weeks of chemotherapy was 0% in the B-LC group versus 31.0% in the C-LC group and 44.4% in the A-LC group. The survival of the A-LC and C-LC groups was significantly longer than that of the B-LC group with the median survival time being 688, 368, and 211 days, respectively.. Combined intra-arterial chemotherapy might be more effective for aHCC in patients with A-LC or C-LC than in patients with B-LC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Survival Rate; Treatment Outcome

Genetically engineered herpes simplex viruses (HSVs) can selectively infect and replicate in cancer cells, and are candidates for use as oncolytic therapy. This long-term report of a phase I trial examines vascular administration of HSV as therapy for cancer. Twelve subjects with metastatic colorectal cancer within the liver failing first-line chemotherapy were treated in four cohorts with a single dose (3 x 10(6) to 1 x 10(8) particles) of NV1020, a multimutated, replication-competent HSV. After hepatic arterial administration, subjects were observed for 4 weeks before starting intra-arterial chemotherapy. All patients exhibited progression of disease before HSV injection. During observation, levels of the tumor marker carcinoembryonic antigen (CEA) decreased (median % drop = 24%; range 13-74%; P < 0.02). One of three individuals at the 10(8) level showed a 39% radiologic decrease in tumor size by cross-section and 75% by volume. HSV infection was documented from liver tumor biopsies. After beginning regional chemotherapy, all patients demonstrated a further decrease in CEA (median 96%; range 50-98%; P < 0.008) and a radiologic partial response. Median survival for this group was 25 months. During follow-up, no signs of virus reactivation were found. Multimutated HSV can be delivered safely into the human bloodstream to produce selective infection of tumor tissues and biologic effects.

Topics: Adult; Aged; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oncolytic Virotherapy; Simplexvirus; Treatment Outcome

Compared with systemic therapy, hepatic arterial infusion (HAI) increases the response to fluoropyrimidines.. Thirty-one patients with non-resectable, colorectal cancer (CRC) liver metastases received irinotecan 120 mg/m(2), followed by leucovorin (LV) 20 mg/m(2) and 5-fluorouracil (5-FU) 500 mg/m(2) administered by HAI every 2 weeks, plus UFT (tegafur-uracil) 200 mg/m(2)/day with LV 30 mg/day on days 1-22, followed by a 6-day rest.. The objective response rate was 65% (all 20 patients achieving a partial response). Ten patients (32%) had stable disease. The median time to progression (TTP) and overall survival (OS) were 12 and 36 months. OS was similar in patients with low versus high expression of thymidylate synthase (TS) and/or dihydropyrimidine dehydrogenase (DPD). The regimen was well tolerated.. UFT with LV plus HAI irinotecan and 5-FU/LV was a feasible and effective treatment for non-resectable CRC liver metastases, increasing response, TTP and OS. TS and DPD levels in liver metastases did not predict outcome.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Tegafur; Uracil

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cetuximab; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Prospective Studies; Stomach Neoplasms; Survival Rate; Treatment Outcome

A phase II study was performed to assess the activity of oxaliplatin plus 5-fluorouracil (5-FU) modulated by leucovorin, as second-line treatment in locally advanced or metastatic pancreas adenocarcinoma pretreated with gemcitabine-containing schedule.. Patients received weekly intravenous infusions of oxaliplatin 40 mg/m, 5-FU 500 mg/m, and leucovorin 250 mg/m (3 weeks on, 1 week off).. Twenty-three patients affected with metastatic (16) or locally advanced (7) pancreas adenocarcinoma were involved in this study. A total of 148 weeks of chemotherapy was delivered (median 2 courses each patient). Among 17 assessable patients, no objective response was registered and 4 patients had stable disease, whereas 13 had tumor progression. Median duration of stable disease was 14 weeks. Median time to progression of disease (TTP) was 11.6 weeks [95% confidence interval (CI), 7.6-5.6]. Kaplan-Meier estimated median overall survival (OS) was 17.1 week (95% CI, 4.0-30.1) and 3 months survival rate was 69.6%. Seven patients experienced grade 3 to 4 toxicity. The regimen was associated with 36% clinical benefit.. The median TTP and median OS in this population with poor prognosis suggests some activity, however, only further investigations will be able to establish the clinical value of this combination.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Prognosis; Salvage Therapy; Survival Rate; Treatment Outcome

FOLFIRI is one of the current standard first-line regimens for advanced colorectal cancer, but its administration is onerous. Because the replacement of 2-day-infusional 5-fluorouracil (5-FU) of FOLFIRI with oral tegafur-uracil/leucovorin (UFT/LV) would be highly beneficial for clinical management, we performed a phase I trial using oral UFT/LV and a pharmacokinetic evaluation.. Treatment consisted of infusional irinotecan (100 mg/m)/l-LV (15 mg/m) and a bolus injection of 5-FU (500 mg/m) on day 1, and oral UFT (300 mg as tegafur/m/d)/LV (75 mg/d) on days 1-5 (level 1), days 1-7 (level 2), or days 1-10 (level 3). Cycles were repeated every 14 days. After determination of the recommended UFT/LV administration period, irinotecan was dose-escalated (level 4: 125 mg/m; level 5: 150 mg/m).. Nineteen patients were enrolled. One dose-limiting toxicity (DLT), grade 4 neutropenia lasting for > or =4 days was observed at level 2. At level 3, one DLT of treatment delay of > or =8 days occurred due to prolonged neutropenia, and 2 patients refused to continue the treatment because of prolonged grade 2 anorexia. Therefore, a 7-day administration of UFT/LV was recommended. No DLT was observed at levels 4 and 5. Pharmacokinetic evaluation suggested continuous exposure to 5-FU by means of oral UFT/LV administration in this combination.. The recommended administration period was 7 days for oral UFT/LV, and the recommended dose of irinotecan was 150 mg/m. A phase II study is ongoing to validate the clinical outcome.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Survival Rate; Tegafur; Tissue Distribution; Treatment Outcome

The purpose of the study was to determine the maximum tolerated dose of systemic oxaliplatin (oxal), 5-fluorouracil (5-FU) and leucovorin (LV) that could be administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) and dexamethasone (Dex) in the adjuvant setting after hepatic resection.. Thirty-five patients with resected liver metastases were entered into a phase I trial using HAI FUDR/Dex with escalating doses of oxal and 5-FU.. The initial dose of HAI FUDR was fixed at 0.12 mg/kg x pump volume divided by pump flow rate plus Dex infused over the first 2 weeks of a 5-week cycle. Systemic chemotherapy was delivered on days 15 and 29 with the doses of oxal escalated from 85 to 100 mg/m2 and the 5-FU 48-h continuous infusion doses from 1000 to 2000 mg/m2. The LV dose was fixed at 400 mg/m). Dose-limiting toxic effects were diarrhea, 8.5%, and elevated bilirubin, 8.5%. With a median follow-up of 43 months, the 4-year survival and progression-free survival were 88% and 50%, respectively.. Adjuvant therapy after liver resection with HAI FUDR/Dex plus systemic oxal at 85 mg/m2 and 5-FU by continuous infusion at 2000 g/m2 with LV at 400 mg/m2 is feasible and appears effective. Randomized studies comparing this regimen to systemic FOLFOX are suggested.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Colorectal Neoplasms; Disease-Free Survival; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome; Vitamin B Complex

Irinotecan has, in general, been administered as a 90-min infusion. However, several studies have demonstrated that continuous infusion seems to be a promising method of delivering irinotecan. This phase I/II trial was performed to evaluate the efficacy and safety of continuous infusion of irinotecan combined with UFT plus leucovorin (LV) for metastatic colorectal cancer.. Escalating doses of irinotecan (90-110 mg/m(2)) were administered by 24-hour infusion on day 1. UFT 300 mg/m(2)/day and LV 75 mg/day were administered orally, in 3 divided daily doses, on days 3-7 and 10-14. The treatment cycles were repeated every 2 weeks.. In the phase I study, the maximum tolerated dose of irinotecan was 110 mg/m(2) and the recommended dose for the phase II study was determined to be 100 mg/m(2). Thirty-six patients, including 3 patients at the recommended dose in the phase I study, were evaluated in the phase II study. The common grade 3/4 toxicities were leucopenia, neutropenia, diarrhea and anorexia. The response rate was 63.9%, and the median progression-free and overall survival times were 8.3 and 24.6 months, respectively.. A 24-hour infusion of irinotecan combined with UFT/LV is feasible and active for metastatic colorectal cancer.

Topics: Adenocarcinoma; Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Peritoneal Neoplasms; Prognosis; Survival Rate; Tegafur; Treatment Outcome; Young Adult

Phase II studies have shown that the combination of capecitabine and irinotecan (the XELIRI regimen) is active in metastatic colorectal cancer (MCRC). There are, however, no data about the use of the XELIRI regimen in the neoadjuvant treatment.. Patients with unresectable liver-only metastases of MCRC with < or = 75 years of age were randomised to either the XELIRI (irinotecan 250 mg/m(2) given on day one and capecitabine 1000 mg/m(2) twice daily from day 2-15, every 21 days) or the FOLFIRI arm (irinotecan 180 mg/m(2), 5-FU 400 mg/m(2), LV 200 mg/m(2), 5-FU 2400 mg/m(2) (46-h infusion)--all given on day one, every 14 days). Primary end points were objective response rate (ORR) and rate of radical (R0) surgical resection. Secondary end points were progression-free survival (PFS), overall survival (OS) and safety.. Altogether 87 patients were enrolled (41 pts in the XELIRI and 46 pts in the FOLFIRI arm). The median age was 63 years (63 years in the XELIRI and 62 years in the FOLFIRI arm) (p = 0.33). ORR was 49% in the XELIRI and 48% in the FOLFIRI arm (p = 0.76). The rate of radical R0 resection was 24% in both arms of patients. At the end of treatment, 37% of patients in the XELIRI and 26% of patients in the FOLFIRI arm were without evidence of the disease (CR+R0 resection) (p = 0.56). There were no statistical differences in grade 3 or 4 adverse events between both arms: diarrhoea 7% vs. 6%, neutropenia 5% vs. 13%, ischemic stroke 0 vs. 2%, acute coronary syndrome 2% vs. 4%, respectively. At the median follow up of 17 (range 1-39) months, the median PFS was 10.3 months in the XELIRI and 9.3 months in the FOLFIRI arm (p = 0.78), the median OS was 30.7 months in the XELIRI arm and 16.6 months in the FOLFIRI arm (p = 0.16).. The XELIRI regimen showed similar ORR as the FOLFIRI regimen in the neoadjuvant treatment of patients with MCRC. In addition, the XELIRI regimen showed similar PFS and OS with acceptable toxicity compared to the FOLFIRI regimen.. Current Controlled Trials ISRCTN19912492.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Diarrhea; Fatigue; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Nausea; Neoadjuvant Therapy; Neutropenia; Prospective Studies; Survival Analysis; Treatment Outcome

A randomized controlled trial is being conducted in Japan to compare hepatectomy alone with hepatectomy followed by adjuvant chemotherapy as treatment in patients with curatively resected liver metastases from colorectal cancer to improve survival with intensive chemotherapy. Between 42 and 70 days after liver resection, patients are randomly assigned to either hepatectomy alone or hepatectomy followed by 12 cycles of modified FOLFOX6 (mFOLFOX6) regimen. A total of 300 patients (including 78 patients in Phase II) will be accrued from 38 institutions within 3 years. The primary endpoint is treatment compliance at nine courses of mFOLFOX6 regimen in Phase II and disease-free survival in Phase III. The secondary endpoints are overall survival, incidence of adverse events and patterns of recurrence.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Invasiveness; Organoplatinum Compounds; Treatment Outcome

Chemotherapy may improve survival in patients undergoing resection of colorectal liver metastases (CLM). Neoadjuvant chemotherapy may help identify patients with occult extrahepatic disease (averting unnecessary metastasectomy), and it provides in vivo chemosensitivity data.. A phase II trial was initiated in which patients with resectable CLM received CPT-11, 5-FU and LV for 12 weeks. Metastasectomy was performed unless extrahepatic disease appeared. Postoperatively, patients with stable or responsive disease received the same regimen for 12 weeks. Patients with progressive disease received either second-line chemotherapy or best supportive care. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and safety.. 35 patients were accrued. During preoperative chemotherapy, 16 patients (46%) had grade 3/4 toxicities. Resection was not possible in 5 patients. One patient died of arrhythmia following surgery, and 1 patient had transient liver failure. During the postoperative treatment phase, 12 patients (55%) had grade 3/4 toxicities. Deep venous thrombosis (DVT) occurred in 11 patients (34%) at various times during treatment. Of those who underwent resection, median DFS was 23.0 mo. and median OS has not been reached. The overall survival from time of diagnosis of liver metastases was 51.6 mo for the entire cohort.. A short course of chemotherapy prior to hepatic metastasectomy may serve to select candidates best suited for resection and it may also direct postoperative systemic treatment. Given the significant incidence of DVT, alternative systemic neoadjuvant regimens should be investigated, particularly those that avoid the use of a central venous line.. ClinicalTrials.gov NCT00168155.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Treatment Outcome

Studies indicate that adjuvant 5-fluorouracil (5-FU) with folinic acid (FA) in colorectal cancer patients with completely resectable liver-limited metastases (LMCRC) offers clinical benefit over surgery alone. This phase III trial compared FOLFIRI with simplified 5-FU/FA in this setting.. LMCRC patients were randomized to receive every 14 days, FA, 400 mg/m2 infused over 2 h, followed by 5-FU as a 400 mg/m2 i.v. bolus, followed by continuous 5-FU infusion, 2400 mg/m2 over 46 h (LV5FUs) with or without irinotecan: 180 mg/m2 infusion (FOLFIRI). The primary end point was disease-free survival (DFS); secondary end points included overall survival (OS) and safety.. Treated patients (n = 306) were balanced for critical prognostic factors in each arm. Median DFS in patients receiving LV5FUs was 21.6 versus 24.7 months for FOLFIRI [hazard ratio (HR) 0.89, log-rank P = 0.44]. No significant differences were found in OS. A trend was observed for improved DFS in patients receiving FOLFIRI within 42 days of surgery (HR 0.75, P = 0.17). Grade 3/4 toxic effects were more common in patients treated with FOLFIRI versus LV5FUs (47% versus 30%) with neutropenia being most common (23% versus 7%).. FOLFIRI in the adjuvant treatment of LMCRC showed no significant improvement in DFS compared with LV5FUs.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Patient Compliance; Treatment Outcome

The aim of this study is to investigate the efficiency and toxicity of the FOLFOX regimen, the combination of oxaliplatin (L-OHP), 5-fluorouracil (5-Fu) and calcium folinate (CF), for patients with locally advanced or metastatic gastric cancer.. Ninety-six patients with locally advanced or metastatic gastric adenocarcinoma, including 72 males and 24 females, were treated with FOLFOX regimen: L-OHP 85 mg/m(2) iv in 2 hours on D1, CF 200 mg/m(2) iv in 2 hours on D1 and D2, 5-Fu 400 mg/m(2) iv on D1 and D2, and then continuous infusion of it at a dose of 600 mg/m(2) for 44 hours. This regimen was repeated every 2 weeks. The first evaluation was done after four cycles. The median cycle of the chemotherapy was 6 (range: 1 to 12 cycles).. Of the 96 patients with gastric cancers, 21 underwent R0 resection and afterward received adjuvant FOLFOX chemotherapy. Ten of those were still alive, while the other 11 died of the disease, with a median disease free survival time of 24.0 months and 3-year survival rate of 51.8%. The other 75 received only palliative chemotherapy due to non-operable advanced disease. Thirty of those achieved partial response (PR), the other 20 had a stable disease (SD), but the remaining 25 experienced disease progression (PD), with an overall response rate of 40.0%. The median TTP and overall survival in those 75 patients was 5.9 and 12.0 months, respectively. All 96 patients were evaluable for toxicity according to NCI criteria. The patients of grade 3 vomiting and neural toxicity were 6 and 4, respectively.. In terms of efficacy and safety, the FOLFOX regimen is effective and well tolerable for patients with locally advanced or metastatic gastric cancers either as adjuvant or palliative chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Remission Induction; Stomach Neoplasms; Survival Rate; Vomiting

Irinotecan (CPT-11), oxaliplatin, 5-fluorouracil (5-FU) and capecitabine are main active agents for advanced colorectal cancer. FORFIRI regimen is recommended for the patients who were treated with oxaliplatin plus 5-FU or capecitabine previously. This study was to investigate the efficacy and safety of FORFIRI regimen in treating advanced colorectal cancer failing to prior oxaliplatin-based chemotherapy, and analyze the impacts of clinical factors on the responses.. A total of 90 patients with advanced colorectal adenocarcinoma, who had received prior adjuvant FOLFOX6 regimen and progressed within 12 months after the completion of therapy or had no response to prior FOLFOX6/CapeOX regimen as first-line therapy, were treated with FORFIRI regimen. The efficacy and adverse events were observed.. Of the 81 evaluable patients, two achieved complete remission, 20 achieved partial remission and 34 had stable disease. The overall response rate was 27.2% and disease control rate was 69.1%. The median time to progression was 6.8 months (95% CI, 4.9-8.8 months) and median overall survival time was 18.8 months (95% CI, 17.5-20.2 months). The main adverse events time were nausea, vomiting, neutropenia, alopecia, fatigue, impaired liver function, oral mucositis and diarrhea. Grade III adverse events included alopecia in 15 patients (16.7%), vomiting in 10 patients (11.1%), nausea in eight patients (8.9%), neutropenia in five patients (5.6%), impaired liver function in two patients (2.2%) and oral mucositis in two patients (2.2%).. FOLFIRI regimen is effective and well-tolerated as salvage therapy for advanced colorectal cancer failing to prior FOLFOX6/CapeOX regimen, and thus can be used widely.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Nausea; Neoplasm Staging; Neutropenia; Rectal Neoplasms; Remission Induction; Salvage Therapy; Survival Rate; Vomiting; Young Adult

The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer.. Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia >7 days or neutropenia grade >1 at day 15.. The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2.. HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoadjuvant Therapy; Survival Analysis; Treatment Outcome

Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials.. After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m(2) administered intravenously [IV] once daily plus dl-leucovorin 200 mg/m(2) [FFCD] x 5 days or FU 370 mg/m(2) plus l-leucovorin 100 mg/m(2) IV x 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm).. A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis.. This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus-based regimen after complete resection of colorectal cancer metastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Survival Rate

To evaluate the antitumor activity and toxicity of 5-fluorouracil (FU)/leucovorin (LV) and capecitabine (C) given with either oxaliplatin (OX) or camptothecin (CPT-11) in the treatment of chemotherapy naive patients with metastatic colorectal cancer.. The outpatient treatment, consisted of 2 consecutive days of LV, 200 mg/m(2), 5-FU 400 mg/m(2), and C 2000 mg/m(2) that, in one cycle, was preceded by 2 days of OX 50 mg/m(2), and, in the subsequent cycle, by CPT-11, 90 mg/m(2).. All 54 patients were assessable for toxicity and response. Thirty-two patients responded, giving an overall response rate of 59.3%. Median progression-free survival was 12.3 months and median survival was 20.5 months. Toxicity included grade 3 to 4 neutropenia in 43% of patients, grade 3 diarrhea in 7% of patients, and grade 2 neurotoxicity in 6% of patients.. The alternating, bimonthly schedule of OX and CPT-11 plus 5-FU/LV/C has substantial antitumor activity and is well tolerated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome

To evaluate the efficacy and toxicity of a biweekly DOF regimen consisting of docetaxel, oxaliplatin, 5-fluorouracil and leucovorin for advanced gastric cancer.. The biweekly DOF regimen was administered in 37 advanced gastric cancer patients. Docetaxel, oxaliplatin and leucovorin were given intravenously at a dose of 35 mg/m2, 85 mg/m2 and 200 mg/m2 for 1 h, 2 h and 2 h on D1, respectively, and 5-Fu was administered as continuous intravenous infusion for 48 h at a dose of 1500 mg/m2 on D1 and D2. This regimen was repeated every 2 weeks. The efficacy and toxicity were evaluated after completion of 3 cycles at least.. The overall response rate (RR) of this series was 67.6%, complete response rate and partial response rate were 27.0% and 40.5%, respectively. The time to progression (TTP) was 9.2 months, and median survival time (MST) was 13.7 months. The RRs of 11 chemotherpy-naïve patients and 26 patients pre-treated with chemotherapy were 81.8% and 61.5%, respectively.. Our preliminary results showed that this biweekly combination regimen of docetaxel, oxaliplatin, 5-fluorouracil and leucovorin is effective and tolerable for advanced gastric cancer. However, further investigation of this regimen is mandatory.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Remission Induction; Stomach Neoplasms; Taxoids; Vomiting; Young Adult

To assess the rate of R(0) resection of liver metastases achieved after chemotherapy with FOLFIRINOX.. Patients with histologically proven primary colorectal cancer and bidimensionally measurable liver metastasis, not fully resectable based on technical inability to achieve R(0) resection, but potentially resectable after tumor reduction, were given FOLFIRINOX: oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), bolus fluorouracil 400 mg/m(2) and fluorouracil 46-h continuous IV infusion 2,400 mg/m(2), every 2 weeks for a maximum of 12 cycles.. Thirty-four patients were enrolled. Response rate before surgery was 70.6% (95%CI: 52.5-84.9). Twenty-eight patients (82.4%) underwent hepatic resection and nine achieved R(0) resection [26.5% (95% CI: 12.9-44.4%)]. The rate of clinical complete remission after surgery was 79.4%. Two-year overall survival was 83%. The most frequent grade 3 or 4 toxicities were neutropenia (64.8%), diarrhea (29.4%), fatigue (23.5%), abdominal cramps (14.7%), neuropathy and nausea (11.8% each), and AST/ALT elevation (14.7/11.8%). Only one patient experienced febrile neutropenia, four patients withdrew due to toxicity and no toxic death was observed.. FOLFIRINOX, with an acceptable toxicity profile, shows a high response rate in liver metastases from colorectal cancer. The rate of hepatic resection in patients initially not resectable, is attractive and warrants further assessment of this regimen in randomized studies compared to standard regimens.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases.. Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n=70); B: other chemotherapeutic agents (OC, n=60); and C: surgery alone without chemotherapy (SA, n=43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared.. Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p=0.01 and p=0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p=0.007 and p=0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p=ns).. Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Survival Analysis

The aim of this study was to assess chemotherapy associated hepatotoxicity after 3 months' treatment and to correlate patterns of hepatotoxicity with perioperative morbidity.. Liver specimens of 50 patients with liver metastases from colorectal cancer receiving XELOX or FOLFOX4 for six cycles and 13 specimens of non-chemotherapy patients subjected to liver resection were analyzed. Different patterns of hepatotoxicity were evaluated according to widely accepted pathohistological scores. Furthermore, the histomorphological findings were correlated with perioperative morbidity.. Steatosis grades did not differ among the chemotherapy treated groups and non-chemotherapy patients. Chemotherapy showed an independent effect on fibrosis stage. Age and chemotherapy were independently associated with sinusoidal dilatation. Centrilobular vein fibrosis correlated with administration of chemotherapy. Higher fibrosis stages were associated with increased transfusion requirements.. XELOX and FOLFOX4 do not correlate with the development of steatosis or steatohepatitis. We do not detect a difference in liver injury between the XELOX and FOLFOX4 group. Although 5-fluorouracil based chemotherapy may cause profound changes in liver parenchyma, it can be safely applied. However, age and oxaliplatin predispose for the development of sinusoidal dilatation; therefore caution must be taken in old patients treated with oxaliplatin.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Fatty Liver; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Morbidity; Organoplatinum Compounds; Oxaloacetates; Prognosis; Retrospective Studies; Risk Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Perioperative Care

Surgical resection of liver metastases arising from colorectal cancer is considered the only curative treatment option. However, many patients subsequently experience disease recurrence. We prospectively investigated whether neoadjuvant chemotherapy reduces the risk of recurrence following potentially curative liver resection. Special emphasis was directed to the importance of response.. 50 patients with resectable liver metastases received neoadjuvant XELOX or FOLFOX4 for six cycles (3 months). Complete resection of liver metastases was intended thereafter. Assessments included response rate, postoperative morbidity and recurrence-free survival.. An objective response was observed in 72% of all patients, including two complete responses. Chemotherapy was well tolerated and the majority of adverse events were mild to moderate (grade 1/2). Potentially curative R0 resection was performed in all patients and postoperative complications were observed in only 12%. The median recurrence-free survival was significantly influenced by tumor response with 24.7 months (95% CI: 4.50 to 44.97) in responding patients, 8.2 months (95% CI: 3.09 to 13.31) in patients with stable disease and 3.0 months (95% CI: 0 to 8.91) in patients with progressive disease.. These data suggest that neoadjuvant Oxaliplatin based chemotherapy provides high response rates without increased risk of perioperative morbidity. Response to chemotherapy can lead to long-term recurrence-free survival. Neoadjuvant chemotherapy may identify best candidates for a potentially curative treatment approach.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Prospective Studies; Treatment Outcome

To investigate the therapeutic index of combining etoposide, doxorubicin (adriamycin), cisplatin, 5-fluorouracil (5-FU), and leucovorin (EAPFL) chemotherapy in the treatment of advanced HCC, a trial of a novel schedule of triweekly administration was conducted.. Sixty-six patients with measurable advanced HCC, adequate liver and renal functions and adequate bone marrow reserves in whom local treatment was not indicated were studied. Triweekly EAPFL treatment consisted of a concomitant boost of etoposide 40 mg/m2 i.v. over 30 min on day 1, 2, and 3, doxorubicin 30 mg/m2 i.v. over 30 min on day 1 to a backbone regimen, triweekly PFL chemotherapy with cisplatin 60 mg/m2, 5-FU 1,200 mg/m2, and leucovorin 120 mg/m2 given simultaneously by a 72-h i.v. infusion. Response, survival, and toxicity were evaluated.. One patient had complete response (1%) and thirteen patients had partial response (20%). The objective response rate was 21% (95% confidence interval 11-31%). The median overall survival and median time to progression were 8.9 months and 3.3 months, respectively. Major treatment toxicities (grade 3-4) were neutropenia (28%), anemia (11%), thrombocytopenia (7%), hepatotoxicity (5%), vomiting (2%), and diarrhea (2%). There was no treatment-related death.. Triweekly EAPFL chemotherapy is a moderately effective regimen with tolerable toxicities in the treatment of advanced HCC.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Doxorubicin; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

Oxaliplatin stop and go in combination with leucovorin and 5-fluorouracil has been successfully used in a previous study (OPTIMOX1) in metastatic colorectal cancer (MCR). Celecoxib is an anti-cyclooxygenase-2 drug with anti-neoplastic properties. In the present study, celecoxib was evaluated in combination with FOLFOX7 regimen and as a single agent in maintenance therapy.. This phase II study examined for previously untreated MCR patients the stop-and-go procedure [six cycles of folinic acid, 5FU and oxaliplatin (FOLFOX7) followed by chemotherapy-free intervals (CFIs) and reintroduction at progression] with continuous administration of celecoxib (800 mg/day).. Forty-four patients were included, 42 eligible: performance status (%) 0/1/2=45/40/15, median age 60 (31-76) years. Response rate (RR) was 43% (95% CI 28%-58%). Median progression-free survival (PFS) was 6 months; median overall survival was 15.8 months. Grade 3/4 toxicity criteria were neurotoxicity 9.5%, thrombocytopenia 21.4%, neutropenia 7.1%, diarrhea 7.1%, nausea 4.8% and vomiting 2.4%. Median CFI 1 (n=27) duration was 3.9 months (range 2-39 months).. With an acceptable safety profile, celecoxib combined with FOLFOX7 achieved RR and PFS in the lower range of that obtained with FOLFOX7 alone. These results indicate the lack of synergy between FOLFOX7 and celecoxib. PFS of 6 months appears lower than PFS obtained in OPTIMOX1 study with simplified LV5FU2 in maintenance therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pyrazoles; Sulfonamides; Survival Rate; Treatment Outcome

To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC).. Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/ m2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir.. The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P < 0.05).. Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cisplatin; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Leukocyte Count; Liver Neoplasms; Male; Middle Aged; Survival Rate

Advanced pancreatic carcinoma (APC) has a poor prognosis and chemotherapy remains the most common approach. Gemcitabine was the only drug recently approved for use as single agent therapy in APC. However, the combination of oxaliplatin and 5-fluorouracil (5-FU) has shown some promising results. This phase II trial was conducted to investigate the efficacy of oxaliplatin, 5-FU, and folinic acid (FOLFOX-6) in previously untreated APC patients.. We studied response rate, time to progression, and toxicity profile. Treatment included oxaliplatin 100 mg/m2 and folinic acid 400 mg/m2 on day 1 followed by a 5-FU bolus 400 mg/m2 and a 46-hour infusion of 3000 mg/m2 every 2 weeks.. From January 2003 through December 2004, 30 eligible patients were included. Median age was 65 (range, 38-75). There were 22 patients who had metastatic disease and 29 had an adenocarcinoma. A total of 181 cycles were delivered with a mean of 6 cycles per patient. There were 23 patients evaluable for response. There were 8 patients with partial response (27.6% response rate) and 10 with stable disease status (34.5%), while tumor growth control was found in 62% of the patients. Recorded toxicities of grade 3/4 were: neutropenia (26.67%), thrombocytopenia and anemia (10% each), diarrhea (6.67%), and mucositis (3.33%). Neurosensory toxicity was mild. The median time to progression and the median survival were 4 and 7.5 months, respectively.. In patients with APC, FOLFOX-6 regimen achieved an interesting response rate within a tolerable level of toxicity. This regimen seems to warrant further controlled investigation to confirm its efficacy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Neuroendocrine Tumors; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Patient Selection

The association between oxaliplatin and 5-fluorouracil (5-FU) has been extensively reported to improve prognosis of gastric cancer patients. The present study is aimed at evaluating response rate and the toxicity profile of the association with oxaliplatin, 5-FU/lecovorin and epirubicin in gastric cancer patients with locally advanced or metastatic disease. Thirty-six patients have been enrolled and 35 evaluated. The treatment schedule was oxaliplatin (100 mg m(-2)), 5-FU (400 mg m(-2)), leucovorin (40 mg m(-2)) and epirubicin (60 mg m(-2)) intravenously. administered every 3 weeks for 6 months, for a total of 185 therapy cycles . Response rate and toxicity were assessed according to the international WHO criteria. Every patient received a mean of 5.3 therapy cycles in a day-hospital setting. Sixteen of 35 patients (46%) showed an objective response, two complete response and 14 partial response. Median time to progression was 33 weeks with an overall median survival of 49 weeks. During the study, anaemia grade 3 and neutropenia grade 3 were observed in 9 and 11% of patients respectively. A grade 3 periferic sensorial neuropathy was observed in 6% of patients. No life threatening or cardiac toxicity was recorded. The regimen used showed anticancer activity against gastric carcinoma, a tolerable toxicity profile and excellent patient compliance.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Colorectal Neoplasms; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

Liver metastases represent the principal cause of death in patients with advanced colorectal cancer (CRC). Injection of resin microspheres (SIR Spheres)--containing the beta-emitter, yttrium-90--into the arterial supply of the liver can cause radioembolization of metastases. This treatment has not been tested with the radiosensitizing chemotherapy, oxaliplatin, which appears synergistic in the treatment of CRC when combined with fluorouracil and leucovorin (FOLFOX).. A phase I study of SIR-Spheres therapy with modified FOLFOX4 systemic chemotherapy was conducted in patients with inoperable liver metastases from CRC who had not previously received chemotherapy for metastatic disease. Oxaliplatin (30 to 85 mg/m2) was administered for the first three cycles with full FOLFOX4 doses from cycle 4 until cycle 12. The primary end point was toxicity.. Twenty patients were enrolled onto the study. Five patients experienced National Cancer Institute (NCI; Bethesda, MD) grade 3 abdominal pain, two of whom had microsphere-induced gastric ulcers. The dose-limiting toxicity was grade 3 or 4 neutropenia, which was recorded in 12 patients. One episode of transient grade 3 hepatotoxicity was recorded. Mean splenic volume increased by 92% following 6 months of protocol therapy. Partial responses were demonstrated in 18 patients and stable disease in two patients. Two patients underwent partial hepatic resection following protocol therapy. Median progression-free survival was 9.3 months, and median time to progression in the liver was 12.3 months.. The maximum-tolerated dose was 60 mg/m2 of oxaliplatin for the first three cycles, with full FOLFOX4 doses thereafter. This chemoradiation regime merits evaluation in phase II-III trials.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Australia; Brachytherapy; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Embolization, Therapeutic; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Microspheres; Middle Aged; Organoplatinum Compounds; Radiopharmaceuticals; Radiotherapy, Adjuvant; Time Factors; Treatment Outcome; United Kingdom; Vitamin B Complex; Yttrium Radioisotopes

Colorectal cancer is the second leading cause of cancer mortality in the United States. Antiangiogenic therapy with bevacizumab combined with chemotherapy improves survival in previously untreated metastatic colorectal cancer. This study was conducted to determine the effect of bevacizumab (at 10 mg/kg) on survival duration for oxaliplatin-based chemotherapy in patients with previously treated metastatic colorectal cancer.. Eight hundred twenty-nine metastatic colorectal cancer patients previously treated with a fluoropyrimidine and irinotecan were randomly assigned to one of three treatment groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The primary end point was overall survival, with additional determinations of progression-free survival, response, and toxicity.. The median duration of survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for death = 0.75; P = .0011), and 10.2 months for those treated with bevacizumab alone. The median progression-free survival for the group treated with FOLFOX4 in combination with bevacizumab was 7.3 months, compared with 4.7 months for the group treated with FOLFOX4 alone (corresponding hazard ratio for progression = 0.61; P < .0001), and 2.7 months for those treated with bevacizumab alone. The corresponding overall response rates were 22.7%, 8.6%, and 3.3%, respectively (P < .0001 for FOLFOX4 with bevacizumab v FOLFOX4 comparison). Bevacizumab was associated with hypertension, bleeding, and vomiting.. The addition of bevacizumab to oxaliplatin, fluorouracil, and leucovorin improves survival duration for patients with previously treated metastatic colorectal.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Medical Oncology; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Probability; Risk Assessment; Salvage Therapy; Single-Blind Method; Survival Analysis; Treatment Outcome; United States

More than two-thirds of patients with gastric cancer present with metastatic disease and their curative options are limited. This phase II study assessed the efficacy and tolerability of cisplatin, epirubicin, tegafur-uracil (UFT) and leucovorin in patients with metastatic gastric cancer (MGC). Thirty-nine patients with previously untreated metastatic or unresectable gastric cancer received intravenous cisplatin 60 mg/m2 and epirubicin 50 mg/m2 on day 1 of a 28-day cycle; UFT 300 mg/m2 was administered with oral leucovorin 30 mg/day in divided doses on days 1-22, followed by a 7-day rest. Two patients achieved a complete response, 13 had a partial response (overall response rate 38%; 95% confidence interval [CI] 24-52%) and 16 patients (41%) had stable disease. Median time to progression was 6.5 months (95% CI 5.5-7.5 months); overall survival was 9.5 months (95% CI 8.5-13.5 months). Grade 3/4 neutropenia, anemia, and thrombocytopenia occurred in 20%, 8%, and 3% of patients, respectively; two patients experienced febrile neutropenia. Grade 3 diarrhea occurred in three patients. The combination of cisplatin, epirubicin, UFT, and leucovorin has significant activity and tolerable toxicities in patients with MGC and represents a convenient treatment option for these patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Epirubicin; Female; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Peritoneal Neoplasms; Stomach Neoplasms; Survival Analysis; Tegafur; Time Factors; Treatment Outcome; Uracil

Intra-arterial chemotherapy in patients with liver metastases from colorectal cancer has some limitations such as hepatic toxicity and extra-hepatic progression. With the aim of overcoming these limitations, a phase II trial was designed to assess the efficacy and tolerability of a hybrid chemotherapy regimen with systemic infusion of oxaliplatin and folinic acid associated with intra-arterial 5-fluorouracil. Thirty-nine patients with colorectal liver metastases were recruited. The median age was 59 years, 30 patients (77%) had synchronous metastases, and half of the patients were chemo-naive. A total of 313 chemotherapy cycles were administered (median number 8). Treatment was well tolerated and hepatic toxicity negligible. Out of 34 evaluable patients an ORR of 41%. was observed. Eight patients (21%) underwent radical liver surgery. The median time to progression (TTP) was 10 months (range 2-63) and the median overall survival (OS) 21 months (range 6-63). Extra-hepatic progression was observed in six patients. Our results suggest that this regimen is active even if technical complications are frequent. Our aim to reduce hepatic toxicity and extra-hepatic progression was reached.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Catheterization; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

To evaluate the efficacy and the toxicity of front line FOLFOX4 combined with bevacizumab in patients with metastatsic CRC (mCRC).. Chemotherapy-naïve patients with mCRC, received bevacizumab (5 mg/kg every 2 weeks d1), oxaliplatin (85 mg/m2 on d1), leucovorin (200 mg/m2) on days 1 and 2 and 5-Fluorouracil (400 mg/m2 as i.v. bolus and 600 mg/m2 as 22 h i.v. continuous infusion on days 1 and 2) every 2 weeks.. Fifty three patients (46 with a PS 0-1) were enrolled. Complete and partial response was achieved in eight (15.1%) and 28 (52.8%) patients, respectively (ORR: 67.9%; 95% C.I.: 53.8%-92%); 11 (20.7%) patients had stable disease and six (11.3%) progressive disease. With a median follow up period of 13.5 months, time to tumor progression was 11 months while the median survival has not yet been reached; the probability of 1-, 2- and 3- year survival was 79.8%, 63.8% and 58.3%, respectively; Two patients relapsed during the follow up period. Eight (15%) patients underwent metastasectomy with R0 resections. Grade 3-4 neutropenia occurred in 15.1% of patients and one (1.9%) of them presented febrile neutropenia. Non-hematologic toxicity included grade 3 diarrhea (7.6%) and grade 2 and 3 neurotoxicity in 16.9 and 15.1% of patients, respectively. One (1.9%) patient presented pulmonary embolism and one (1.9%) cardiac ischaemia. There was one (1.9%) sudden death after the first cycle.. The combination of FOLFOX4/bevacizumab appears to be highly effective, well tolerated and merits further evaluation in patients with mCRC.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Patient Compliance; Treatment Outcome

We have previously reported that neoadjuvant therapy with modified FOLFIRI enabled nearly a third of patients with metastatic colorectal cancer (mCRC) to undergo surgical resection of liver metastases. Here, we present data from the long-term follow-up of these patients. Forty patients received modified FOLFIRI: irinotecan 180 mg m(-2), day 1; folinic acid, 200 mg m(-2); and 5-fluorouracil: as a 400 mg m(-2) bolus, days 1 and 2, and a 48-h continuous infusion 1200 mg m(-2), from day 1. Treatment was repeated every 2 weeks, with response assessed every six cycles. Resected patients received six further cycles of chemotherapy postoperatively. Nineteen (47.5%) of 40 patients achieved an objective response; 13 (33%) underwent resection. After a median follow-up of 56 months, median survival for all patients was 31.5 months: for non-resected patients, median survival was 24 months and was not reached for resected patients. Median time to progression was 14.3 and 5.2 months for all and non-resected patients, respectively. Median disease-free (DF) survival in resected patients was 52.5 months. At 2 years, all patients were alive (8 DF), and at last follow-up, eight were alive (6 DF). Surgical resection of liver metastases after neoadjuvant treatment with modified FOLFIRI in CRC patients achieved favourable survival times.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Survival Analysis; Treatment Outcome

Recently, some scholars advocate perioperative chemotherapy for colorectal cancer. This study aimed to investigate the impact of perioperative chemotherapy on the prognosis of colorectal cancer.. From Aug. 2001 to Aug. 2003, 167 patients with Dukes'B or C colorectal cancer were randomized into two groups: 82 in trial group received perioperative chemotherapy using 5-fluorouracil (5-FU), while 85 in control group received no perioperative chemotherapy. All patients received adjuvant chemotherapy of 5-FU/leucovorin regimen. The adverse events, recurrence rate and survival rate were compared between these two groups.. There was no difference in adverse events between the two groups. The overall recurrence rate was 42.5%û it was significantly lower in trial group than in control group (34.6% vs. 49.4%, P=0.038). The overall 1-, 3-, and 4-year survival rates were 97.6%, 74.7% and 61.8%û they were significantly higher in trial group than in control group (100% vs. 95.3%, 82.7% vs. 67.1%, and 69.1% vs. 54.8%, P=0.046).. Perioperative chemotherapy can improve the prognosis of colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Perioperative Care; Rectal Neoplasms; Stomatitis; Survival Rate; Young Adult

To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase II study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA).. Thirty-one patients with hystologically-confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity.. The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated.. PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Doxorubicin; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polyethylene Glycols; Treatment Outcome; Vitamin B Complex

The main aim of the present work was to determine response rates and time to progression in patients with locally advanced or metastatic pancreatic cancer treated with intra-arterial chemotherapy.. Nineteen chemotherapy-naive patients with measurable lesions were treated with intra-arterial 5-fluorouracil 1000 mg/m2, leucovorin 100 mg/m2, carboplatin 300 mg/m2 and epirubicin 60 mg/m2 (FLEC regimen) every 21 days. Prophylactic granulocyte colony-stimulating factors were administered on days 4-10 of each cycle.. There were 16 patients evaluable for response, of whom 4 (25%) had a partial response, 7 (44%) showed stable disease, and 5 (31%) progressed. Marker response rate was 43%. Median time to progression was 4 months and median overall survival was 6 months. One-year overall survival was 16%. No grade 4 toxicity or severe complications relating to the angiographic procedure were observed.. Our results show that intra-arterial FLEC is well tolerated and active against advanced pancreatic cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Cancer, Regional Perfusion; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Because HCC usually presents as an advanced disease and occurs in the background of liver cirrhosis, most patients are not suitable for treatment with curative intent, thus effective systemic chemotherapy is required. However, the outcome of systemic chemotherapy has been disappointing in advanced HCC. This study was conducted to test the efficacy and toxicity of the combined regimen of epirubicin, cisplatin, and UFT moderated by leucovorin in advanced or recurrent HCC.. All 53 patients received epirubicin (50 mg/m2 i.v.) on day 1 and cisplatin (60 mg/m2 i.v.) after epirubicin administration. Oral UFT 400-600 mg/day, determined by body surface area, and leucovorin 75 mg/day were administered for 21 consecutive days, followed by a 7-day drug free interval.. Nine had a partial response, representing 16.9% of response rate (95% confidence interval rate; 7.0-26.8%) with median response duration of 17.1 weeks (95% CI; 5.0-29.3 weeks, range; 7.1-51.7 weeks). Fifteen patients had stable disease and the disease progressed in 26 patients. The median overall survival for the patients was 24.6 weeks (95% CI; 17.3-31.9 weeks, range; 3.0-131.3 weeks). The main toxicities were hematologic toxicities including neutropenia, which reached grade 3/4 in 17 patients (38.5%), and grade 3 or 4 thrombocytopenia in five patients (9.4%).. The combination of epirubicin, cisplatin, and UFT moderated by leucovorin showed modest anti-tumor activity with relatively tolerable toxicities. However, a randomized phase III trial based on this regimen is warranted to clarify its survival benefit in patients with advanced HCC.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antidotes; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Dose-Response Relationship, Drug; Epirubicin; Female; Hematologic Diseases; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Tegafur; Tomography, X-Ray Computed; Treatment Outcome; Uracil

The prognosis of unresectable metastatic colorectal cancer might be improved if a radical surgical resection of metastases could be performed after a response to chemotherapy.. We treated 74 patients with unresectable metastatic colorectal cancer (not selected for a neoadjuvant approach) with irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin (FOLFOXIRI and simplified FOLFOXIRI). Because of the high activity of these regimens (response rate, 72%), a secondary curative operation could be performed in 19 patients (26%).. Four patients underwent an extended hepatectomy, nine patients underwent a right hepatectomy, three patients underwent a left hepatectomy, and three patients had a segmental resection. In five patients, surgical removal of extrahepatic disease was also performed. In seven patients, surgical resection was combined with intraoperative radiofrequency ablation. The median overall survival of the 19 patients who underwent operation is 36.8 months, and the 4-year survival rate is 37%. The median overall survival of the 34 patients who were responsive to chemotherapy, but who did not undergo operation, is 22.2 months (P = .0114).. The FOLFOXIRI regimens we studied have significant antitumor activity and allow a radical surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer not selected for a neoadjuvant approach and also those with extrahepatic disease. The median survival of patients with resected disease is promising.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Analysis; Treatment Outcome

Several clinical trials have demonstrated that oxaliplatin is a useful agent in combination with 5-fluorouracil (5-FU) and folinic acid (FA) for the treatment of patients with colorectal carcinoma. The aims of this pilot study were to evaluate non-hematological toxicity and patient characteristics in gastrointestinal cancer patients treated with chronomodulated chemotherapy consisting of oxaliplatin, 5-FU and sodium folinate.. Patients with metastatic gastrointestinal cancer received a chronomodulated regimen with oxaliplatin (25 mg/m2), 5-FU (750 mg/m2) and sodium folinate (150 mg/m2). Non-hematological toxicities were evaluated and analyzed in relation to patient characteristics, i.e. age, sex, body weight, body mass index (BMI), body surface area and smoking status. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria.. The severity of non-hematological toxicity was generally moderate. Grade 4 toxicity was only found in 2 patients with diarrhea (12.5%). The most frequent common adverse events were nausea, Grades 1 - 2 in 13 patients (81.3%), followed by motor neuropathy, Grades 1 - 3 in 11 patients (68.9%). The analyses showed that patient characteristics such as BMI and smoking status were associated with mucositis/stomatitis, vomiting or mood alteration. Furthermore, there was a relationship between smoking status and the overall non-hematological toxicity. Smokers had significantly higher overall toxicity than non-smokers and body mass index correlated significant with overall toxicity.. The results of this pilot investigation suggest that a chronomodulated regimen with oxaliplatin, 5-FU and sodium folinate has a manageable non-hematological toxicity profile and that toxicity of the chronomodulated schedule studied depends on the patient characteristics. In further investigations, risk factors determining chemotherapeutic toxicity should be considered. Because of the small number of patients in this pilot investigation, the findings need to be confirmed in a larger clinical study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Chronotherapy; Diarrhea; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Motor Neurons; Mucositis; Nausea; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Pilot Projects; Risk Factors; Severity of Illness Index; Stomatitis; Vomiting

As no standard chemotherapy regimen has been established for advanced gastric cancer, this study sought to evaluate the efficacy and safety of combination chemotherapy that included paclitaxel and leucovorin (LV)-modulated infusional 5-fluorouracil (5-FU) in metastatic gastric cancer. Patients received a three-hour infusion of 175 mg/m2 of paclitaxel on day 1. A bolus of 20 mg/m2 of LV was then administered, followed by a 24-h infusion of 1,000 mg/m2 of 5-FU on days 1 through 3. The treatment cycle was re-peated every 3 weeks until disease progression. Response evaluation was performed according to the RECIST criteria, with toxicity determined by NCI-CTC (version 2.0). A total of 66 patients, including 21 (31.8%) with a history of prior chemotherapy, were enrolled. Fifteen (71.4%) of the 21 patients with prior chemotherapy received prolonged infusional 5-FU. In the 56 evaluable patients (37 in the chemotherapy-naïve group and 19 in the prior chemotherapy group), tumor responses according to prior exposure to chemotherapy were as follows: 17 (45.9%) partial response (PR), 6 (16.2%) stable disease (SD) and 14 (37.8%) progressive disease (PD) in the chemotherapy-naïve group; 1 (7.1%) complete response, 3 (15.8%) PRs, 8 (42.1%) SDs and 7 (36.8%) PDs in the prior chemotherapy group. The overall median response duration was 20 weeks (range, 8-61 weeks), with a median progression-free survival of 20 weeks [95% confidence interval (CI), 13.4-26.6 weeks] and 12 weeks (95% CI, 5.7-18.3 weeks) in the chemotherapy-naïve and prior chemotherapy groups, respectively. The median overall survival was 48 weeks (95% CI, 38-58 weeks) in the chemotherapy-naïve group and 28 weeks (95% CI, 22-34 weeks) in the prior chemotherapy group. The most frequent grade III/IV toxicity was neutro-penia. Non-hematological toxicity of grade III/IV was rare. Paclitaxel in combination with 5-FU/LV is clinically beneficial for patients with advanced gastric cancer and is a feasible salvage regimen for 5-FU-refractory gastric cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Diarrhea; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mucositis; Multivariate Analysis; Neutropenia; Paclitaxel; Prognosis; Stomach Neoplasms; Survival Analysis; Treatment Outcome

Conventional systemic chemotherapy for metastatic urothelial carcinoma (UC) such as methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) or cisplatin, methotrexate, and vinblastine (CMV) is associated with significant dose-limiting toxicities and even treatment-related death. The authors developed a regimen that was designed to maintain efficacy, while reducing toxicities.. Between January 1998 and July 2003, 35 patients (median age, 71 yrs) with metastatic UC were treated with 4-week cycles of P-HDFL (cisplatin 35 mg/m(2), high-dose 5-fluorouracil [5-FU] 2,600 mg/m(2), and leucovorin 300 mg/m(2), on Days 1 and 8, all given by 24-hr infusion). On Day 15, only HDFL was given again.. Among the 32 patients treated with > or = 2 cycles, 9 (28.1%) and 11 (34.4%) were complete and partial responders, respectively, with an overall response rate of 62.5% (95% confidence interval [CI], 45.9-79.2%). The median overall and progression-free survival was 12.3 months (95% CI, 8.2-16.4 mos) and 10.5 months (95% CI, 8.4-12.6 mos), respectively. Toxicity in a total of 121 courses (mean, 3.5 per patient) was modest, with WHO Grade 3 or 4 leukopenia and thrombocytopenia noted in only 1 and 0 patients, respectively. Grade 3 or 4 nausea, vomiting, mucositis, and diarrhea were noted in 3, 2, 0, and 2 patients, respectively. In general, patients tolerated the regimen very well.. P-HDFL is a moderately active and considerably low-toxic regimen for metastatic UC. The excellent toxicity profile makes it a viable option for patients with poor general conditions. To reach any conclusion, randomized trials comparing P-HDFL with traditional cisplatin-based regimens are necessary.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Survival Rate; Treatment Outcome; Urinary Bladder Neoplasms

Hepatic metastases derive most of their blood supply from the hepatic artery; therefore, for patients with hepatic metastases from colorectal cancer, hepatic arterial infusion (HAI) of chemotherapy may improve outcome.. In a multi-institutional trial, 135 patients were randomly assigned to receive HAI versus systemic bolus fluorouracil and leucovorin. The primary end point was survival; secondary end points were response, recurrence, toxicity, quality of life, cost, and the influence of molecular markers.. Overall survival was significantly longer for HAI versus systemic treatment (median, 24.4 v 20 months; P = .0034), as were response rates (47% and 24%; P = .012) and time to hepatic progression (THP; 9.8 v 7.3 months; P = .034). Time to extrahepatic progression (7.7 v 14.8 months; P = .029) was significantly shorter in the HAI group. Quality-of-life measurements showed improved physical functioning in the HAI group at the 3- and 6-month follow-up assessments. Toxicity included grade > or = 3 neutropenia (2% and 45%; P < .01), stomatitis (0% and 24%; P < .01), and bilirubin elevation (18.6% and 0; P < .01) in the HAI and systemic treatment groups, respectively. A greater proportion of men versus women receiving HAI experienced biliary toxicity (37% and 15%, respectively; P = .05). For HAI patients with thymidylate synthase levels in tumor less than or > or = 4, the median survival was 24 and 14 months, respectively (P = .17).. HAI therapy increased overall survival, response rate, THP, and was associated with better physical functioning compared with systemic therapy. Additional studies need to address the overall benefit and cost of new chemotherapy agents versus HAI alone or the combination of HAI with new agents.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Injections, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Quality of Life; Survival Analysis; Treatment Outcome

Hepatic arterial infusion (HAI) chemotherapy has a number of limitations, including a low rate of complete response and frequent extrahepatic recurrence, in colorectal cancer patients with non-resectable hepatic metastases.. Twenty-nine colorectal cancer patients with non-resectable hepatic metastases were consecutively enrolled for HAI alternating with systemic chemotherapy (HA + SC group). The protocol comprised six cycles of alternating HAI (5-FU + leucovorin for 14 days, and mitomycin C on the first day) and systemic chemotherapy (5-FU + leucovorin). Colorectal cancer patients with two or more hepatic metastases treated using hepatic resection and systemic chemotherapy (HR + SC group) were selected as a comparative group.. Within the HA + SC group, complete response was achieved in eight patients (28%), whereas 13 patients (45%) showed progressive disease. Six of the eight patients with complete response lived for more than 38 months. Extrahepatic recurrences were more frequent in the HR + SC group than the HA + SC group (47 vs 21%, P = 0.024). The two groups did not differ with respect to overall and hepatic progression-free survival (P = 0.947 and 0.444, respectively), displaying median +/- SE values of 38 +/- 7 and 20 +/- 3 months in the HA + SC group, and 39 +/- 9 and 33 +/- 14 months in the HR + SC group, respectively. One patient in each group experienced toxic hepatitis, and sclerosing cholangitis occurred in one patient of the HA + SC group. Other complications were mostly grade 1 or 2.. HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Treatment Outcome

The postresectional tumor recurrence rate is high in patients with hepatocellular carcinoma (HCC). Tumor portal venous invasion is the most important factor related to recurrence. Adjuvant intraportal infusion chemotherapy (IPIC) was used in HCC patients to improve the outcomes.. Between June 1998 and May 1999, 28 HCC patients (IPIC group) underwent postresectional IPIC daily for 2 days with 5-fluorouracil (650 mg/m(2)), leucovorin (45 mg/m(2)), doxorubicin (10 mg/m(2)), and cisplatin (20 mg/m(2)). Treatment was repeated every 3 weeks for six cycles. Patient outcomes were compared with those of 66 matched HCC patients (control group) who underwent hepatectomy without adjuvant therapy.. The IPIC group received an average of 5.2 cycles of chemotherapy, starting 5 to 24 days after surgery. The most frequent IPIC-related adverse events were upper abdominal pain, vomiting, and myelosuppression. Five-year disease-free and overall survival rates for the IPIC group were 44.6% and 60.7%, respectively. Subgroup analysis of patients with tumor-node-metastasis stage I and II disease identified significantly lower recurrence rates for the IPIC group (33.3%) than the control group (65.0%; P = .025). For patients with stage I and II disease, 5-year disease-free and overall survival rates for the IPIC group (70.6% and 83.3%, respectively) were significantly higher than those of the control group (33.4% and 46.9%, respectively; P < .05). Patients with stage III disease do not benefit from IPIC.. Postoperative IPIC benefits HCC patients with tumor-node-metastasis stage I and II disease. The survival advantages demonstrated justify a selection of patients for future trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Chemotherapy, Adjuvant; Cisplatin; Doxorubicin; Female; Fluorouracil; Hepatectomy; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Portal Vein; Postoperative Period; Survival Rate; Treatment Outcome

Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit.. In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity.. The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13).. Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; France; Hepatectomy; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Survival Analysis; Switzerland; Treatment Outcome

This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with 5-fluorouracil/leucovorin in patients with advanced solid tumours, and to identify the maximum tolerated dose and the dose for use in future studies.. BAY 12-9566 and 5-fluorouracil/leucovorin were administered to 17 patients in 3 cohorts. Each patient served as his/her own control, with 5-fluorouracil being given alone on days 1-5 of cycle 1. In cohort 1, BAY 12-9566 at 800 mg p.o. b.i.d. was given with 350 mg/m2 5-fluorouracil/20 mg/m2 leucovorin x 5 days q28 days. In cohort 2, the BAY 12-9566 dose was reduced to 400 mg p.o. b.i.d., with the 5-fluorouracil/leucovorin doses remaining unchanged. Finally, in cohort 3, BAY 12-9566 400 mg bid was given with 5-fluorouracil 400 mg/m2/day. Patients were continued on therapy until unacceptable toxicity or tumour progression occurred. Pharmacokinetic analyses for both BAY 12-9566 and 5-fluorouracil were performed.. The maximum tolerated dose was 400 mg p.o. b.i.d. BAY 12-9566 plus 5-fluorouracil/leucovorin at 400 mg/m2/day and 20 mg/m2/day, respectively. Thrombocytopenia necessitated a decrease of the dose of BAY 12-9566 by 50% from cohort 1 to cohort 2. Two dose-limiting toxicities occurred in cohort 3 consisting of neutropenic fever, and ileitis, causing severe diarrhea. Of 17 patients treated on study, 7 of 14 patients evaluable for response achieved stable disease. Pharmacokinetic analysis suggested there was no interaction between BAY 12-9566 and 5-fluorouracil.. BAY 12-9566 400 mg bid and 5-fluorouracil 350 mg/m2 plus leucovorin 20 mg/m2 can be co-administered. Although there is some evidence of a clinical interaction, there is no apparent pharmacokinetic interaction. Future studies with these 2 types of agents administered in combination are warranted.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Biphenyl Compounds; Canada; Cohort Studies; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Kidney Neoplasms; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Matrix Metalloproteinase Inhibitors; Maximum Tolerated Dose; Organic Chemicals; Phenylbutyrates; Safety; Salvage Therapy

Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease.. Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated.. Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free.. Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheter Ablation; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Patient Selection; Treatment Outcome

A phase I-II multicenter trial was conducted to define the maximal tolerated dose and describe the activity of an OCFL combination using oxaliplatin (OHP), irinotecan (CPT-11) and 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (CRC).. CRC patients not pretreated with palliative chemotherapy, with performance status < or =1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m(2))/LV (30 mg) and alternating OHP (70-85 mg/m(2), days 1 and 15) and CPT-11 (80-140 mg/m(2), days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients.. Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m(2), CPT-11 100 mg/m(2), LV 30 mg and 5-FU 2300 mg/m(2)/24 h. Grade > or =3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection.. OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prognosis; Survival Analysis; Treatment Outcome

We evaluated the efficacy and tolerability of a modified biweekly irinotecan, 5-fluorouracil and leucovorin regimen (modified Douillard regimen) as the first-line therapy in patients with advanced colorectal cancer.. A total of 80 patients (41 male, 39 female) with recurrent or metastatic colorectal cancer were enrolled between April 2001 and December 2003. The treatment cycle consisted of irinotecan 150 mg/m(2) as a 90 min infusion on day 1, leucovorin 20 mg/m(2) intravenous bolus, immediately followed by a 48 h continuous infusion of 5-fluorouracil 3000 mg/m(2) on day 1. The primary end-point was response rate, and the secondary end-points were time to progression and toxicity profile.. An overall objective response rate of 38.7% [95% confidence interval (CI) 27.84-49.66%] was achieved. The median time to progression was 6.1 months (95% CI 4.63-7.57 months) and the median overall survival time was 20.2 months (95% CI 15.50-24.90 months). The median duration of follow-up for patients was 16.9 months. The toxicity profile was more favorable than for the conventional Douillard regimen.. We conclude that the modified Douillard regimen may be a practical and more tolerable treatment option in patients with advanced colorectal cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Rectal Neoplasms; Survival Analysis; Treatment Outcome

To verify the experience of the GOIM in the treatment of advanced colorectal cancer patients with the FOLFIRI combination therapy.. Patients entered in three consecutive trials of the GOIM (protocols no. 9706, 9901, and 2301) were reported in this analysis. A total of 287 chemotherapy-naive patients were treated with FOLFIRI regimen: Irinotecan 180 mg/m(2) on day 1 with LV5FU2 regimen (LV at 100 mg/m(2) administered as a 2-hour infusion before FU at 400 mg/m(2) as an intravenous bolus injection, and FU at 600 mg/m(2) as a 22-hour infusion immediately after 5FU bolus injection on day 1 and 2); the treatment was repeated every 2 weeks.. 287 patients entered in these three trials, and 264 (92%) were evaluable for response. The overall response rate was 34.5% (95% confidence interval [CI]: 29% to 40%). When only assessable patients were analyzed, overall response rate was 37% (95% CI: 31% to 43%). Median time to progression, median duration of response and survival were 7 months, 10.5 months and 14 months, respectively. All but three patients were evaluable for toxicity which was globally mild; grade 3-4 toxicity was uncommon, and gastrointestinal disturbances were the most common.. FOLFIRI regimen is effective and well-tolerated as first-line treatment in patients with advanced colorectal cancer. Further studies needed to evaluate the improvement in results with the addition of new drugs to this combination therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Celecoxib; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Pyrazoles; Sulfonamides; Treatment Outcome

Pharmacokinetic modulating chemotherapy (PMC) is designed to boost high serum 5-fluorouracil (5-FU) concentrations through modulation by uracil. The therapeutic efficacy of PMC and the sensitivity of metastatic lesions to 5-FU were evaluated in advanced colorectal cancer patients.. Thirteen patients with colorectal carcinoma metastases to multiple organs were enrolled. PMC was initiated with a combination of 400 mg of uracil-tegafur daily and 24-hour continuous intravenous infusion of 600 mg/m2 of 5-FU once weekly. The 5-FU dose was escalated when the disease progressed. When PR was achieved, serum 5-FU concentrations were monitored in order to evaluate the chemosensitivity of each metastatic lesion to 5-FU.. PR in the target lesion was observed in 7 of 11, 6 of 10, 2 of 2, and 2 of 4 patients with metastatic lesions to the liver, lungs, peritoneum and lymph nodes, respectively. The area under the concentration-time curve (AUC ng x hr/ml) of the 5-FU sufficient to induce PR in pulmonary lesions, 3528 to 9684, was significantly higher than for hepatic lesions, 2413 to 6323 (p = 0.028). The median survival was 13 months.. PMC, having a chronomodulating nature, is highly effective in treating colorectal carcinoma metastases with a superior safety profile. Pulmonary metastases are more resistant to 5-FU than hepatic metastases, as they require a higher 5-FU AUC to respond.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Chronotherapy; Colorectal Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Tegafur; Uracil

To determine the maximum-tolerated dose (MTD) of concurrent systemic oxaliplatin (Oxal) combinations plus hepatic arterial infusion (HAI) in patients with unresectable hepatic metastases from colorectal cancer.. Thirty-six patients (89% previously treated) with unresectable liver metastases were treated with concurrent HAI and systemic Oxal plus irinotecan (CPT-11; group A) or Oxal, fluorouracil (FU), and leucovorin (LV; group B). Systemic chemotherapy was administered every 2 weeks concurrent with 2 weeks of HAI floxuridine (FUDR) and dexamethasone (Dex) every 28 days.. The MTD for patients in group A was Oxal 100 mg/m(2), CPT-11 150 mg/m(2), and FUDR 0.12 mg/kg x 30 mL divided by pump flow rate. The MTD for group B was Oxal 100 mg/m(2), LV 400 mg/m(2), and FU 1,400 mg/m(2) by continuous infusion over 48 hours, with the same FUDR dose as in group A. Grade 3 or 4 toxicities in groups A and B included diarrhea (24% and 20%), neutropenia (10% and 7%), neurotoxicity (24% and 20%), and bilirubin more than 3 mg/mL (5% and 7%, respectively). The complete and partial response rate totaled 90% for group A and 87% for group B. Median survival time was 36 and 22 months for groups A and B, respectively. Seven patients in group A were ultimately able to undergo liver resection.. Combination therapy with HAI FUDR and Dex plus systemic Oxal combinations may be safely administered to patients with colorectal cancer. The high response rate (88%) and the possibility of conversion to resectability, despite disease progression on prior systemic regimens, suggest that these combinations should be evaluated in larger studies as first- or second-line therapy in patients with hepatic metastases from colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Treatment Outcome

Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks).. Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months.. Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively.. The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

To determine whether floxuridine (FUDR) can be delivered with low hepatic toxicity through the portal vein (PV) as an adjuvant to surgically treated colorectal metastases.. Fifty-one patients undergoing complete resection and/or ablation for colorectal hepatic metastases were prospectively enrolled at a National Cancer Institute-designated comprehensive cancer center. Two sequential phase II trials were performed. Each trial included complete surgical treatment followed by sequential, alternating (22 patients) or concurrent (29 patients) regional PV FUDR and systemic fluorouracil (FU) with leucovorin chemotherapy.. Fifty percent of patients were male. The mean age at diagnosis was 57 years. The mean number of lesions resected was three (range, one to 11 lesions). The stage at diagnosis was II, III, and IV in 16.9%, 52.8%, and 28.3% of patients, respectively. One- and 3-year overall survival rates were 92.7% and 41.8%, respectively. The 1- and 3-year disease-free survival rates were 64.5% and 19%, respectively. The site of first recurrence was hepatic in 35.9% of patients. Treatment was terminated early in 24 patients (17 patients progressed, two refused treatment, and five had nonhepatic toxicities). Fifty-five percent of patients received 75% to 100% of the planned FUDR courses, and 72% received greater than 50% of the planned FUDR dose. Only four patients required dose reductions of FUDR because of grade 3 hepatic toxicity. No patient required biliary stenting or had discontinuation of PV infusion because of hepatic toxicity.. The delivery of PV FUDR and FU with leucovorin can be performed with a high percentage of expected drug delivery and a low drug-induced hepatic toxicity rate, while achieving acceptable overall and disease-free survival.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Portal Vein

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neutropenia; Survival Analysis

We conducted a phase I/II randomized trial to evaluate the clinical and immunologic effect of chemotherapy combined with vaccination in primary metastatic colorectal cancer patients with a carcinoembryonic antigen-derived peptide in the setting of adjuvants granulocyte macrophage colony-stimulating factor, CpG-containing DNA molecules (dSLIM), and dendritic cells.. HLA-A2-positive patients with confirmed newly diagnosed metastatic colorectal cancer and elevated serum carcinoembryonic antigen (CEA) were randomized to receive three cycles of standard chemotherapy (irinotecan/high-dose 5-fluorouracil/leucovorin) and vaccinations with CEA-derived CAP-1 peptide admixed with different adjuvants [CAP-1/granulocyte macrophage colony-stimulating factor/interleukin-2 (IL-2), CAP-1/dSLIM/IL-2, and CAP-1/IL-2]. After completion of chemotherapy, patients received weekly vaccinations until progression of disease. Immune assessment was done at baseline and after three cycles of combined chemoimmunotherapy. HLA-A2 tetramers complexed with the peptides CAP-1, human T-cell lymphotrophic virus type I TAX, cytomegalovirus (CMV) pp65, and EBV BMLF-1 were used for phenotypic immune assessment. IFN-gamma intracellular cytokine assays were done to evaluate CTL reactivity.. Seventeen metastatic patients were recruited, of whom 12 completed three cycles. Therapy resulted in five complete response, one partial response, five stable disease, and six progressive disease. Six grade 1 local skin reactions and one mild systemic reaction to vaccination treatment were observed. Overall survival after a median observation time of 29 months was 17 months with a survival rate of 35% (6 of 17) at that time. Eight patients (47%) showed elevation of CAP-1-specific CTLs. Neither of the adjuvants provided superiority in eliciting CAP-1-specific immune responses. During three cycles of chemotherapy, EBV/CMV recall antigen-specific CD8+ cells decreased by an average 14%.. The presented chemoimmunotherapy is a feasible and safe combination therapy with clinical and immunologic efficacy. Despite concurrent chemotherapy, increases in CAP-1-specific T cells were observed in 47% of patients after vaccination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoembryonic Antigen; CD3 Complex; CD4 Antigens; CD8 Antigens; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Flow Cytometry; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; HLA-A2 Antigen; Humans; Immunodominant Epitopes; Immunotherapy; Interferon-gamma; Interleukin-2; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oligopeptides; Prospective Studies; T-Lymphocytes; Treatment Outcome

A clinical study has been conducted since August 2001 to investigate whether chemotherapy with CPT-11/l-LV/ 5-FU/UFT could be an effective regimen for advanced or recurrent colorectal cancer. The chemotherapy consisted of CPT-11 30 mg/m2 iv, as a 120-minute infusion, followed by l-LV 30 mg/m2, as a 60-minute infusion, followed by 5-FU 300 mg/m2, as a 120-minute infusion. This treatment was administered weekly for 6 weeks followed by a 2-week rest period and repeated every 8 weeks. UFT (250 mg/m2/day) was orally administered daily. All patients were evaluable for efficacy, 2 CR, 5 PR, 3 SD and 7 PD. The overall response rate was 41.1% with a median time to progression of 7.1 months and a median survival time of 12.0 months. No grade 3/4 toxicities were observed. The present study suggests that combination chemotherapy with CPT-11, l-LV, 5-FU, and UFT is well tolerated and might be a promising regimen for advanced or recurrent colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Nausea; Rectal Neoplasms; Survival Rate; Tegafur; Uracil; Vomiting, Anticipatory

Surgical resection of liver-only metastases from colorectal cancer has undergone extensive evaluation and review. The use of neoadjuvant chemotherapy to improve the likelihood of resection in disease that is not optimally resectable has not been as well studied.. Patients with liver-only metastases from colorectal cancer deemed not optimally resectable by a surgeon with expertise in liver surgery received fluorouracil, leucovorin, and oxaliplatin (FOLFOX4). Patients were periodically reassessed for resectability. Surgical response was classified as completely resectable (S-CR), partially resectable (S-PR), or unresectable (S-UR). Study design specified the accrual of 39 patients, with two or more S-CRs considered evidence of promising activity with respect to increasing the S-CR rate.. Forty-two of 44 patients were assessable for this analysis. Twenty-five patients (60%) had tumor reduction by serial imaging. Seventeen patients (40%) underwent surgery (S-CR, n = 14; S-PR, n = 1; and S-UR, n = 2) after a median of 6 months of chemotherapy. With a median postsurgical follow-up of 22 months (range, 13 to 32 months), 11 recurrences have occurred in the 15 S-CR and S-PR patients. Median survival time was 26 months.. Our data suggest that FOLFOX4 has a high response rate (complete response, partial response, or reduction) in patients with liver-only metastases from colorectal cancer, allowing for successful resection of disease in a portion of patients initially not judged to be optimally resectable. However, a high recurrence rate after surgery was observed, which, in 73% of patients, involved the liver. Further trials are indicated based on the promising results observed in this trial.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds

Standard chemotherapy for advanced gastric cancer remains undefined. Phase II trials show that taxol is effective in treating advanced gastric cancer. This multi-center prospective open randomized controlled study was to compare the efficacy of Taxol plus calcium folinate (CF)/5-fluorouracil (5-FU), Taxol plus oxaliplatin (OXA), and CF/5-FU plus cisplatin (DDP) on advanced gastric cancer, and analyze their toxicities.. Patients with measurable unresectable and/or metastatic gastric carcinoma were randomized into CF/5-FU+DDP (control), CF/5-FU + Taxol, and Taxol + OXA groups, and received up to 8 cycles of chemotherapy. Treatment efficacy and adverse events were evaluated according to WHO criteria.. A total of 180 patients were enrolled from May 2002 to May 2004, and randomized into the 3 groups; each group contained 60 patients. Of the 180 patients, 14 received 2 cycles of chemotherapy, 49 received 4 cycles, and 103 received 8 cycles. Treatment outcomes of 166 cases were evaluable. The response rate (RR) of naive patients or the patients with retroperitoneal lymph node metastasis was significantly higher in CF/5-FU+Taxol and Taxol+OXA groups than in control group (50.00% and 80.00% vs. 20.75%, P<0.05; 65.96% and 85.71% vs. 36.36%, P<0.05). But the RR of the patients with liver metastasis was similar among the 3 groups (28.57% and 39.13% vs. 34.62%, P>0.05). The occurrence rates of nausea/vomiting, anepithymia, stomatitis, and kidney damage were lower in study groups than in control group, but the occurrence rates of myelosuppression and peripheral nerve damage were higher in study groups than in control group. Allergic response occurred in 7 (5.88%) patients in study group, and 3 (2.52%) of them were serious. There was no treatment-related death.. Despite its hematotoxicity, the treatment efficacy of Taxol-based combination regimens on advanced gastric cancer is better than that of CF/5-FU + DDP regimen with tolerable toxicities. We recommend Taxol-based combination regimens as first-line regimens for advanced gastric cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Prospective Studies; Remission Induction; Stomach Neoplasms; Thrombocytopenia

The purpose of this report is to evaluate the efficacy and toxicity (Tx) of a double modulation of 5-fluorouracil (5-FU) by trimetrexate (TMTX) and leucovorin (LV) in patients with advanced recurrent (inoperable) or metastatic colorectal cancer (ACC). Between December 1997 and August 2000, 36 patients were entered in this phase II study. Median age was 61 years, and 18 patients (50%) were female. Median performance status was 0 (range: 0-1), whereas primary tumor location was colon in 21 patients (58%) and rectum in 15 patients (42%). The number of metastatic sites was 1:29 patients (81%); 2:6 patients (17%) and 3:1 patient (3%). Hepatic involvement was observed in 33 patients (92%). Treatment consisted of TMTX 110 mg/m2 IV over 1 hour at hour (H) 0; LV 50 mg/m2 IV over 2 hours IV infusion starting at H 18; and 5-FU 900 mg/m2 IV bolus at H 20. LV (rescue) 15 mg/m2 orally was administered every 6 hours (total 6 doses) beginning at H 24. Cycles were repeated every 2 weeks until progressive disease (PD) or severe Tx. Thirty-four patients are assessable for response (R) (two patients refused further treatment after the first course of therapy), whereas all patients were assessable for Tx. Complete response: 1 patient (3%); partial response: 4 patients (12%), with an overall objective response rate of 15% (95% CI, 1%-25%); no change: 12 patients (35%); and progressive disease: 17 patients (50%). The median time to treatment failure was 4 months and median survival was 11 months. Tx was within acceptable limits. The dose-limiting side effect was mucositis. Eight episodes of grade II or III stomatitis were observed and were responsible for dosage modifications of TMTX and 5-FU. Leukopenia was observed in 16 patients (44%); neutropenia was registered in 19 patients (53%); anemia was seen in 18 patients (50%); emesis in 22 patients (61%); and dermatitis in 3 patients (8%). There were no therapy-related deaths. The double modulation of 5-FU by TMTX and LV showed modest antitumoral activity with mild to moderate Tx.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Survival Analysis; Treatment Failure; Trimetrexate

This phase I-II trial was designed to assess the effect of irinotecan on oxaliplatin pharmacokinetics and to determine the MDT of both drugs when administered in combination. Treatment was repeated every 2 weeks. Pharmacokinetic studies were performed on cycle 1 and 2 to assess the best sequence and detect any interaction between the two drugs. Thirty-four patients with advanced colorectal cancer were enrolled; 28 of them (82%) had liver involvement. The main toxicities were neutropenia and delayed diarrhea; 5 patients (14%) experienced febrile neutropenia. Dose-limiting toxicity was experienced at levels 1/2/3/4/5 by 4/10, 1/6, 3/6, 3/8, and 3/4 patients, respectively. Fifteen patients responded (2 CR; 13 PR) for an ORR of 44%. No pharmacokinetic interactions between irinotecan and oxaliplatin were detected. The recommended dose for future phase II trials is oxaliplatin 85 mg/m and irinotecan 180 mg/m2 on day 1 combined with 5FU/leucovorin according to the de Gramont regimen at days 2 and 3. Twenty-nine percent of patients underwent secondary hepatectomy with curative intent, and two of them are long-term disease-free survivors. It would appear that the dose and schedule defined by this trial could be proposed as front-line therapy for advanced colorectal carcinoma to establish rapid disease control and to permit patients to proceed to surgery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Analysis

This phase II clinical trial was performed in order to evaluate the pharmacokinetics, toxicity and anti-tumor activity of a novel combination of gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) designed on a specific translational basis. Every 4 weeks, 44 patients with various gastroenteric malignancies, 29 of whom had pancreas carcinoma, received a short intravenous (i.v.) infusion of FA (100 mg/m2) and 5-FU (400 mg/m2) on days 1-5, and GEM 1000 mg/m2 on days 1, 8 and 16. Our results suggest that, although this treatment leads to hematological and gastroenteric toxicity, it is very active in patients with pancreatic carcinoma. We therefore believe that an improved version would merit further investigation in larger scale trials.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Digestive System Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Gemcitabine; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Treatment Outcome

Following resection of liver metastases from colorectal cancer, 5-year survivals are reportedly 30 - 39%. It can be assumed that this clinical situation represents systemic disease. Therefore, it is postulated that systemic chemotherapy would improve outcomes, particularly in those whose disease is sensitive to the agents administered. One potential advantage of neoadjuvant chemotherapy is that it provides in vivo chemosensitivity data. Response to neoadjuvant chemotherapy could therefore guide adjuvant chemotherapy following resection of liver metastases from colorectal cancer.. This is a prospective Phase II evaluation of outcomes in patients with potentially resectable liver metastases. Patients will receive neoadjuvant chemotherapy and will undergo resection. Postoperative chemotherapy will be directed by the degree of response to preoperative chemotherapy. All patients with Stage IV colorectal adenocarcinoma isolated to the liver that have disease that is amenable to complete ablation by resection, radiofrequency ablation, and/or cryoablation will be candidates for the trial. Patients will receive CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2, every 2 weeks. Altogether, six cycles of chemotherapy will be administered. Patients will then undergo resection and/or radiofrequency ablation. Patients who had stable disease or a clinical response with preoperative chemotherapy will receive an additional 12 cycles of CPT-11 180 mg/m2 IV (over 90 minutes) on day 1 with 5-FU 400 mg/m2 bolus and 600 mg/m2 by 22 hour infusion and calcium folinate 200 mg/m2 on days 1 and 2 (given every 2 weeks). Patients with resectable disease who had progressive disease during neoadjuvant chemotherapy will receive best supportive care or an alternative agent, at the discretion of the treating physician. Those patients who are not rendered free of disease following the neoadjuvant chemotherapy and surgery will receive best supportive care or an alternative agent, at the discretion of the treating physician. The primary endpoint of the study is disease-free survival. Secondary endpoints include overall survival, safety and feasibility, response to chemotherapy, and quality of life.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cause of Death; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Quality of Life

Combination therapy of irinotecan, folinic acid (FA) and 5-fluorouracil (5-FU) has been proven to be highly effective for the treatment of metastatic colorectal cancer. However, in light of safety and efficacy concerns, the best combination regimen for first-line therapy still needs to be defined. The current study reports on the bimonthly FOLFIRI protocol consisting of irinotecan with continuous FA/5-FU in five German outpatient clinics, with emphasis on the safety and efficiency, quality of life, management of delayed diarrhea, and secondary resection of regressive liver metastases.. A total of 35 patients were treated for metastatic colorectal cancer. All patients received first-line treatment according to the FOLFIRI regimen, consisting of irinotecan (180 mg/m2), L-FA (200 mg/m2) and 5-FU bolus (400 mg/m2) on day 1, followed by a 46-h continuous infusion 5-FU (2400 mg/m2). One cycle contained three fortnightly administrations. Staging was performed after 2 cycles. Dosage was reduced at any time if toxicity NCI CTC grade III/IV was observed. Chemotherapy was administered only to diarrhea-free patients.. The FOLFIRI regimen was generally well tolerated. It was postponed for one-week in 51 of 415 applications (12.3%). Dose reduction was necessary in ten patients. Grade III/IV toxicity was rare, with diarrhea (14%), nausea/vomiting (12%), leucopenia (3%), neutropenia (9%) and mucositis (3%). The overall response rate was 31% (4 CR and 7 PR), with disease control in 74%. After primary chemotherapy, resection of liver metastases was achieved in three patients. In one patient, the CR was confirmed pathologically. Median progression-free and overall survival were seven and 17 months, respectively.. The FOLFIRI regimen proved to be safe and efficient. Outpatient treatment was well tolerated. Since downstaging was possible, combinations of irinotecan and continuous FA/5-FU should further be investigated in neoadjuvant protocols.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Diarrhea; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Hematologic Diseases; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Nausea; Quality of Life; Remission Induction; Treatment Outcome

Patients with measurable liver metastases due to breast cancer and elevated liver enzymes were enrolled into the study. The planned schedule was mitomycin C 8 mg/m2 on day 1, 5-fluorouracil 750 mg/m2 and folinic acid 300 mg/m2 on day 1 and 2 every 4 weeks (Mi-Fu-Fo). Between May 1998 and December 2002, 30 patients with a median age of 51 years (range 33-74) were enrolled. All of them suffered from extensive metastases of the liver resulting in liver dysfunction. Myelosuppression was the most frequent toxicity. Six patients had a partial remission, 12 patients had stable disease and 12 patients progressed during treatment. The median time to progression was 4.5 months in all patients and 7.0 months in patients who responded to the therapy. The median overall survival for the total population was 6.0 months and in the group of responding patients 12.0 months. Mi-Fu-Fo, therefore, provides a valid option for breast cancer patients with liver dysfunction due to liver metastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Liver Function Tests; Liver Neoplasms; Middle Aged; Mitomycin; Remission Induction; Salvage Therapy; Survival Analysis

To assess the outcome of interventional hepatic arterial port placement in a prospective phase II trial.. One-hundred five consecutive patients were included in this study. Primary endpoint was port patency; secondary endpoints were complications, toxicity, response, and progression free and overall survival. Seventy-eight patients presented with liver metastasis only, 6 patients had additional minor extrahepatic disease, and 21 patients had no evidence of disease after liver resection, laser-induced thermotherapy, or computed tomography (CT)-guided interstitial brachytherapy of liver metastasis. Exclusive access route was the femoral artery. Subgroup analysis compared either 4-F catheters (n = 58) to 2.2-F (n = 33) and 2.7-F (n = 20) microcatheters or different strategies in anatomic variants of the celiac branch: neglect (n = 10) or embolization of minor hepatic feeders (n = 11), splenic arterial port (n = 8), double port (n = 7).. Technical success was 99%. Assisted port patency after 6 months was 93%. Complications demanding port revisions were significantly lower in patients receiving 4-F versus 2.2-F and 2.7-F systems (P <.001), with disconnection as the major problem with use of microcatheters. Hepatic artery thrombosis occurred in 10 patients (9%), with successful lysis in two patients. With use of 4-F and 2.2-F catheters, there was no difference with respect to catheter occlusion or hepatic thrombosis. No differences were noted in complications or outcome applying four different strategies in celiac branch variants. In a subgroup of patients receiving folinic acid/5-fluorouracil (170 mg/600 mg; 10% dose escalation per cycle) for 5 days every 4 weeks only 15% experienced Grade 3 toxicity. Patients with liver metastasis and salvage therapy demonstrated progression-free survival of 63% after 6 months and a median survival of 16 months.. Interventional placement of hepatic arterial port systems may overcome frequent hepatic arterial chemotherapy failures as encountered in all published major trials on hepatic arterial infusion.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Catheterization, Peripheral; Disease-Free Survival; Embolization, Therapeutic; Equipment Safety; Female; Femoral Artery; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome; Vascular Patency

This single-centre phase I trial was designed to determine the maximum tolerated dose of irinotecan and the recommended dose to use in combination with a fixed dose of 5-fluorouracil (5-FU) administered as a protracted venous infusion, for the first-line treatment of metastatic colorectal cancer (CRC). Tolerability and efficacy were secondary end points. In all, 22 patients, median age 57 years, were treated with escalating, weekly doses of irinotecan (50, 75, 100 and 85 mg m(-2)) in combination with 250 mg m(-2) 5-FU administered as a continuous infusion. All patients had measurable disease. The combination was well tolerated up to an irinotecan dose of 75 mg m(-2). However, three out of five patients at the 100 mg m(-2) irinotecan dose level had their dose reduced due to multiple grade 2 toxicities, and eventually one patient stopped treatment due to grade 3 diarrhoea and multiple grade 2 toxicities. Subsequent patients were recruited at an irinotecan dose level of 85 mg m(-2). The overall response rate was 55%, comprising one complete and 11 partial responses (PRs). Six patients also achieved sustained stable disease (SD), giving a clinical benefit (complete response/PR/SD) response of 82%. The median duration of response was 238 days (8.5 months) and median time to progression was 224 days (8.0 months). Two patients who achieved PRs underwent partial hepatectomies. Thus, irinotecan (85 mg m(-2)) combined with a continuous infusion of 5-FU (250 mg m(-2)) is an active and well-tolerated regimen for the treatment of metastatic CRC. It represents an effective treatment for patients who require close supervision and support, throughout their initial exposure to chemotherapy for this disease, and this dose combination was recommended for an ongoing phase II study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Prognosis; Survival Rate; Treatment Outcome

Selective internal radiation therapy (SIRT) with SIR-Spheres(R) is a new technique for selectively targeting high doses of radiation to tumours within the liver. The primary objectives of this randomised trial were to compare the response rate, time to progressive disease (PD), and toxicity of a regimen of systemic fluorouracil/leucovorin chemotherapy versus the same chemotherapy plus a single administration of SIR-Spheres in patients with advanced colorectal liver metastases. The trial was designed to presage a larger trial that would have survival as the primary outcome.. Twenty-one patients with previously untreated advanced colorectal liver metastases, with or without extrahepatic metastases, were randomised into the study.. Using RECIST criteria, the response rate for 11 patients receiving the combination treatment was significantly greater than for 10 patients receiving chemotherapy alone (First Integrated Response; 10 PR, 1 SD vs. 0 PR, 6 SD, 4 PD, P < 0.001 and Best Confirmed Response; 8 PR, 3 SD vs. 0 PR, 6 SD, 4 PD P < 0.001). The time to PD was greater for patients receiving the combination treatment (18.6 months vs. 3.6 months, P < 0.0005). Median survival was significantly longer for patients receiving the combination treatment (29.4 months vs. 12.8 months, P = 0.02). One patient in the combination arm died from chemotherapy induced neutropenic sepsis after the fourth chemotherapy cycle. There were more Grade 3 and 4 toxicity events in patients receiving the combination treatment. There was no difference in quality-of-life over a 3 month period between the two treatments when rated by patients (P = 0.96) or physicians (P = 0.98).. This small phase 2 randomised trial demonstrated that the addition of a single administration of SIR-Spheres to a regimen of systemic fluorouracil/leucovorin chemotherapy significantly increased both treatment related response, time to PD, and survival with acceptable toxicity. The combination of SIR-Spheres plus systemic chemotherapy is now the subject of ongoing trials to further define patient benefit.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Quality of Life; Radiotherapy Dosage; Survival Rate

To evaluate the efficacy and safety of neoadjuvant treatment comprising weekly high-dose 5-fluorouracil (5-FU) as a 24-hour infusion, folinic acid (FA) and biweekly oxaliplatin (L-OHP), followed by metastatic resection in patients with primarily resectable liver metastases of colorectal cancer (CRC).. 20 patients with primarily resectable liver metastases of CRC were enrolled in a prospective phase II study. On an outpatient basis, the patients received a treatment regimen comprising biweekly 85 mg/m(2) L-OHP in the form of a 2-hour intravenous infusion and 500 mg/m(2) FA as a 1- to 2-hour intravenous infusion, followed by 2,600 mg/m(2 ) 5-FU administered as a 24-hour intravenous infusion once weekly. A single treatment cycle comprised one infusion per week during a period of 6 weeks followed by a 2-week rest. Two cycles were administered, with a third being added when the treatment was well tolerated. Thereafter, curative resection of the liver metastases was attempted, and the patients were followed up.. After neoadjuvant therapy, 2 of the original 20 patients showed complete remission (CR; 10%) and 18 patients partial remission (PR; 90%). As the main symptom of toxicity, diarrhea (CTC toxicity grade 3-4) was observed in 6 patients (30%), followed by vomiting in 3 patients (15%). The curative resectability rate was 80% (16 of 20). In 9 of 18 patients (50%) undergoing surgical intervention, mild postoperative complications, mainly wound healing disturbances (n = 5), occurred. No postoperative mortality was observed. Over a median follow-up of 23 months (12-38) 6 of 16 curatively resected patients developed distant metastases and 1 patient a local pelvic recurrence. The 2-year disease-free survival rate was 52% and the 2-year cancer-related survival rate 80%.. The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24-hour infusion combined with FA and L-OHP is very effective and well tolerated. Surgical morbidity does not appear to be increased by the neoadjuvant treatment.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome

The liver is the most frequent site for metastases of colorectal cancer, which is the second largest contributor to cancer deaths in Europe. We did a randomised trial to compare an intrahepatic arterial (IHA) fluorouracil and folinic acid regimen with the standard intravenous de Gramont fluorouracil and folinic acid regimen for patients with adenocarcinoma of the colon or rectum, with metastases confined to the liver.. We randomly allocated 290 patients from 16 centres to receive either intravenous chemotherapy (folinic acid 200 mg/m2, fluorouracil bolus 400 mg2 and 22-h infusion 600 mg/m2, day 1 and 2, repeated every 14 days), or IHA chemotherapy designed to be equitoxic (folinic acid 200 mg/m2, fluorouracil 400 mg/m2 over 15 mins and 22-h infusion 1600 mg/m2, day 1 and 2, repeated every 14 days). The primary endpoint was overall survival, and analysis was by intention to treat.. 50 (37%) patients allocated to IHA did not start their treatment, and another 39 (29%) had to stop before receiving six cycles of treatment because of catheter failure. The IHA group received a median of two cycles (0-6), compared with 8.5 (6-12) for the intravenous group. 45 (51%) IHA patients who did not start or did not receive six cycles switched to intravenous treatment. In both groups, grade 3 or 4 toxicity was uncommon. Median overall survival was 14.7 months for the IHA group and 14.8 months for the intravenous group (hazard ratio 1.04 [95% CI 0.80-1.33], log-rank test p=0.79). Similarly, there was no significant difference in progression-free survival.. Our results showed no evidence of an advantage in progression-free survival or overall survival for the IHA group; thus continued use of this regimen cannot be recommended outside of a clinical trial.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Germany; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Ireland; Karnofsky Performance Status; Leucovorin; Liver Neoplasms; Male; Middle Aged; Proportional Hazards Models; Survival Analysis; Treatment Outcome; United Kingdom

Since there are currently no data available from a prospective trial, the primary objective of this prospective study was to investigate whether the rate of R0-liver resections without morbidity would be at least 50 % in patients with neoadjuvant chemotherapy for colorectal liver metastases.. 42 patients were treated with a biweekly FOLFOX regimen. Chemotherapy consisted of a 2-hour infusion of folinic acid (FOL) 500 mg/m2, followed by a 24-hour infusion of 5- fluorouracil (F) 2000 mg/m2 daily for two days. Oxaliplatin (OX) 85 mg/m 2 was given simultaneously with FOL. Treatment allocation was randomized with either 3 or 6 cycles for the final 30 patients. A liver resection was performed 2 to 5 weeks after the final infusion.. An objective response was observed in 20 of 42 patients (response rate was 27 % higher after 6 cycles). Liver resection (R0) could be performed in 34 patients. Postoperative complications were reported in 14 patients (13 occurring within 30 days after resection) and severe complications in 5 cases (including two deaths after extended resection). Liver failure and persistent biliary fistula were the most frequently documented complications. There was no relevant difference in safety criteria between 3 and 6 applications.. The use of neoadjuvant chemotherapy in resectable liver metastases induced significant remissions without increasing morbidity. The rate of severe complications and cases of no R0-resection in this study was 31 % and was with that significantly lower than 50 % (95 % CI 17.6 %-47.1 %). The risk to the patient is therefore acceptable when undergoing neoadjuvant treatment in a prospective intergroup trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pilot Projects; Postoperative Complications; Prospective Studies; Survival Rate

The purpose of this study was to evaluate the prognostic value of quantitative dynamic FDG PET studies in patients with metastastic colorectal cancer receiving FOLFOX (fluorouracil, folinic acid and oxaliplatin) chemotherapy.. The evaluation includes 28 patients with 55 metastases from primary colorectal cancer. Reference for the FDG studies was the clinical response data, according to the WHO classification. Three response groups were defined: progressive disease (PD), stable disease (SD) and partial response (PR). The FDG studies were accomplished as dynamic series for 60 min. The evaluation of the FDG kinetics was performed using the SUV, and fractal dimension (FD) of the time activity curves based on the box counting procedure (parameter for the inhomogeneity of the tumors).. The median SUV as measured in the tumor lesions prior to onset to FOLFOX was 3.15, in comparison with 2.68 SUV after the first cycle and 2.61 SUV after the second cycle. Discriminant analysis (DA) was used for the classification of the data into the 3 categories. Both parameters SUV and FD provided 2 of the 3 "predicted" categories, namely PD and SD. It was possible to correctly classify PR in only 10% of the patients, using the FD of both studies. Generally, DA inclined to misclassify the data towards PD. Even the first PET study was predictive with respect to therapy outcome (96% for PD and 47% for SD using only the baseline SUV). Metastases with a baseline SUV lower than 4.6 did not respond to FOLFOX chemotherapy. The combination of SUV and FD of the first study lead to a correct classification of 93% of PD and 60% of SD. Best results were obtained for the FD of the initial PET study (90% for PD and 75% for SD) as well as for the FD of both studies (77% for PD, 73% for SD, 10% for PR).. Quantitative, dynamic FDG-PET should be used preferentially for monitoring patients with metastatic colorectal cancer receiving chemotherapy. Even the first FDG study prior to onset to chemotherapy is predictive for the therapy outcome.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorodeoxyglucose F18; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Radiopharmaceuticals; Risk Assessment; Tomography, Emission-Computed; Treatment Outcome

A prospective phase II study was performed to determine the feasibility, efficacy and safety of arterial hepatic infusion (HAI) using pirarubicin combined with intravenous chemotherapy.. From December 1991 to April 1994, 75 patients with unresectable colorectal metastases confined to the liver were included in this multicenter study to receive intra-arterial hepatic pirarubicin and a systemic monthly regimen of 5-fluorouracil (5-FU) and folinic acid. Sixty-four patients were analyzed in the intention-to-treat analysis and 61 in the per-protocol analysis.. Tolerance of this regimen was rather good; however, functional catheter problems were observed in 29 patients (45%) resulting in failure of HAI in 21 cases (33%) after a median of three cycles; vomiting grade 3 was present in 12.5% of patients, neutropenia grade 4 in 23% and alopecia grade 3 in 19%. The overall response rate was 31.9% in intention-to-treat analysis, and 39.3% in per-protocol analysis. Extrahepatic progression was reported in only 21.7% of patients. Time to hepatic progression and extra-hepatic progression was 8.3 and 15 months, respectively, in intention-to-treat analysis, and 11 and 18 months, respectively, in per-protocol analysis. Median survival was 19 and 20 months in intention-to-treat analysis and per-protocol, respectively.. In our study, the combination of intra-arterial pirarubicin and intravenous chemotherapy demonstrated some efficacy and good tolerance in the treatment of isolated colorectal liver metastases. This treatment seems to prevent extra-hepatic spread and prolong survival time. The results of this study have to be confirmed by new trials using more active systemic chemotherapy.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease Progression; Doxorubicin; Feasibility Studies; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate; Time Factors

Irinotecan has shown activity in advanced colorectal cancer resistant to leucovorin and fluorouracil. Preclinical experiments on cell cultures and human tumor xenografts indicated potential synergy when combining irinotecan and fluorouracil. We designed a new regimen combining leucovorin, fluorouracil, irinotecan, and hydroxyurea (FOLFIRI-2) and conducted a phase II study to establish its efficacy and tolerance in advanced colorectal cancer refractory to fluorouracil and oxaliplatin. Treatment was repeated every 2 weeks and consisted of leucovorin 400 mg/m2 on day 1, immediately followed by 46 hours of continuous infusion of fluorouracil 2,000 mg/m2, irinotecan 180 mg/m2 on day 3, and hydroxyurea 1,500 mg the day before leucovorin, and on days 1 and 2. Treatment was continued until progression or limiting toxicity. Twenty-nine heavily pretreated patients entered the study. Five patients achieved an objective response (17%), and 12 obtained stabilization of disease or minor response (52%). Five patients failed to continue treatment (17%) because of toxicity or worsening condition. From the start of FOLFIRI-2 treatment, median progression-free survival was 4.1 months and median survival was 9.7 months. Grade III/IV National Cancer Institute-Common Toxicity Criteria toxicities were nausea 17%, diarrhea 31%, mucositis 14%, neutropenia 52%, and febrile neutropenia 14%. FOLFIRI-2 achieved a good rate of response and stabilization in heavily pretreated patients despite significant toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Hydroxyurea; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Survival Analysis

The purpose of this study was to evaluate the tolerance and efficacy of combining i.v. irinotecan, 5-fluorouracil (5-FU) and leucovorin (LV) with hepatic arterial infusion (HAI) of pirarubicin in non-resectable liver metastases from colorectal cancer.. Thirty-one patients were included in a phase II trial with i.v. irinotecan/5-FU/LV administered every 2 weeks, combined with HAI pirarubicin 60 mg/m(2) on day 1 every 4 weeks. In most cases HAI was administered via a percutaneous catheter.. The main grade 3/4 toxicity was neutropenia, encountered in 78% of the patients. When all patients were considered in the analysis, tumour response rate was 15 out of 31 [48%; 95% confidence interval (CI) 32% to 65%]. Liver resection was made possible in 11 patients (35%; 95% CI 21% to 53%). There were no toxic death. Median overall survival was 20.5 months, and median progression-free survival was 9.1 months. In patients with completely resected metastases, median overall survival was not reached and median progression-free survival was 20.2 months.. The multimodality approach used in the present study was well-tolerated and yielded dramatic responses. An aggressive approach combining i.v. and HAI chemotherapy deserves further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neutropenia

In clinical practice, regional chemotherapy of the liver applied as 'hepatic arterial infusion' (HAI) is often limited by device dysfunction or hepatic arterial obstruction. We report the case of a patient with mixed hepato/cholangiocellular carcinoma in which HAI with folinic acid (FA) and 5-fluorouracil (5-FU) was continued after thrombotic occlusion of the A. hepatica, resulting in a flow of drugs into the V. portae (via A. lienalis and V. lienalis). By using this 'spleno-portal' access for further chemotherapy with FA/5-FU, long-term control of the patient's disease was achieved. Analyzing our experience with this and three other patients with hepatic arterial thrombosis in which we continued HAI, a total of 33 regional treatment courses were applied, containing 5-FU/FA, mitomycin C, doxorubicin or combinations of these drugs. No unexpected toxicities were observed. In addition, the clinical course of three of those four patients strongly suggests the effectiveness of this approach. Thus, our results indicate that thrombosis of the A. hepatica does not necessarily have to result in an interruption of HAI. Continuation of regional chemotherapy despite hepatic arterial occlusion preserved control of intrahepatic tumor manifestations in patients who previously responded to regular HAI.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Arterial Occlusive Diseases; Catheterization; Disease Progression; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged

Unresectable biliary tract carcinoma (BTC) is associated with a very poor prognosis. To improve efficacy and tolerance of the 5-fluorouracil (5-FU)/cisplatin combination in BTC, we designed a new therapeutic schedule, the LV5FU2-P regimen.. Twenty-nine patients with advanced or metastatic BTC were prospectively enrolled in the study. The treatment (LV5FU2-P regimen) consisted of a biweekly administration of a 2-h infusion of leucovorin 200 mg/m(2), a 400 mg/m(2) bolus of 5-FU followed by a 22-h continuous infusion of 600 mg/m(2) 5-FU on two consecutive days and cisplatin 50 mg/m(2) on day 2. Clinical symptoms, performance and weight changes were monitored.. Objective responses were observed in 10 patients (34%) (95% confidence interval 23% to 45%) including one complete response and nine partial responses (stabilization 38%, progression 28%). Median progression-free survival and overall survival were 6.5 and 9.5 months, respectively. Weight gain was observed in 45% of patients and performance status improved in 60%. One patient had a grade 4 thrombocytopenia, and grade 3 toxicity occurred in 41% of patients. There were no treatment-related deaths.. This study, one of the largest phase II trials performed for this disease, shows that the LV5FU2-P regimen is an active and well-tolerated chemotherapy for advanced and metastatic BTC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Cholangiocarcinoma; Cisplatin; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Prospective Studies; Survival Rate; Thrombocytopenia; Treatment Outcome

Previous studies have shown that the taxane, docetaxel, is effective in treating gastric cancer. The aim of this study was to assess the efficacy and safety of docetaxel in combination with 5-fluorouracil (5-FU) and leucovorin (LV).. Thirty patients with histologically proven locally advanced and/or metastatic gastric cancer with WHO performance status 0-2 were enrolled and received either 75 or 100 mg/m(2) docetaxel as a 1-h intravenous infusion on day 1 every 28 days. All patients also received 5-FU (1800 mg/m(2)) plus LV (500 mg/m(2)), by continuous intravenous infusion over 24 h on days 1, 8, and 15 every 28 days. Chemotherapy was given for at least two cycles.. Of the 25 evaluable patients, 3 showed a complete response, 4 showed a partial response, and 11 patients had stable disease. The overall response rate was 28.0% (95% confidence interval [CI], 10.4, 45.6). The median time to progression was 5.9 months (95% CI, 5.4, 6.5), and the median overall survival was 7.7 months (95% CI, 7.2, 8.3) for the intent-to-treat population. The most frequent grade III and IV hematological toxicities were neutropenia and anemia. Febrile neutropenia was observed in 10% of patients and 2.4% of cycles. The prophylactic use of granulocyte colony-stimulating factor (G-CSF) in 3 patients reduced the incidence and severity of neutropenia. Other hematological toxicities were rare.. Docetaxel in combination with weekly 5-FU and LV is effective in treating patients with advanced/metastatic gastric cancer. This new docetaxel-containing combination shows promise as a third-generation treatment option for gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Disease Progression; Docetaxel; Female; Fluorouracil; Humans; Incidence; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Paclitaxel; Severity of Illness Index; Stomach Neoplasms; Survival Analysis; Taxoids; Time Factors; Treatment Outcome

Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.

Topics: Adenoviruses, Human; Adult; Aged; Antibodies, Viral; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Cytokines; Female; Fluorouracil; Genome, Viral; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Virus Replication

Topics: Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Hepatic Veins; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged

The present study aimed at evaluating the efficacy of Raltitrexed, a specific thymidilate synthase inhibitor, in patients with advanced colorectal cancer (ACC) in relapse (>8 weeks) after a prior response or disease stabilization to first-line chemotherapy combination with lrinotecan+5-Fluorouracil (5-FU)+Leucovorin (LV).. Twenty-five patients with metastatic ACC entered; 17 males/8 females, median age 61 (range: 47-70), median Karnovsky PS: 80 (70-90), and sites of metastases; liver: 21, lung: 4, lymph nodes: 7, peritoneal: 5 and a life expectancy of at least 3 months, were entered in the present pilot study. All patients had progressed after prior chemotherapy with lrinotecan+5-FU+LV. Raltitrexed was administered at a dose of 3 mg/m2 i.v. every 21 days.. Three patients (12%) achieved a partial response (PR), 8 (32%) had stable disease (SD), and the remaining 14 (56%) developed progressive disease (PD). Median time-to-progression (TTP) was 5.5 months (range, 2-8.5), and median overall survival (OS) 8 months (range, 4.0-12.5). Toxicity was generally mild; it consisted mainly of myelosuppression; neutropenia grade 1-2: 52%-grade 3: 28%, and anemia grade 1-2 only: 36%. Mild mucositis grade 1-2 occurred in 13.5% of patients and was the principal non-hematologic toxicity.. Response to treatment with Raltitrexed is limited in patients with ACC failing after an initial response or non-progression to the weekly lrinotecan+5-FU+LV combination. However, it appears that a limited number of patients with PR/SD may derive clinical benefit, but final proof would require a randomized study.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Peritoneal Neoplasms; Quinazolines; Salvage Therapy; Secondary Prevention; Thiophenes; Treatment Outcome

5-fluorouracil remains the standard therapy for patients with advanced/metastatic colorectal cancer. Pre-clinical studies have demonstrated the biological modulation of 5-fluorouracil by methotrexate and leucovorin. This phase II study was initiated to determine the activity and toxicity of sequential methotrexate--leucovorin and 5-fluorouracil chemotherapy in patients with advanced colorectal cancer.. Ninety-seven patients with metastatic colorectal cancer were enrolled onto the study. Methotrexate--30 mg/m2 was administered every 6 hours for 6 doses followed by a 2 hour infusion of LV--500 mg/m2. Midway through the leucovorin infusion, patients received 5-fluorouracil--600 mg/m2. This constituted a cycle of therapy and was repeated every 2 weeks until progression.. The median age was 64 yrs (34-84) and the Eastern Cooperative Group Oncology performance score was 0 in 37%, 1 in 55% and 2 in 8% of patients. Partial and complete responses were seen in 31% of patients with a median duration of response of 6.4 months. The overall median survival was 13.0 months. The estimated 1-year survival was 53.7%. Grade III and IV toxic effects were modest and included mucositis, nausea and vomiting.. This phase II study supports previously reported data demonstrating the modest clinical benefit of 5-FU modulation utilizing methotrexate and leucovorin in patients with metastatic colorectal cancer. Ongoing studies evaluating 5-fluorouracil modulation with more novel agents (Irinotecan and/or oxaliplatin) are in progress and may prove encouraging.

Topics: Abdominal Neoplasms; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Routes; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Survival Rate; Treatment Outcome

A phase II trial investigated the activity and toxicity of a bolus administration schedule of oxaliplatin, fluorouracil (5-FU), and leucovorin (LV) therapy in patients with untreated advanced colorectal cancer.. Forty-five patients in this multicenter, open, nonrandomized study received oxaliplatin 130 mg/m(2) on the first day of each course and 5-FU and LV 350 mg/m(2) and 20 mg/m(2), respectively, as a daily bolus for 5 days, every 21 days, for a maximum of six courses.. Partial responses occurred in 18 patients, giving an intent-to-treat response rate of 40.0%. Median time to response was 12.7 weeks; median duration of response was 18.4 weeks. Median progression-free survival was 5.9 months; median survival was 14 months. The independent prognostic factors for improved overall survival were good performance status and negative carcino-embryonic antigen blood level. Incidences of adverse effects were reduced after the 5-FU dose was reduced to 300 mg/m(2). Reversible neurologic toxicity occurred in 44.4% of patients.. Bolus administration of oxaliplatin, 5-FU, and LV as first-line therapy for untreated advanced colorectal cancer is efficacious and safe. In addition to a more favorable safety profile, the 300 mg/m(2) dosage offered improved dose-intensity compared with the initial dosage.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

The clinical value and costs of different diagnostic tools used to identify potentially curable recurrent disease in patients treated adjuvantly for curatively resected Dukes' C colonic cancer were examined.. The study group comprised 496 patients treated with chemotherapy over a 1-year interval. Follow-up consisted of interim history, physical examination, liver ultrasonography or computed tomography (CT), measurement of carcinoembryonic antigen (CEA) levels, chest radiography and colonoscopy.. Two hundred and thirteen patients had recurrent disease (median follow-up 43 months). Forty-two patients with recurrence (20 per cent) were treated with curative intent (median survival 38 months; 5-year survival rate 40 per cent). Recurrence was identified by liver ultrasonography or CT (n = 14), evaluation of symptoms (n = 12), colonoscopy (n = 8), CEA measurement (n = 3), chest radiography (n = 2), physical examination (n = 1) and other modalities in two patients. The mean cost of diagnostic procedures per curative resected recurrence for patients amenable to salvage surgery was US$9011. Of all treatable recurrences, 12 of 42 were identified by evaluation of symptoms only. Ultrasonography and colonoscopy identified 22 recurrences at a cost of US$11 790 per patient, while routine follow-up by CEA measurement, chest radiography and physical examination identified a further six at a cost of US$19 850 per patient.. Potentially curable recurrences were detected primarily by liver imaging and colonoscopy. The yield of CEA measurement, chest radiography and physical examination was relatively low; such methods were expensive and should not be recommended in the routine follow-up of these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colonic Neoplasms; Costs and Cost Analysis; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Liver Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Physical Examination; Survival Analysis; Tomography, X-Ray Computed; Ultrasonography

Unresectable colorectal liver metastases are a significant clinical problem. Isolated hepatic perfusion (IHP) is a regional treatment technique that delivers high dose chemotherapy, biologic agents, and hyperthermia via a completely isolated vascular recirculating perfusion circuit as a means of regionally treating liver tumors. This study presents our results of IHP with tumor necrosis factor (TNF) plus melphalan or IHP with melphalan alone followed by infusional floxuridine (FUDR) and leucovorin in patients with advanced or refractory unresectable hepatic colorectal metastases.. Fifty-one patients with unresectable colorectal hepatic metastases underwent a 60-minute IHP with 1.5 mg/kg melphalan and hyperthermia (39 degrees C to 40 degrees C). Thirty-two patients received IHP with 1 mg TNF with melphalan and 19 patients had IHP with melphalan alone followed by monthly hepatic intra-arterial infusional (HAI) FUDR (0.2 mg/kg/day) and leucovorin (15 mg/M(2)/day) for 14 days monthly for up to 12 months. Twenty-six patients failed 1 or more previous treatment regimens for established hepatic metastases and 27 had greater than 25% hepatic replacement (PHR) by tumor. Patients were monitored for response, toxicity, and survival.. There was 1 perioperative death (2%), and only 2 patients (4%) had measurable perfusate leak during IHP (both less than 4%). In the 32 patients treated with IHP alone there were no detectable systemic TNF or melphalan levels during perfusion. The overall objective radiographic response rate (all partial [PR]) was 76% (38 of 50 assessable patients) with a median duration of 10.5 months (range, 2 to 21 months). Twenty-four of 31 patients (77%) had a PR after IHP alone and 14 of 19 (74%) after IHP with postperfusion HAI. Median duration of response was 8.5 months after IHP alone and 14.5 months after IHP and HAI; median survival was 16 and 27 months, respectively. There were 18 PRs in 26 patients (69%) whose prior therapy had failed and 18 PRs in 27 patients (67%) with PHR of 25 or greater.. IHP can be performed with acceptably low morbidity and has significant antitumor activity in patients with unresectable hepatic metastases from colorectal cancer including those with refractory disease or PHR of 25 or greater. HAI appears to prolong the duration of response after IHP, and this combined treatment strategy deserves additional clinical evaluation as a therapeutic modality in this setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Floxuridine; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Melphalan; Middle Aged; Neoplasm Metastasis; Radiography; Survival Analysis; Tumor Necrosis Factor-alpha

To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L).. Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression.. Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months.. The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate

A multicenter phase II trial was initiated in order to evaluate the weekly, high-dose 24-hour infusion of 5-fluorouracil (5-FU) plus folinic acid (FA) in patients with unresectable colorectal cancer hepatic metastases.. A weekly hepatic arterial infusion (HAI) of FA 500 mg/m2 followed by a 24-hour infusion of 5-FU 2,600 mg/m2 (later reduced to 2,200 mg/m2) was given via a surgically implanted intra-arterial port system. One treatment cycle consisted of six weekly applications followed by a two-week rest period. Toxicity was assessed according to the WHO criteria. Chemotherapy was continued until disease progression or complete response occurred.. A total of 50 patients (40 chemonaive, 10 pre-treated) entered this trial. An objective tumor response occurred in 28 patients (56%), while 13 patients (26%) had stable disease. The median progression free survival was 12 months, and the median survival 22.3 months. Due to a high rate of gastrointestinal side-effects in the initial phase of the trial, the dosage of 5-FU was reduced to 2,200 mg/m2 for all subsequent patients. Diarrhea and nausea led to a dose reduction in 40% of applications and 24% of patients, respectively. One patient died of cardiac insufficiency unrelated to chemotherapy before response evaluation.. This HAI approach using high-dose 5-FU was relatively well tolerated when 2,200 mg/m2 instead of 2,600 mg/m2 was used. The activity of this regimen is promising and warrants further evaluation and modification.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate; Treatment Outcome

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Treatment Outcome

This phase II study examined a regimen (FOLFOX7) of leucovorin (LV), high-dose intensity oxaliplatin, and 5-fluorouracil (5-FU), as second-line therapy for metastatic colorectal cancer. 48 patients were enrolled - 36 refractory and 12 resistant to prior therapy with LV-5-FU. Oxaliplatin (130 mg/m2) was infused with LV (400 mg/m2) over 2 h on day 1, followed by bolus 400 mg/m2 and a 46-h infusion (2400 g/m2) of 5-FU, every 2 weeks. Patients who responded or were stable received eight cycles. Patients were evaluated every 2 months. 20 patients (42%) had partial responses (95% confidence interval (CI): 28-56%), 19 (40%) had stable disease and 9 (19%) progressed. Median progression-free survival (PFS) was 6 months and median survival 16.1 months. Toxic effects of National Cancer Institute-Common Toxicity Criteria (NCI-CTC) grade 3/4 were: peripheral neuropathy 15%, nausea 8%, diarrhoea 11%, neutropenia 9%, thrombocytopenia 11%. Overall, 38% of patients experienced grade 3/4 toxicities, and 64% received 90% or more of the scheduled oxaliplatin dose intensity during the first four cycles. FOLFOX7 was highly active, with good tolerability, in pretreated patients resistant to LV-5-FU [corrected].

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Peritoneal Neoplasms; Survival Analysis; Treatment Outcome

To determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of oxaliplatin administered as hepatic arterial infusion.. Patients with isolated hepatic metastases from colorectal cancer were treated every three weeks with increasing doses of oxaliplatin (4 hours; starting dose 25 mg/m2, escalation in steps of 25 mg/m2) in combination with folinic acid (1 hour, 200 mg/m2) and 5-fluorouracil (2 hour, 600 mg/m2).. Twenty-one patients (median age, 61 years) have been entered all of whom are fully evaluable. The DLT has been observed at dose level 6, i.e., at 150 mg/m2/cycle and consisted of leucopenia, obliteration of the hepatic artery, and acute pancreatitis. Overall, toxicity mainly consisted of nausea/vomiting (16 of 21 patients), anemia (16 of 21), upper abdominal pain (15 of 21), sensory neuropathy (10 of 21), diarrhea (9 of 21), and thrombocytopenia (9 of 21). The mean PK parameters were: terminal half-life of ultrafiltrable platin, 17.75 +/- 9.29 hours; renal elimination, 48.7% +/- 14.1% of the applied dose; renal clearance 135.55 +/- 45.32 ml/min. The mean area under the plasma-concentration curve (AUC) increased linearly from 3.22 +/- 0.61 microg x h/ml to 18.45 +/- 8.90 microg x h/ml through the first five dose levels (P = 0.0004). Ten of eighteen evaluable patients achieved a complete or partial response (59%).. The recommended dose for phase II studies is 125 mg/m2 oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

This study was designed to determine response rate, survival and toxicity associated with combination chemotherapy delivered intra-arterially to liver in patients with hepatic metastases of colorectal origin refractory to standard systemic treatment. A total of 28 patients who failed prior systemic treatment with fluoropyrimidines received a median of 5 cycles of intra-arterial treatment consisting of 5-fluorouracil 700 mg/m(2)/d, leucovorin 120 mg/m(2)/d, and cisplatin 20 mg/m(2)/d for 5 consecutive days. Cycles were repeated at intervals of 5-6 weeks. A major response was achieved in 48% of patients: complete response in 8% and partial response in 40%. The median duration of response was 11.5 months. Median survival was 12 months at a median follow up of 12 months. On multivariate analysis, the only variables with a significant impact on survival were response to treatment and performance status. Toxicity was moderate: grades III-IV neutropenia occurred in 29% of patients. Most of the patients complained of fatigue lasting for a few days following each cycle. There were no cases of hepatobiliary toxicity. These findings indicate that regional intra-arterial treatment should be considered in selected patients with predominantly liver disease following failure of standard treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fatigue; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neutropenia; Survival Analysis; Treatment Outcome

Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5-Fluorodeoxyuridine (5-FUDR) has been the drug studied in most Phase II and III trials. The meta-analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5-FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5-FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM. PATIENTS AND METHODS Between February 1993 and August 2000, 63 patients with CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomycin C (MFFM) via port catheters with a protocol planing up to 11 cycles of treatment. Toxicity and response were analyzed according to World Health Organization (WHO) criteria, and survival was analyzed according to Kaplan-Meier. All patients were treated with more than two HAI cycles.. The objective response rate (complete remission and partial remission) was 54% and primary intrahepatic progression (progressive disease) occurred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease was evaluated as no change. Median survival times from the first diagnosis of CRLM or start of HAI were 25.7 months and 23.7 months, respectively, and 7 patients lived longer than 40 months. Grade 3 toxicity according to WHO occurred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurred.. Our new HAI protocol with MFFM seems to be superior to HAI with 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at acceptable toxicity. Currently, HAI with MFFM is compared with systemic chemotherapy using 5-FU and FA intravenously in a randomized Phase III trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitoxantrone; Survival Analysis; Treatment Outcome

In palliative first-line treatment of colorectal cancer, the secondary resection of distant metastases after downstaging has constantly gained in importance. The objective of this prospective study was to examine the tumor response rate, the toxicity, the median survival time and the prognostic impact of metastatic resection after downstaging of consecutively enrolled patients with primary nonresectable colorectal cancer treated with once weekly 24-hour (24-h) infusion of high-dose 5-fluorouracil (5-FU) and folinic acid.. Between January 1995 and July 1997, 53 consecutive patients with primary nonresectable metastases were recruited for a prospective phase II study. The patients received in out-patient care 500 mg/m2 folinic acid in the form of a 1-2-hour infusion followed by 2600 mg/m2 5-FU administered as a 24-h infusion once weekly. One treatment cycle comprised six weekly infusions followed by a two week rest. Three cycles were administered, and in the event of complete remission (CR) or partial remission (PR) and good tolerability, a fourth cycle was undertaken. Thereafter, the possibility of performing a curative metastatic resection was investigated.. Of the 53 patients treated, 7 showed a CR (13%), 15 patients a PR (28%), 26 patients stable disease (SD) (49%), and 5 patients progressive disease (PD) (10%). As the main symptom of toxicity, diarrhea (CTC grade 3 + 4) was observed in 11 patients (21%), followed by leucocytopenia (CTC grade 3 + 4) in 2 patients (4%), and the hand-foot syndrome in 1 patient (2%). The median survival time was 17 months with a median follow-up of 41 months (range: 28-59 months). In 9 patients (17%), a secondary metastatic resection was considered; in 6 patients (11%) curative resection was performed, and 4 patients (8%) showed no evidence of disease for at least three years.. In this phase II study, we have been able to show prospectively that, after downstaging by palliative treatment using a weekly 24-h infusion of high-dose 5-FU and folinic acid, secondary curative metastatic resection was technically feasible in 11% of the patients. For some of these patients, long-term survival is therefore possible. Secondary metastatic resection should be carried out in close interdisciplinary cooperation, and should be further investigated in prospective phase III studies.

Topics: Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Infusions, Intravenous; Kidney Neoplasms; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Palliative Care; Prognosis; Prospective Studies; Survival Rate

Both replication-incompetent and replication-selective adenoviruses are being developed for the treatment of cancer and other diseases. Concerns have been raised about the safety of intra-vascular adenovirus administration following a patient death on a clinical trial with a replication-defective adenovirus. In addition, the feasibility of vascular delivery to distant tumors has been questioned. dl1520 (ONYX-015) is a replication-selective adenovirus that has previously shown safety and antitumoral activity following intratumoral injection. This is the first report of intra-vascular administration with a genetically engineered, replication-selective virus. A phase I dose-escalation trial was performed in patients with liver-predominant gastrointestinal carcinoma (n = 11 total; primarily colorectal). dl1520 was infused into the hepatic artery at doses of 2 x 10(8)-2 x 10(1)2 particles for two cycles (days 1 and 8). Subsequent cycles of dl1520 were administered in combination with intravenous 5-fluorouracil (5-FU) and leucovorin. No dose-limiting toxicity, maximally tolerated dose or treatment-emergent clinical hepatotoxicity were identified following dl1520 infusion. Mild to moderate fever, rigors and fatigue were the most common adverse events. Antibody titers increased significantly in all patients. Viral replication was detectable in patients receiving the highest two doses. An objective response was demonstrated in combination with chemotherapy in a patient who was refractory to both 5-FU and dl1520 as single agents. Therefore, hepatic artery infusion of the attenuated adenovirus dl1520 was well-tolerated at doses resulting in infection, replication and chemotherapy-associated antitumoral activity.

Topics: Adenoviridae; Adenovirus E1B Proteins; Aged; Antibodies, Viral; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Gene Deletion; Genetic Therapy; Genome, Viral; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Virus Replication

To assess the efficacy and tolerability of three treatments for patients with documented adenocarcinoma of the colon and/or rectum who have undergone complete resection of primary tumor and have nonresectable liver metastases that do not exceed 75% of the liver volume.. A total of 168 patients at 25 treatment centers were enrolled onto this prospective, multicenter, randomized study. The three treatment arms were as follows: (1) fluorouracil (5-FU)/leucovorin (LV) administered via hepatic arterial infusion (HAI), (2) 5-FU/LV administered via intravenous (IV) infusion, and (3) fluorodeoxyuridine (FUDR) administered via HAI.. Median times to disease progression for the three treatment arms were as follows: 9.2 months for patients treated with HAI 5-FU/LV, 6.6 months for IV 5-FU/LV, and 5.9 months for HAI FUDR. Median survival times for patients treated with HAI 5-FU/LV, IV 5-FU/LV, and HAI FUDR were 18.7 months, 17.6 months, and 12.7 months, respectively. There was a nearly two-fold increase in time to progression in addition to a survival benefit among patients with an intrahepatic tumor burden of less than 25% who were treated with HAI 5-FU/LV. The most common adverse events were stomatitis, nausea and vomiting, skin irritation, diarrhea, and elevated serum levels of liver enzymes. Some patients exhibited severe reactions, including biliary sclerosis and chemical hepatitis.. Although the use of HAI 5-FU/LV as a means of treating liver metastases after resection of colorectal carcinoma warrants further investigation, it cannot be recommended as a routine therapeutic measure at this time.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Catheters, Indwelling; Colonic Neoplasms; Disease Progression; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Rectal Neoplasms; Survival Analysis; Treatment Outcome

To evaluate the toxicity and efficacy of combination chemotherapy with paclitaxel, cisplatin and 24 h continuous infusion of 5-FU/folinic acid in patients (pts) with unresectable, locally advanced or metastatic gastric adenocarcinoma. Forty-five chemotherapy-naive pts (28 male and 17 female) with a median age of 60 years (range 35-74) were enrolled. 5-FU 2 g/m2 was given weekly over 24 h i.v. preceded by folinic acid 500 mg/m2 as a 2 h infusion. Paclitaxel 175 mg/m2 was administered as a 3 h-infusion on days 1 and 22 and cisplatin 50 mg/m2 as 1 h infusion on days 8 and 29. Six weeks of therapy (days 1, 8, 15, 22, 29, 36) followed by 2 weeks rest were considered one cycle. A median of 3 cycles (range 1-4) were administered to 45 pts assessable for response, survival and toxicity. Five pts (11%) obtained a CR and 18 pts (40%) a PR (ORR 51%; 95% CI: 35.8-66.3%). Responses were achieved in the liver, lymph nodes, lungs and at the site of the primary tumour. Nine pts (20%) had stable disease. Thirteen pts (29%) were considered to have failed treatment, 8 pts (18%) due to progressive disease and 5 pts (11%) who did not receive one complete cycle of therapy due to acute non-haematologic toxicity. The median progression-free and overall survival times were 9 months (range 1-36+) and 14 months (range 2-36+), respectively. Neutropenia WHO III(o)/IV(o) occurred in 7 pts (15%) with only 1 pt having grade IV. Additional non-haematologic WHO III(o)/IV(o) toxicities included nausea/vomiting in 5 (11%), alopecia in 22 (49%), and diarrhoea in 1 patient each (2%). Dose reductions or treatment delays were necessary in 8 pts (17%), mainly due to neutropenia. All pts were treated on an outpatient basis. The combination of paclitaxel, cisplatin and continuously infused 5-FU/folinic acid appears to be a highly active regimen for the treatment of pts with advanced gastric cancer. While the overall acceptable toxicity allows its use in the palliative setting, it may also be an attractive option to be tested for neoadjuvant or adjuvant treatment.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Paclitaxel; Peritoneal Neoplasms; Stomach Neoplasms; Survival Analysis

The purpose of this study was to examine the interpatient and intrapatient variability of the Michaelis-Menten plasma parameters of 5-fluorouracil administered according to a schedule combining a bolus of 400 mg/m2 followed by 22-hour infusion of 600 mg/m2 for 2 consecutive days.. A pharmacokinetic population approach was used to analyze the data from 21 patients with colorectal cancer.. The 5-fluorouracil plasma concentrations versus time were best described by a two-compartment model with nonlinear elimination from the central compartment. The relationships between the pharmacokinetic parameters and patient characteristics were tested. On day 1 the mean values (with interindividual variability as expressed by the coefficient of variation) were 1390 mg x h(-1) (20%), and 5.57 mg x L(-1) (22%) for the maximum rate of elimination, and the half-saturating plasma concentration. The maximum rate of elimination was positively correlated to the body surface area and the percentage of liver involvement by metastatic disease determined by tomodensitometric examination. The model was successfully tested with independent data sets corresponding to other schedules. The analysis of this intrapatient variability showed that the half-saturating plasma concentration increased from day 1 to day 2, especially in the patients with low lymphocyte cell dihydropyrimidine dehydrogenase activity.. The pharmacokinetic parameters obtained in this study would be useful to predict the 5-fluorouracil plasma concentrations following other schedules of administration of 5-fluorouracil and to study the possible pharmacokinetic interactions between 5-fluorouracil and other drugs.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Models, Theoretical; Time Factors

We report a prospective randomized study comparing survival, response and toxicity in colorectal liver metastasis (CLM) patients treated by either hepatic arterial floxuridine (HAI) plus continuous systemic fluorouracil/folinic acid or systemic fluorouracil/folinic acid.. Eighty-four CLM patients received either HAI plus systemic fluorouracil/folinic acid or systemic fluorouracil/ folinic acid.. Significantly more HAI plus systemic, compared with systemic only, patients developed WHO grade 3 or 4 diarrhoea (P=0.004), but significant quality of life differences were not detected. Liver metastasis partial response at 4 months after randomization was significantly greater (P=0.003) in HAI plus systemic (13/29, 45%) compared with systemic only (7/30, 23%) patients. There was no significant difference between groups in the proportion of patients who died from extrahepatic disease progression, or in survival.. Combining regional with systemic fluorinated pyrimidines did not improve survival compared with systemic fluorinated pyrimidine.

Topics: Aged; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Carcinoembryonic Antigen; Colorectal Neoplasms; Disease Progression; Female; Floxuridine; Hematinics; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Quality of Life; Survival Analysis; Treatment Outcome

The aim of this phase II study was to investigate the therapeutic value of second-line treatment with oxaliplatin, irinotecan (CPT-11) and mitomycin C (MMC) in patients with metastatic colorectal cancer pretreated with 5-fluorouracil (5-FU)-based chemotherapy. A total of 10 patients with metastatic colorectal cancer, all of whom had developed progressive disease from advanced or metastatic colorectal cancer while receiving or within 6 months after discontinuing first-line chemotherapy with 5-FU and leucovorin, were entered in this study. At the time of relapse, cytotoxic chemotherapy consisting of oxaliplatin 80 mg/m2 plus CPT-11 80 mg/m2 given i.v. on therapeutic day 1, and MMC 6 mg/ m2 given i.v. on day 15, respectively, was initiated. Treatment courses were repeated every 4 weeks for a total of six courses unless there was prior evidence of progressive disease. The overall response rate was 30% with three partial responses for all 10 assessable patients. Two additional patients (20%) had stable disease and five patients (50%) progressed. The median overall survival duration has not been reached yet and is longer than 7.1 months (range 2-23.5+) from the beginning of second-line therapy. Four patients are currently alive with progressive disease. The tolerance of second-line treatment was generally mild to moderate and easy to treat. Our data suggest that the combination of oxaliplatin, CPT-11 and MMC in patients with metastatic colorectal cancer pretreated with 5-FU-based chemotherapy is feasible and has substantial antitumor activity. Further evaluation of this regimen seems warranted.

Topics: Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

The objectives of the current study were: 1) to verify whether the addition of modulating low doses of interferon-2b (IFN) to 5-fluorouracil (5-FU) and levofolinic acid (1-FA) could improve clinical results in patients with advanced colorectal carcinoma; and 2) to evaluate the role of tumor burden and liver involvement as prognostic factors.. A total of 204 untreated patients were randomized to receive 1-FA at 100 mg/m2 and 5-FU at 375 mg/m2 for 5 consecutive days with or without IFN every 3 weeks. IFN was given subcutaneously at 3 MU/day for 7 days starting 2 days before chemotherapy administration. Patients were stratified according to the presence or absence of hepatic disease (H+ or H-) and to total tumor burden defined as "low" or "high" using an area of 10 cm2 as the cutoff value. Thus, four patient categories were obtained: Group 1: H+ > or = 10 cm2; Group 2: H+ < 10 cm2; Group 3: H- > or = 10 cm2; and Group 4: H- < 10 cm2.. No differences were observed in the objective response rate (23% for the combination of 1-FA and 5-FU vs. 24% for the 1-FA, 5-FU, and IFN regimen), median duration of response (11 months vs. 10 months), time to progression (5 months in both arms), and median survival (11 months vs. 12 months). A statistically significant improvement in response rate was observed in patients with limited liver involvement versus those with massive involvement independent of the chemotherapy arm (44% vs. 22%; P = 0.02). Overall survival also was improved in patients with limited liver disease (P = 0.0001) and in those without liver involvement (P = 0.004). Multivariate analysis confirmed these data and identified response and female gender as positive prognostic factors. Toxic side effects (mainly diarrhea, mucositis, and fever) were statistically more frequent in the IFN arm.. The addition of low modulating doses of IFN to the regimen of 5-FU and I-FA failed to increase the response rate and survival of patients with advanced colorectal adenocarcinoma and significantly worsened toxicity. High tumor burden and the presence of liver involvement were confirmed prospectively as poor prognostic factors and should be taken in account in designing future Phase II or comparative trials.

Topics: Adenocarcinoma; Adult; Aged; Analysis of Variance; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Recombinant Proteins; Rectal Neoplasms; Survival Analysis

Nonresectable colorectal cancer metastases in the liver respond to chemotherapy in 20-25% only. Early identification of nonresponders might allow the use of other regimens. In a limited feasibility study, it should be determined whether (a) a single high-dose chemotherapy application has an early effect on glucose-utilization, detectable and quantitatable by noninvasive positron emission tomography using [18F]-Fluoro-deoxyglucose (FDG-PET) and (b) assess its value as a predictor of the final therapeutic outcome. A total of 10 patients with documented nonresectable liver metastases of a colorectal cancer were studied by FDG-PET, prior and 72 h after a single infusion of 5-Fluorouracil and Folinic acid (5-FU/FA). Glucose utilization was quantitated by determination of standard-uptake values and correlated with final therapy outcome following completion of the anticipated therapy cycle. Patients were followed up for at least 6 months. All metastases responding to therapy (n = 6) exerted a statistically significant decrease of FDG uptake (-22+/-10%), metastases (n = 2) showing a short-term effect (duration of tumor reduction <3 months) had a slightly diminished, and progressing metastases (n = 3) an enhanced FDG uptake (13+/-17%). Our preliminary data indicate that acute changes of glucose utilization-as detected by FDG-PET-following a single application of chemotherapy, seems to be indicative for the final therapeutic outcome, at least in liver metastases of colorectal cancer.

Topics: Adenocarcinoma; Aged; Animals; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Feasibility Studies; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Radiopharmaceuticals; Tomography, Emission-Computed; Treatment Outcome

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease Progression; Drug Administration Schedule; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Ontario; Severity of Illness Index; Treatment Outcome

Long-term survival of patients with metastatic colorectal cancer has been achieved only in patients who underwent complete resection of metastases. Such surgery could be performed in a greater proportion of patients if effective chemotherapy could downstage previously unresectable metastases. This approach has been limited by the low tumor response rate achieved with conventional chemotherapy.. We studied the outcome of patients with initially unresectable liver metastases from colorectal cancer treated with a three-drug chemotherapy regimen followed by liver metastases surgery whenever possible.. From March 1988 to June 1994, 151 patients with colorectal liver metastases were considered initially unresectable because of large tumor size (> 5 cm), multinodular (> 4) or ill-located metastases. All patients received fully ambulatory chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (chronotherapy in 83% of them). They were periodically reassessed for surgery by a joint medico-surgical team.. In 151 patients, the size of liver metastases decreased by > 50% in 89 patients (59%) and median overall survival was 24 months (95% confidence interval (95% CI): 19-28 months), with 28% surviving at five years (20%-35%). Surgery with curative intent was attempted in 77 patients (51%), complete resection of liver metastases was achieved in 58 patients (38%). The median survival of the 77 operated patients was 48 months (25-71), with a five-year survival rate of 50% (38-61).. This new strategy of combining effective chemotherapy with surgery apparently altered the natural history of unresectable colorectal cancer metastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survivors

Two studies were carried out to determine the activity and evaluate the toxicity of oral chemotherapy with uracil and tegafur in a 4:1 molar ratio (UFT) plus or minus calcium folinate in elderly patients with advanced colorectal cancer. In one study, 106 patients received a fixed dose of UFT 400 mg/day in two daily doses every 12 hours continuously, plus calcium folinate 45 mg/day administered in three divided doses every 8 hours continuously. In study 2, calcium folinate was omitted, and the dose of UFT was increased to 400 mg/m2/day in two daily doses administered every 12 hours continuously to 95 patients. Treatments for both studies were administered until grade 3 or grade 4 toxicity occurred or disease progressed. The response rate among the 96 available patients in study 1 was 17.7% (95% confidence interval [CI], 10% to 27%); 41 patients (43%) achieved an objective response or stable disease. Overall survival was 13.7 months with a statistically significant difference between patients with no progressive disease and patients with progressive disease (P < .01). In study 2, 62 of 95 patients have now been evaluated for response. The response rate was 21% (95% CI, 13% to 30%); 38 patients (61%) experienced an objective response or stable disease. The overall survival for study 2 has not yet been evaluated. Toxicity was generally mild, consisting of grade 3 nausea/vomiting (6% in study 1 and 2% in study 2), grade 3 or grade 4 diarrhea (11% in study 1 and 7% in study 2), plus one case of grade 3 mucositis in study 1. These findings suggest that chemotherapy with UFT (with or without modulation with calcium folinate) is feasible for elderly patients with advanced colorectal carcinoma.

Topics: Adenocarcinoma; Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Retrospective Studies; Survival Rate; Tegafur; Treatment Outcome; Uracil

To compare two regimens of intra-arterial chemotherapy for the treatment of hepatic metastases from colorectal cancer.. Open study.. Teaching hospital, UK SUBJECT: 57 patients with unresectable metastases confined to the liver, and an indwelling catheter in the hepatic artery.. The first 33 patients had a 24-hour intra-arterial infusion of 5-fluorouracil (5-FU) 1500 mg/m2, together with folinic acid 200 mg/m2 intravenously for the first and last two hours of the 5-FU infusion. This was repeated at weekly intervals for six weeks followed by a two-week gap before the next cycle. The remaining 24 patients had a two-weekly regimen in which folinic acid 200 mg/m2 was infused intravenously over 2 hours followed by an intra-arterial loading dose of 5-FU 400 mg/m2 over 15 minutes; 5-FU 1600 mg/m2 was then given by intra-arterial infusion over 22 hours. This was repeated on day 2 and then at two-weekly intervals.. Response rate and toxicity.. Median follow-up was 21 months, and estimated median survival 19 months. 29 patients (51%) have responded, 5 completely. There are no significant differences between the groups. Sites of progression were liver alone 26 (53%), lung alone 9 (18%), liver and lung 3 (6%), and the remainder in local or regional nodes (n = 7) or bone (n = 4). Six patients experienced WHO grade 3 or 4 toxicity.. The two regimens have high response rates and cause little systemic toxicity. Intra-arterial chemotherapy for hepatic metastases from colorectal cancer is currently being compared with conventional systemic chemotherapy in a randomised controlled trial.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Time Factors

Rates of response to systemic chemotherapy among patients with advanced colorectal carcinoma rarely exceed 25- 30%, and complete responses are rare. The liver is the most common site of metastasis; however, regional therapies have not improved survival rates. The Southwest Oncology Group designed a clinical trial combining hepatic arterial chemoembolization with systemic infusion of 5-fluorouracil chemotherapy in an attempt to increase the complete response rate and prolong the time to disease progression.. Patients with documented liver metastasis from colorectal carcinoma were treated with two or three cycles of chemoembolization using a collagen suspension with doxorubicin, mitomycin C, and cisplatin. Subsequently, systemic chemotherapy with continuous infusion of 5-fluorouracil and weekly leucovorin was initiated. Patients were assessed for response at 12-week intervals, with treatment continuing until disease progression.. Thirty-one eligible, evaluable patients were treated. One complete and 8 partial responses were observed, for an overall response rate of 29%. Fifty-eight percent of patients survived 1 year, and the median survival for the whole cohort was 14 months. The median time to progression was 8 months. Seven patients (23%) experienced Grade 4 toxicity and 21 patients (67%) had Grade 3 toxicity.. The response rate in this trial was comparable to that achieved with systemic chemotherapy consisting of a fluorinated pyrimidine-based regimen for patients with this disease. No improvement in complete response rate or time to progression was observed compared with the Southwest Oncology Group's experience with systemic therapy. The authors are not planning to study this regimen further as a treatment for patients with metastatic colorectal carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemoembolization, Therapeutic; Cisplatin; Colorectal Neoplasms; Combined Modality Therapy; Doxorubicin; Feasibility Studies; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Pilot Projects; Survival Analysis

Recently, we have demonstrated that thymidylate synthase (TS) protein expression predicts for the clinical response to a regimen of infusional 5-fluorouracil (5FU) in advanced colorectal cancer patients. Previous studies by other groups that showed a correlation between TS gene expression and response to the fluoropyrimidine also involved infusional regimens. Considering the putatively different mechanism of action of bolus compared with continuous infusion of 5FU, the aim of the present study was to test whether the correlation between TS expression and the clinical response to 5FU is valid for bolus regimens. A secondary aim was to compare TS levels between liver metastases and abdominal recurrences from colon cancer, because these sites have a distinctly different responsiveness to 5FU chemotherapy. The study population consisted of 41 patients (25 males and 16 females; median age, 60 years) with unresectable metastatic or recurrent colon cancer, homogeneously treated with 5FU (420 mg/m2 i.v., days 1-5) and leucovorin (20 mg/m2 i.v., days 1-5); cycles were repeated every 28 days. Twenty-seven patients (66%) showed high levels of TS expression as defined by TS scores equal to 3 and 4. The proportion of cases with high levels of TS expression was significantly higher in abdominal recurrences (18 of 22, 82%) compared with liver metastases (9 of 19, 47%; P = 0.02). Intratumoral TS protein expression was inversely correlated with response to chemotherapy (response rate: 7 of 14, 50%, versus 0 of 27 in patients with low and high levels of TS expression, respectively; P = 0.0001). These results confirm that the level of TS protein expression predicts for response to 5FU, even with a bolus schedule. The higher TS levels observed in abdominal compared with liver metastases may account for their different responsiveness to 5FU chemotherapy. Immunohistochemical quantitation of TS protein levels may thus allow us to change the therapeutic approach to advanced colorectal cancer from a general to an individual treatment strategy at a time when new non TS-targeted drugs have become available for this disease.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Thymidylate Synthase; Treatment Outcome

At the time of surgery, occult metastases (micrometastases) are present in more than 50% of colorectal cancer patients, and the liver is the most frequent site of apparent metastatic disease. Frequently, adjuvant chemotherapy is unable to prevent tumor recurrence. Thus, novel therapeutic strategies are warranted. The aim of this study was to establish a model of human colon cancer metastatic to the liver of nude mice, to assess, in this setting, the therapeutic efficacy of radioimmunotherapy (RAIT) compared to standard chemotherapy and to evaluate, in a Phase I/II trial, the toxicity and therapeutic efficacy of RAIT in colorectal cancer patients with small volume disease metastatic to the liver. Multiple liver metastases of the human colon cancer cell line GW-39 were induced by intrasplenic injection of a 10% tumor cell suspension. Whereas controls were left untreated, therapy was initiated on day 10 or 20 after tumor inoculation with the 131I-labeled, low affinity anticarcinoembryonic antigen (anti-CEA) monoclonal antibody (MAb), F023C5 (Ka = 10(7) liters/mol), or the high-affinity anti-CEA MAb, MN-14 (Ka = 10(9) liters/mol), or chemotherapy (5-fluorouracil/leucovorin (folinic acid) versus irinotecan) at their respective maximum tolerated doses (MTDs). Twelve colorectal cancer patients with small volume disease metastatic to the liver (all lesions < or = 2.5 cm) were entered into a mCi/m2-based Phase I dose escalation study with 131I-labeled humanized version of MN-14, hMN-14. The patients were given single injections, starting at 50 mCi/m2 and escalating in 10-mCi/m2 increments. The MTD was defined as the dose level at which < or = 1 of 6 patients develop grade 4 myelotoxicity. In the mice, untreated controls died from rapidly progressing hepatic metastases at 6-8 weeks after tumor inoculation. The life span of mice treated with 5-fluorouracil/leucovorin was prolonged for only 1-3 weeks, whereas irinotecan led to a 5-8-week prolongation. In contrast, at their respective MTDs, the 131I-labeled low-affinity anti-CEA MAb, F023C5, led to a 20% permanent cure rate, and the high affinity MAb, MN-14, led to an 80% permanent cure rate, when therapy was initiated at 10 days after tumor inoculation. In the 20-day-old tumor stage, although it prolonged life, 131I-F023C5 was unable to achieve cures, whereas 131I-MN-14 was still successful in 20%. Histologically, no remaining viable tumor cells could be demonstrated in these animals surviving > 6 months. In patients

Topics: Adult; Aged; Animals; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Mice; Mice, Nude; Middle Aged; Radioimmunotherapy

Twenty-seven patients with liver metastasis from colorectal cancer were treated with intermittent intra-arterial infusion chemotherapy for 5 years starting from 1993. Five to ten mg of CDDP, 250 mg of 5-FU and/or 3-6 mg of Leucovorin were administered weekly. In the case of nonresponders, the dose of 5-FU was allowed to increase toward 500 mg. The above schedule was repeated as long as possible. The average number of administrations in 12 out of 27 unresectable patients was 28.7. The response rate was 50% (CR; 4 cases, PR; 2), with 2 NC and 3 PD. Four patients given 500 mg of 5-FU showed some response. The 50% survival period was 466 days, and the 1- and 3-year survival rates were 66.7% and 18.3%, respectively. The average number of administrations in the group of patients who underwent prophylactic treatment and resection of the metastasis was 33.1. During an average observational period 681 days, 7 patients (46.7%) had a recurrence in the liver. The 5-year survival rate was 85.7%. The patients who were treated with 250 mg 5-FU experienced no severe side effects, but one who was given 500 mg 5-FU developed a duodenal ulcer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Rectal Neoplasms; Survival Rate

Two years after undergoing resection of liver metastases from colorectal cancer, about 65 percent of patients are alive and 25 percent are free of detectable disease. We tried to improve these outcomes by treating patients with hepatic arterial infusion of floxuridine plus systemic fluorouracil after liver resection.. We randomly assigned 156 patients at the time of resection of hepatic metastases from colorectal cancer to receive six cycles of hepatic arterial infusion with floxuridine and dexamethasone plus intravenous fluorouracil, with or without leucovorin, or six weeks of similar systemic therapy alone. Patients were stratified according to previous treatment and the number of liver metastases identified at operation. The study end points were overall survival, survival without recurrence of hepatic metastases, and survival without any metastases at two years.. The actuarial rate of overall survival at two years was 86 percent in the group treated with local plus systemic chemotherapy and 72 percent in the group given systemic therapy alone (P=0.03). The median survival was 72.2 months in the combined-therapy group and 59.3 months in the monotherapy group, with a median follow-up of 62.7 months. After two years, the rates of survival free of hepatic recurrence were 90 percent in the monotherapy group and 60 percent in the monotherapy group (P<0.001), and the respective rates of progression-free survival were 57 percent and 42 percent (P=0.07). At two years, the risk ratio for death was 2.34 among patients treated with systemic therapy alone, as compared with patients who received combined therapy (95 percent confidence interval, 1.10 to 4.98; P=0.027), after adjustment for important variables. The rates of adverse effects of at least moderate severity were similar in the two groups, except for a higher frequency of diarrhea and hepatic effects in the combined-therapy group.. For patients who undergo resection of liver metastases from colorectal cancer, postoperative treatment with a combination of hepatic arterial infusion of floxuridine and intravenous fluorouracil improves the outcome at two years.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Dexamethasone; Disease-Free Survival; Equipment Failure; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate

Recurrence after resection of colorectal liver metastases occurs after 9-12 months in up to 80% of patients. Half of the relapses is isolated to the liver. An intraarterial chemotherapy with 5-FU and folinic acid was compared to only resection. Main objective of the trial was survival. Within 14 days after resection followed the 6-month therapy with 5-FU 1000 mg/m2 continuously over 5d/28d and Folinic Acid 200 mg/m2 over 15 minutes 5d/28d. The first interim-analysis with 226 randomised patients showed in the intention-to-treat-analysis a median survival of 34.5 months (m.) with therapy versus 40.8 months (p = 0.1519 with a negative trend. (95%-Confidence interval for hazard ratio: [0.5; 1.15]) and time to progression of 14.2 m. with therapy versus 13.7 m. Severe toxicities (WHO grade III/IV) occurred in 25.6% of cycles and 62.9% of patients. Mainly registered were stomatitis (57.6%) and nausea (55.4%). The recruitment of patients for study was terminated, because in best case the risk to die could be lowered only by 15% and therefore clinical relevant prolongation of survival is not to achieve with this type of adjuvant therapy.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Rate

Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control.. Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression.. Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed.. Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Treatment Outcome

Eleven patients with liver metastasis from gastric cancer were treated by intermittent arterial infusion using OK-432 and recombinant IL-2 in combination with anticancer drugs. The direct effects for liver metastasis were PR 3 (response rate 30%), MR 2, NC 3, PD 1 and NE 1. Papillary adenocarcinoma showed a highly effective rate. The mean survival period was 326 days and the 50% survival period was 318 days. Out of 4 patients who underwent surgical resection for metastatic liver tumor, one showed recurrence, and the other is now healthy without any sign of recurrence for 8 years after the operation. In 7 patients with liver metastasis from colorectal cancer, intermittent arterial infusion therapy using Leucovorin, CDDP and 5-FU was performed. The direct effects were CR 2, PR 1, MR 1, PD 2, NE 1; the mean survival period was 478 days, and the 50% survival period 556 days. Out of 8 patients who underwent liver resection for metastasis, all patients remained alive for 687 mean survival days without liver recurrence. No severe side effects were noted in either therapy.

Topics: Adenocarcinoma, Papillary; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Immunotherapy; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Interleukin-2; Leucovorin; Liver Neoplasms; Male; Middle Aged; Picibanil; Recombinant Proteins; Stomach Neoplasms

To determine the acute toxicity, post-operative complications, pathologic response and extent of downstaging to high dose pre-operative radiation using a hyperfractionated radiation boost and concurrent chemotherapy in a prospective Phase I trial.. To be eligible for this study, patients had to have adenocarcinoma of the rectum less than 12 cm from the anal verge with either Stage T4 or T3 but greater than 4 cm or greater than 40% of the bowel circumference. All patients received 45 Gy pelvic radiation (1.8 Gy per fraction). Subsequent radiation was given to the region of the gross tumor with a 2 cm margin. This "boost" treatment was given at 1.2 Gy twice daily to a total dose of 54.6 Gy for Level I, 57 Gy for Level II, and 61.8 Gy for Level III. 5-FU was given at 1g/m2 over 24 hours for a four day infusion during the first and sixth weeks of radiation, with the second course concurrent with the hyperfractionated radiation. Surgical resection was carried out 4-6 weeks following completion of chemoradiation (in curative cases) and additional adjuvant chemotherapy consisting of 5-FU and Leucovorin was given for an additional 4 monthly cycles Days 1 through 5 beginning four weeks post surgery.. Twenty-seven patients, age 40-82 (median 61), completed the initial course of chemoradiation and are included in the analysis of toxicity. The median follow-up is 27 months (range 8-68). Eleven patients were treated to a dose of 54.6 Gy, nine patients to 57 Gy, and seven patients to 61.8 Gy. Twenty-one patients had T3 tumors, and six patients T4 tumors. Grade III acute toxicity from chemoradiation included proctitis (5 patients), dermatitis (9), diarrhea (five), leukopenia (1), cardiac (1). Grade IV toxicities included one patient with diarrhea (on dose Level I) and one patient (on dose Level III) with cardiac toxicity (unrelated to radiation). Surgical resection consisted of abdominal perineal resection in 16 and low anterior resection in 7. Four patients did not undergo a curative resection; three initially presented with metastases and one developed metastasis during the pre-operative regimen. Post-operative complications included pelvic or perineal abscess in two (on dose Levels I & II), and delayed wound healing in two (one of whom, on dose Level III, developed perineal wound dehiscence requiring surgical reconstruction). Of the 23 patients who had a curative resection, four manifested pathologic complete responses (17.4%). Thirteen of 23 patients (57%) had evidence of pathologic downstaging and only 1/23 patients (on dose Level I) had a positive resection margin. Of these 23 patients (with a minimum follow-up of 8 months), the patient with positive margins was the only one who developed a local failure (Fisher's Exact p=.04). The 3-year actuarial OS, DFS and LC rates are 82%, 72% and 96%, respectively. Twelve of 13 patients (92% at 3 years) > or = 61 years vs. 5/10 patients (45% at 3 years) < 61 years remained disease-free (log-rank p=0.017).. This regimen of high dose pre-operative chemoradiation employing a hyperfractionated radiation boost is feasible and tolerable and results in significant downstaging in locally advanced rectal cancer. The vast majority of patients (96%) achieved negative margins, which appears to be a prerequisite for local control (p= 0.04). Older age (> or =61 years) was a significant predictor for improved DFS. This regimen (at dose Level III, 61.8 Gy) is currently being tested in a Phase II setting.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Postoperative Complications; Prospective Studies; Radiotherapy Dosage; Rectal Neoplasms; Treatment Failure

To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases.. Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases.. Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only.. The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients.. According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate

This prospective multicenter trial was performed to determine the response rate, toxicity and applicability of continuous 24 h hepatic arterial infusion of high-dose 5-FU and folinic acid. An improved response rate (60.5% in non-pretreated patients) was however associated with many systemic side-effects (340/509), mainly nausea and diarrhea. Therefore this treatment should be applied only in selected patients in specialized centers.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate; Treatment Outcome

The relative efficacy of HAI FUDR, HAI 5-FU/FA, and i.v. 5-FU/FA chemotherapy for the treatment of unresectable colorectal liver metastases was compared in a prospective randomized clinical trial. The response rate after HAI treatment was significantly higher as compared to i.v. treatment with no statistical benefit regarding survival and time to progression. HAI FUDR treatment was inferior as compared to HAI or i.v. 5-FU/FA. i.v. 5-FU/FA-therapy is therefore the method of choice outside clinical trials.

Topics: Adult; Aged; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate; Treatment Outcome

Since systemic and regional (HAI) fluorinated pyrimidine chemotherapies offer similar survival benefit in treatment of colorectal liver metastases (CLM), we sought to identify their impact on quality of life (QoL), which might be a useful indicator of treatment preference.. We compared QoL in 135 CLM patients managed by symptom control (n = 49 patients), systemic fluorouracil (5FU)/folinic acid (n = 35), or hepatic arterial floxuridine (FUDR) (n = 51). Full blood count and liver function tests, World Health Organization (WHO) toxicity criteria, and QoL (Rotterdam Symptom Checklist [RSC], the Sickness Impact Profile [SIP], and the Hospital Anxiety and Depression scale [HAD]) were measured monthly in all patients.. The HAD anxiety score was significantly increased in symptom control compared with chemotherapy patients 1 month after randomization. There was a significant increase in RSC physical score (repeated measures, P = .05), and in scores for sore mouth (P < .01), dry mouth (P < .01), and tingling hands and feet (P < .01) in systemic chemotherapy compared with symptom control patients. Significant QoL differences (repeated measures and Mann-Whitney U [MWU]) between HAI and symptom control patients were not detected. Systemic chemotherapy patients lived for significantly longer (log-rank test, P < or = .0001) with abnormal HAD anxiety, RSC psychosocial, or RSC sore mouth scores compared with HAI patients, but there were no overall survival differences.. Randomization to symptom control only was associated with increased anxiety. QoL with systemic chemotherapy was impaired by side effects. HAI was associated with similar survival to systemic chemotherapy but with better sustained QoL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Floxuridine; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Middle Aged; Pain Measurement; Quality of Life; Survival Analysis

To determine the toxicity, response rate, and survival in patients treated with hepatic arterial infusion (HAI) of fluorouracil (5-FU) plus recombinant human interferon alfa-2b (rIFN-alpha 2b) (Intron-A; Schering-Plough, Inc, Kenilworth, NJ) for colorectal carcinoma (CRC) liver metastases refractory to systemic 5-FU plus leucovorin (LCV).. Forty-eight patients were given a 6-hour HAI of rIFN-alpha 2b 5 MU/m2 followed by an 18-hour HAI of 5-FU, 1,500 mg/m2 daily for 5 days. Twenty-nine patients were treated through percutaneously placed catheters and 19 through implantable infusion pumps (Shiley Infusaid Inc, Noorwood, MA). Treatment cycles were repeated every 28 to 35 days.. There were three (6.6%) complete remissions (CRs) and 12 (26.6%) partial remissions (PRs), for a CR plus PR rate of 33.3% among 45 assessable patients (95% confidence interval [CI], 20% to 49%). The median response duration was 7 months, while median survival duration was 15 months. Grade 3 to 4 treatment-related toxic effects included mucositis (40%), neutropenia (42%), and thrombocytopenia (12%). No hepatobiliary toxicity was encountered in any of the patients. Treatment was discontinued because of progressive liver disease in 23 patients and extrahepatic progression in 16, while six patients continue treatment through an infusaid pump.. HAI of 5-FU plus rIFN-alpha 2b is well tolerated, devoid of hepatobiliary toxicity, and can produce a response rate of 33.3% among patients refractory to bolus intravenous (IV) 5-FU plus LCV. The lack of hepatobiliary toxicity may permit salvage HAI with floxuridine (FUDR) in patients whose liver tumors fail to respond to HAI of 5-FU plus rIFN-alpha 2b. Because diarrhea was not a common side effect of HAI of 5-FU plus rIFN-alpha 2b, it would be of interest to investigate whether alternating HAI of 5-FU and rIFN-alpha 2b with systemic irinotecan (CPT-11) will decrease the incidence of both hepatic and extrahepatic disease progression.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Recombinant Proteins; Survival Analysis; Treatment Failure; Treatment Outcome

5-Fluorouracil in combination with leucovorin has been shown to be active in therapeutic trials of metastatic colorectal carcinoma. In this study, we administered these drugs to 72 patients with metastatic colorectal carcinoma. Thirty-six of them without previous exposure to 5-fluorouracil were treated with weekly bolus injections of 5-fluorouracil (425 mg/m2) and leucovorin (25 mg/m2) supplemented with oral levamisole. Another 36 patients with or without prior 5-fluorouracil treatment received 5-fluorouracil 3,000 mg/m2 and leucovorin 300 mg/m2 in a 48-hour continuous infusion every two weeks. Clinical efficacy and toxicity were assessed by WHO criteria. Variables were tested for relations to response and survival by univariate and multivariate analysis. The response rate was 19.4% in weekly bolus arm and 13.9% in biweekly high-dose infusion arm (P = 0.527). Median survivals in the two arms were 18.4 months (weekly) and 21 months (biweekly) respectively (P = 0.708). Gastrointestinal side effects including nausea, vomiting, diarrhea and mucositia were the major toxicities of these regimens. By multivariate analysis, the only factor to influence response rate was the site of metastases (P = 0.009). The only factor to affect survival was performance status of the patient (P = 0.0001). We concluded that the two 5-fluorouracil based regimens are well-tolerated and shown to have a response rate comparable with previous reports of similar regimens in patients with metastatic colorectal cancer. Only liver metastases seemed to have a better response to therapy. Performance status is the most important prognostic factor in patients with metastatic colorectal cancer.

Topics: Adjuvants, Immunologic; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections; Leucovorin; Levamisole; Liver Neoplasms; Male; Middle Aged; Prognosis; Remission Induction; Survival Analysis

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative, which is preferentially converted to 5-fluorouracil (5-FU) within tumour tissues. Although the activity of 5-FU in metastatic colorectal cancer is well recognised, resistance to this agent is frequently observed and remains its major limitation. The aim of this phase II study was to evaluate the activity of oral and i.v. 5-dFUR in metastatic or locally advanced colorectal cancer patients, who had been previously treated with a 5-FU containing regimen in either an adjuvant or metastatic setting. We treated 48 patients who, on the basis of tumour progression during, or within 8 weeks of the discontinuation of 5-FU therapy, were considered 5-FU resistant, 14 of the patients received 5-dFUR 3000 mg/m2 as a 1-h i.v. infusion, combined with L-leucovorin 25 mg/dose on days 1-5, every 3 weeks; the remaining 34 received oral 5-dFUR 1200 mg/m2 for 5 days followed by 5 days off. Oral L-leucovorin 25 mg/dose was administered 2 h before 5-dFUR. On the basis of WHO criteria, 4/14 (29%, 95% CI 4-51) partial responses were noted in the i.v. treated patients, and 4/34 (12%, 95% CI 1-23) in those treated orally. The radiological examinations documenting the response were a CT scan in 4 cases, ultrasound in 2 and NMR in 2. The median response duration was 6 months (range 3-11+), whereas the median time to treatment failure was 4 months (range 2-17). The responses were achieved in cases previously treated with a median of 9250 mg/m2 (range 5500-18,650) of 5-FU. No CTC-NC1 grade 4 toxicity was observed, although grade 3 diarrhoea occurred in 5 of the orally treated and in 3 of the intravenously treated patients. This is the first report documenting the efficacy of 5-dFUR in patients resistant to 5-FU therapy, and suggests that there is an absence of complete cross-resistance between these two fluoropyrimidines.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Tomography, X-Ray Computed

The efficacy of chemotherapy may be affected by circadian rhythms. Therefore, we tested chronomodulated infusion (administered to coincide with relevant circadian rhythms) of oxaliplatin, fluorouracil, and folinic acid compared with a constant-rate infusion method. The combination of three drugs was delivered for 5-day courses with 16-day intervals.. We expected chronotherapy to increase objective response rate by 20% compared with constant-rate infusion. We tested this effect in a randomised multicentre trial involving patients with previously untreated metastases from colorectal cancer who were enrolled at nine institutions in three countries. 93 patients were assigned chronotherapy and 93 were assigned constant-rate infusion via multichannel programmable ambulatory pumps. The trial was interrupted when a significant difference in main outcome was reached. All data were analysed by intention to treat.. On enrollment, we found significant imbalances in two characteristics-abdominal gland or bone metastases (constant-rate infusion two patients, chronotherapy ten patients) and relapse from surgically treated metastases (constant-rate infusion seven patients, chronotherapy 22 patients). An objective response was obtained in 47 (51%) of the chronotherapy group, and in 27 (29%) of the constant-rate group (difference 21.5% [95% CI 13.7-31.2], p = 0.003). Chronotherapy reduced five-fold the rate of severe mucosal toxicity (14% vs 76%, p < 0.0001) and halved that of functional impairment from peripheral sensitive neuropathy (16% vs 31%, difference 15.0% [9.5-25.7], p < 0.01). Median time to treatment failure was 6.4 months on chronotherapy and 4.9 months on constant-rate infusion (p = 0.006), and 24% of the patients from the constant-rate infusion group received chronotherapy after failure. With a minimum follow-up of 3 years, median survival times and 3-year survival were similar in both groups (15.9 vs 16.9 months and 22% vs 21%, respectively).. Chronotherapy was significantly less toxic and more effective than constant-rate infusion. The results support the concept of temporal selectivity of cancer chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusion Pumps; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Survival Analysis

The value of intratumoral thymidylate synthase (TS) quantitation as a predictive parameter for hepatic artery infusion (HAI) chemotherapy in patients with colorectal liver metastases was investigated. Relative TS mRNA levels were determined in 29 tumor samples using a quantitative RT-PCR amplification method. The median level of expression was 3.0 x 10(-3) (no units) and varied considerably among the tumors over a range of 135-fold. Patients with low TS levels were 4.1-fold more likely to respond (P < 0.03) compared to patients with high TS levels. Our results indicate that TS quantitation is a valuable predictive marker for tumor response to HAI therapy.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Colorectal Neoplasms; Drug Administration Schedule; Drug Resistance, Neoplasm; Epirubicin; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitoxantrone; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; RNA, Messenger; Survival Rate; Thymidylate Synthase; Transcription, Genetic

UFT (tegafur and uracil) has been studied extensively in Japan, with documented efficacy in hepatobiliary and pancreatic cancer. In the United States, UFT with or without leucovorin has not undergone phase II testing in these malignancies. Our current trial is designed primarily to assess the efficacy in terms of response rates to UFT with leucovorin in patients with advanced hepatobiliary and pancreatic cancer. Secondary objectives include determining response duration, time to disease progression, overall survival, quality of life, and toxicity.

Topics: Adenocarcinoma; Adult; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Cholangiocarcinoma; Drug Combinations; Humans; Leucovorin; Liver Neoplasms; Pancreatic Neoplasms; Quality of Life; Tegafur; Treatment Outcome; Uracil

Forty patients with unresectable colorectal metastases confined to the liver were evaluated in a phase II study. 5-Fluorouracil (5-FU) was delivered via a surgically placed hepatic artery catheter. Patients received folinic acid (200 mg m-2) intravenously over 2 h followed by a loading dose of intra-arterial 5-FU (400 mg m-2) over 15 min, then 5-FU (1600 mg m-2) by intra-arterial infusion over the following 22 h. This was repeated on day 2 and the whole schedule was repeated every 2 weeks. Response was assessed after six treatments. The median follow-up was 17 months. Overall response rate was 46% with 8% complete response. Estimated median survival is 19 months. Site of progression was the liver alone in 55%, liver and lung in another 16% and 29% in other sites. Eight patients experienced grade 3 or 4 toxicity. The response rate of this regimen compares favourably with reported trials of intra-arterial FUDR, and our schedule is currently being compared with a similar schedule of intravenous 5-FU and folinic acid in a randomized Medical Research Council trial (CR05).

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged

A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m2 to be the maximum tolerable dose of 5-fluorouracil (5-FU) administered as a five-day continuous infusion modulated by short infusions of 100 mg/m2 folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effectiveness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m2 recommended dose of 5-FU and 100 mg/m2 folinic acid twice daily every three weeks.. From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemotherapy were included in this trial.. In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months.. This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Quality of Life; Rectal Neoplasms; Treatment Outcome

Recent advances in biochemical pharmacology have revealed the basis for the biological modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and folinic acid (FA). Sequential use of MTX given 24 h prior to 5-FU has resulted in enhanced cell kill in vitro and in vivo. In addition, administration of FA prior to 5-FU has led to potentiation of 5-FU action by stabilization of the ternary complex of thymidine synthase. In the present randomized study, two groups of patients with advanced colorectal cancer were treated as follows: 43 patients (pts) in group A received 5-FU + FA, whereas 45 pts in group B received 5-FU + FA + MTX. The dosage was as follows: group A received FA i.v. at 300 mg/m2 per day, prior to i.v. 5-FU at 500 mg/m2 per day on days 1-4; group B was given MTX i.v. at 130 mg/m2 per day on day 0, followed 24 h later by FA at 15 mg q6h x 6, and 5-FU + FA was started on day 1 and given at the same doses and schedule described for group A. Objective responses were achieved by 8/43 pts in group A (1 complete response and 7 partial responses) and by 18/45 pts in group B (3 complete and 15 partial responses), all occurring in the liver. There was no significant difference in the median time to progression (group A 6.1 months, group B 6.8 months) or the median survival (group A 9.2 months, group B 10.3 months). Toxicity was significantly greater in group B [grade 2-3 mucositis 20% versus only 2% in group A (P < 0.0001); grade 3 diarrhea in group B 15% versus 3% in group A (P < 0.001)]. According to our results, double biological modulation of 5-FU with MTX + FA led to an enhanced response rate with increased toxicity as compared with the 5-FU + FA regimen given at less than its maximally tolerated dose.

Topics: Adenocarcinoma; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cell Death; Colorectal Neoplasms; Dose-Response Relationship, Drug; Enzyme Stability; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Methotrexate; Middle Aged

The primary objective of this study was to determine the response rate of patients with metastatic colorectal cancer to combined therapy with 5-fluorouracil (5-FU), leucovorin, and intravenous azidothymidine (AZT), a thymidine nucleoside analog. By itself, AZT has limited antineoplastic efficacy. However, experimental studies indicate that 5-FU enhances the antitumor activity of AZT by inhibiting synthesis of normal thymidine nucleotides with which AZT competes for incorporation into nucleic acids. A phase I study defined the maximum tolerated dose of AZT as 7 g/m2 with hypotension during the infusion being the dose-limiting toxicity. A phase II study was performed with oral leucovorin (100 mg p.o. hourly for 4 h prior to 5-FU and 4 h and 8 h after 5-FU), bolus 5-FU (400 mg/m2) followed 1 h later by a 2-h infusion of AZT (7 g/m2). Treatment was given weekly for 4 weeks followed by a 1-week break, which constituted a cycle of therapy. Responses were evaluated after every two cycles. Patients continued on therapy as long as they tolerated treatment and did not have progressive disease. Of 15 evaluable patients who had received no chemotherapy there was 1 complete response and 4 partial responses (a 33% response rate), whereas only 1 of 6 patients who had received prior adjuvant chemotherapy had a partial response (17%). An additional 10 patients had stable disease lasting 2-14 months. Therapy was well tolerated with the only one instance each of grade 3 nausea and vomiting, diarrhea, anemia, and hypotension. Approximately 50% of treatments were accompanied by mild hypotension, which was easily corrected by increasing the rate of normal saline infusion. There was no difficulty administering this regimen in the outpatient setting. While the overall response rate (29%) is comparable to that seen with combinations of 5-FU and leucovorin alone, in most reported series a considerably higher dose of 5-FU was utilized than in this study. Since patients in the present study experienced relatively little 5-FU toxicity, increasing the dose of 5-FU in this regimen would appear to be feasible and might result in a higher response rate.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Zidovudine

Focusing our effort on the importance of FUra scheduling we have tested the hypothesis that pulse and continuous infusion (CI) of the fluoropyrimidine have different mechanisms of cytotoxicity. Our initial approach was to compare the mechanism of resistance of a cell line resistant to a short term exposure to FUra (HCT-8/FU4hR) to that of a cell line resistant to a prolonged exposure to the fluoropyrimidine (HCT-8/FU7dR). Cytotoxicity studies showed that HCT-8/FU4hR cells were still sensitive to FUra given as a 7-d exposure, suggesting different mechanisms of resistance. Indeed, rapid recovery of TS activity after drug removal was evident in the HTC-8/FU7dR cell line while HCT-8/FU4hR cells were similar to the parental cell line with regard to both the degree of in situ TS inhibition by FUra and duration of inhibition after FUra removal. In contrast, labelling studies with [3H-6]FUra(4 h exposure, 100 microM) showed that the incorporation of the fluoropyrimidine into RNA is significantly decreased in HCT-8/FU4hR cells as compared to parental HCT-8 cells. Given the lack of cross resistance between the two schedules in vitro, a pilot trial was done on patients with colorectal cancer refractory to bolus FUra. On 15 patients failing after FUra+LV or FUra alone 1 PR, 3 MR, 3 SD and 8 P were observed, confirming a certain degree of activity of CI FUra in patients clinically resistant to bolus FUra. Based on this rationale, a phase II trial of schedule-oriented biochemical modulation of FUra in advanced colorectal cancer patients was conducted, employing a hybrid regimen of 2 biweekly cycles of FUra bolus (600 mg/sqm), preceeded by (24 h interval) methotrexate, 200 mg/sqm (in order to maximize the RNA effect of the drug) alternating with Fura continuous infusion, 200 mg/sqm daily for 3 weeks, modulated by leucovorin, 20 mg/sqm weekly bolus (in order to maximize the DNA effect). Thirty-three consecutive patients (median ECOG PS 1) with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study, from February 1992 to August 1993. Three complete and 13 partial responses were obtained among these 33 patients (RR = 48%, 95% confidence limits, 31-66%). After a median follow-up time of 23 months, 16 patients are still alive. The median progression free survival and overall survival were 9.6 and 20.8 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was:

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Methotrexate; Palliative Care; Pilot Projects; Remission Induction; Treatment Outcome; Tumor Cells, Cultured

A prospective decision-aiding trial was performed to select drugs for regional chemotherapy of various liver tumors (n = 36) by individual drug testing. The drugs were chosen for hepatic artery infusion according to the individual chemosensitivity of tumor biopsies in the human tumor colony-forming assay (HTCA). In vitro HTCA sensitivity correlated with complete response (CR) + partial response (PR) + no change (NC) 93% of the time and with CR + PR 55% of the time. The test sensitivity was 90%, and the specificity was 67% for CR + PR + NC versus progressive disease (PD), whereas the sensitivity and specificity were 89% and 28%, respectively, for CR + PR versus NC + PD. The overall predictive accuracy of the test was 86% for CR + PR + NC versus PD and 58% for CR + PR versus NC + PD. Overall, 83% of this heterogenous patient group with various tumors achieved CR + PR + NC and a 50% clinical response (CR + PR). In vitro-sensitive patients showed a significantly lower intrahepatic progression rate (7% PD) than in vitro-resistant patients (57%; P < 0.05). These results indicate that the HTCA could identify active drugs for individualized hepatic artery infusion, and patients may profit from the use of in vitro-sensitive drugs.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Doxorubicin; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitoxantrone; Neoplastic Stem Cells; Prospective Studies; Tumor Stem Cell Assay

Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25-80 mg/m2/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Kidney Diseases; Leucovorin; Liver; Liver Neoplasms; Methotrexate; Neoplasms; Nervous System Diseases; Ovarian Neoplasms; Remission Induction; Spectrophotometry, Atomic; Tumor Cells, Cultured; Vinblastine

The prognosis for patients with advanced (stage III and IV) hepatocellular carcinoma (HCC) remains poor. Liver resection and liver transplantation have limited effects on overall survival. Our study was carried out to assess a novel therapeutic approach, which includes transarterial locoregional chemotherapy and in vivo locoregional dual immunostimulation, in patients with unresectable HCC. A group of 20 patients with stage III and IV hepatocellular carcinoma had 10 courses (once per day) of transarterial targeted locoregional immunotherapy with interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), emulsified in a Lipiodol-Urografin mixture. The target organs were the spleen and the liver tumor itself. One course of intrahepatic locoregional targeting transarterial chemotherapy was given 10 days after completion of immunotherapy (mitomycin C, carboplatin, Farmorubicin, Leucovorin, 5-fluorouracil, and IFN-gamma). This was followed after 2 months by another course of transarterial targeted locoregional immunotherapy-chemotherapy. All patients survived the operation and had a mean survival time of 18 months (4-22 months). There was a decrease in the tumor size of 14 of the 20 patients. Serum alpha-fetoprotein (AFP) levels declined in 14 patients, reaching normal levels in 12 patients. These preliminary results indicate that combined locoregional immunotherapy-chemotherapy is a promising therapeutic approach in patients suffering from advanced nonresectable HCC and merits further evaluation.

Topics: Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Hepatocellular; Combined Modality Therapy; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Interferon-gamma; Interleukin-2; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Mitomycin; Necrosis; Pilot Projects; Spleen; Survival Rate; Tomography, Emission-Computed

A phase II trial of 5-fluorouracil (5-FU) [250-450 mg/m2/day x 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m2/day x 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

We have performed intra-arterial 5-fluorouracil (5-FU)/intra-venous methotrexate (MTX) therapy for 4 patients with multiple metastatic liver tumors at out-patient clinic. Primary lesions were of the stomach (one patient, synchronous) and colon (3 patients, two were synchronous and one was metachronous). 5-FU (250-350 mg/day) was continuously infused for two weeks into the hepatic artery through the reservoir using the Baxter Infuser (multi-day type). MTX (100 mg/m2) was infused into the peripheral vein on days 1, 8 and 15. Leucovorin calcium (15 mg) was orally administered three times after MTX infusion. All patients partially responded, and no remarkable side effect was detected. We propose that this new combination therapy, that is intra-arterial 5-FU and intra-venous MTX for metastatic liver cancer, can be useful and safe even for out-patients.

Topics: Administration, Oral; Adult; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Neoplasms; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Methotrexate; Middle Aged; Remission Induction

A new modality of locoregional chemotherapy based on biochemical double modulation of 5-fluorouracil (FU) with both leucovorin (LV) and cisplatin (CDDP) against liver metastases of colorectal cancer was devised. The schedule for the locoregional therapy was as follows; bolus infusion of LV (6 mg/body) followed by 30-minute infusion of CDDP (10 mg/body) and 30-minute infusion of 5-FU (250 mg/body). Four colorectal cancer patients with numerous metastases to both lobes of liver were given intraarterial administration of above anticancer drugs every 1-2 weeks after resection of primary lesions. On the one hand, 3 colorectal cancer patients, who developed a few metastases to both lobes of liver, were treated preventively by the same schedule every 2-3 weeks after the resection of metastatic tumors. As for the clinical (radiographic) response, complete response and partial response were observed in 1 and 2 of 4 patients, respectively. The response rate was 75%. No new lesions appeared for over 1 year by the preventive treatment in 2 of 3 patients, whereas new lesions appeared in one patient at 3 months after discontinuation of treatment because of mild toxicity. The toxicity, however, was within acceptable limits. These results indicated that biochemical double modulation of 5-FU with both LV and CDDP is a very promising locoregional chemotherapy against liver metastases of colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged

Thirty previously untreated patients with metastatic colorectal carcinoma were randomized as part of two multicenter Phase III trials. Twenty-two patients were randomized to receive either 5-fluorouracil (5-FU)/interferon alfa-2A (IFN-alpha) or 5-FU/leucovorin (11 patients in each arm). Eight patients were randomized to receive 5-FU/IFN-alpha or 5-FU alone (4 patients in each arm).. Twenty-three patients (13 patients treated with 5-FU/IFN-alpha and 10 patients treated with 5-FU/leucovorin or 5-FU alone) were evaluated regularly for response by computed tomography (CT) scans of the abdomen when treatment began and then every 6-8 weeks.. Incidentally, four patients developed hepatic steatosis during treatment with IFN-alpha and 5-FU. The diagnosis was based on a decreased CT value of the liver parenchyma by repeated CT scans of the abdomen during treatment, and this diagnosis was verified histologically by liver biopsy. There was no relationship to cumulative IFN-alpha or 5-FU dose. Based on posttreatment CT scans, the liver parenchyma changes were reversible after therapy was stopped, and there were no significant clinical sequelae. No patients treated with 5-FU/leucovorin or 5-FU alone experienced a decreased CT value of the liver parenchyma.. Hepatic steatosis was been observed in approximately 30% of patients treated with IFN-alpha and 5-FU. The hepatic changes were fully reversible after the treatment was stopped. Recognition of this condition is important to prevent a patient from being labeled as having progressive hepatic metastases.

Topics: Adenocarcinoma; Colonic Neoplasms; Fatty Liver; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Recombinant Proteins; Rectal Neoplasms; Tomography, X-Ray Computed

There is no known effective salvage chemotherapy for patients with refractory or relapsed urothelial tumors after methotrexate/cisplatin-based regimen. We report the results of a phase II trial with the FIFO regimen that includes from day 1 to 5: fluorouracil 350 mg/m2, folinic acid 20 mg/m2, and ifosfamide 1000 mg/m2, Q4W. Fifteen patients with metastatic measurable urothelial cancer were enrolled in this trial. Previous therapy included M-VAC regimen in 11 patients, CMV regimen in 3 patients, and both regimens in 1 patient. Thirty-one courses were delivered. Toxicity was moderate, including encephalopathy grade 2 in 2 patients and hematological toxicity grade 3 in 2 others. However, an early death occurred on day 1 in a patient who progressed rapidly and died from hepatic insufficiency after initial encephalopathy. No objective response was seen. Twelve patients progressed during FIFO therapy and 3 patients experienced a stable disease. Despite almost encouraging results of fluorouracil and ifosfamide in the literature, their combination according to our schedule is not active in urothelial cancer.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Transitional Cell; Fluorouracil; Hepatic Encephalopathy; Humans; Ifosfamide; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retroperitoneal Neoplasms; Salvage Therapy; Treatment Failure; Urologic Neoplasms

Topics: Adenocarcinoma; Aged; Anorexia; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis

Chemotherapy is most effective when applied during the biologically active stage of tumor cells. According to the authors' previous tumor marker kinetic study, methotrexate plus 5-fluorouracil (MF) was found to yield either a cytolytic effect in an MF-sensitive tumor cell population or a cytostatic effect in an MF-resistant population. In the latter, the suppressive effect was transient and the biologic activity resumed in one week after MF administration.. Based on this marker kinetic study, an alternating chemotherapy program was designed to study its antitumor and side effects. Methotrexate (M) (200 mg/m2) and 5-fluorouracil (F) (500 mg/m2) were administered intravenously on day 1 followed 24 hours later by leucovorin (L) (10 mg/m2 orally every 6 hours for 6 doses). Cyclophosphamide (C) 300 (mg/m2), doxorubicin (A) (50 mg/m2), and vincristine (V) (1 mg/m2) were given on day 8. The MFL/CAV was given every 4 weeks.. Forty-nine patients with metastatic breast cancer were enrolled; 41 were eligible. There were 5 complete and 23 partial remissions, producing a total response rate of 68%. In 15 patients with liver metastases, the response rate was 73% and the median survival 13.7 months, results superior to those previously reported for this subgroup of patients. Side effects were manageable.. This regimen, which can be given safely in an outpatient setting, yielded encouraging response and survival rates in patients with visceral-dominant disease with poor prognoses.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cyclophosphamide; Doxorubicin; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Middle Aged; Neoplasm Metastasis; Pilot Projects; Remission Induction; Vincristine

A total of 56 consecutive patients with metastatic colorectal cancer received treatment with 5-fluorouracil (5-FU) given at 425 mg/m2 by rapid intravenous infusion, immediately preceded by leucovorin (LV) given at 20 mg/m2, with cycles being repeated every 4 weeks. Of 48 evaluable patients undergoing this treatment, a tumor response was observed in 16 (33%); a complete response, in 2 (4%); and a partial response, in 14 (29%). The median survival was 8.5 months for all patients and 16.5 months for responders. An improvement in symptoms was seen in 9 (26%) of 34 symptomatic patients. In all 15 (27%) of 44 evaluable patients showed an improvement in performance status. The most significant toxicity attributable to the treatment was mucositis of grade 3 or 4, seen in 27% of the patients. Altogether, 2 patients (3.5%) were hospitalized for treatment-related toxicity. We conclude that the combination of 5-FU and low-dose LV is active in advanced colorectal cancer and is associated with acceptable toxicity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Neoplasm Recurrence, Local; Pilot Projects

Between September 1990 and August 1994, 11 patients (pts) with liver metastases (mets) from colorectal cancer were treated with continuous hepatic arterial infusion chemotherapy of 5-fluorouracil (FU) plus leucovorin (LV). Eight pts had non-resectable liver mets (H3: 7, H2: 1), and 3 had residual small mets after resection of major mets. Drugs were administered via an extracorporeal infusion device connected to the hepatic arterial infusion port. 5-FU and LV were given through a 5- to 7-day continuous infusion at 500-750 mg/body/day and 30 mg/body/day, respectively, with a 3- to 4-week rest period. In the recent 6 pts, cisplatin was administered as a 2-hour infusion at 25 mg/body, one or two times simultaneously. Grade 2 toxicity was noted in two pts (18%). One was stomatitis and another was uncontrolled ascites in an advanced cirrhotic pt. The response rate in the 9 evaluable pts was 67% with 6 PR and no CR. The duration of the response was 5 to 9 months. One- and two-year survival rates were 75% and 22%, respectively. These results were superior to those of the intermittent bolus injection of 5-FU plus MMC (or epirubicin) in 40 pts from 1977 to 1994. These results suggest that continuous 5-FU plus LV arterial infusion is an effective regimen in pts with liver metastases from colorectal cancer. However, the infusion with an extracorporeal device limits the pts' quality of life. Further investigation is needed for a schedule that can be practiced for a longer period.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged

A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer.. Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU.. Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy.. A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged

Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patient with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of S6-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day -2, and the other preparation on day -1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23-60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p = 0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Cohort Studies; Colorectal Neoplasms; Digestive System; Dose-Response Relationship, Drug; Drug Interactions; Drugs, Investigational; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Reproducibility of Results; Stereoisomerism; Treatment Outcome

We initiated a pilot study of adjuvant hepatic arterial infusion chemotherapy (AHAIC) using 5-fluorouracil (5-FU) and leucovorin. Hepatic arterial infusion ports were placed in 15 consecutive patients undergoing curative resection of colorectal liver metastases. The chemotherapy regimen consisted of a weekly infusion of 5-FU (12 mg m 2 per day) and leucovorin (200 mg m 2 per day) for 12 months. The mean follow-up was 22 months (range 3-62 months, SD 21-37 months). There were no clinical or biological complications related to chemotherapy, except for sharp epigastric burns in four patients immediately after 5-FU infusions. Catheter irreversible occlusions led to early cessation of the treatment in three patients. Four of the 15 evaluable patients developed recurrent disease. The site of relapse was the liver in two patients and extra-hepatic sites in the two remaining patients. Three of these four patients died of their recurrent disease. These results suggest that 5-FU and leucovorin can be combined for AHAIC in a long duration regimen with a very low rate of side-effects. This protocol could be safely employed in a prospective randomized study in combination with 5-FU systemic infusions.

Topics: Aged; Antidotes; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome

We have performed intra-arterial biochemical modulation chemotherapy of 5-FU with Leucovorin for patients with unresectable liver metastases from colorectal cancer. Three regimens were performed. A; weekly bolus injection of 5-FU and Leucovorin (6 cases), B; 7 days continuous injection of 5-FU after bolus injection of Leucovorin (4 cases), C; 5 days simultaneously continuous injection of 5-FU with Leucovorin (6 cases). The results were; response rate was A:0%, B:25%, C:33% and survival rate for patients of C method was better than that for patients of A and B method. Four patients complained mild nausea of less than Grade 2, but only one patient of C method. These results suggest that simultaneously continuous intra-arterial injection of 5-FU with Leucovorin is an excellent therapy for patients with unresectable liver metastases from colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Home Infusion Therapy; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms

Regional chemotherapy, delivered via the hepatic artery, may significantly increase tumour response rates in patients with colorectal liver metastases. However, survival is limited by extrahepatic disease progression. We have developed a novel therapeutic approach for patients with metastases confined to the liver. In order to achieve high local response rates and also inhibit extrahepatic progression, 5-fluorouracil (5-FU) was infused intra-arterially at a dose previously calculated to achieve both high-dose regional therapy and adequate systemic levels. To enhance efficacy further, 5-FU was combined with high-dose systemic folinic acid (FA). Thirty-one patients were evaluated in a phase II study. 5-FU (1.5 g m2) was infused via a surgically implanted hepatic artery catheter over a 24 h period; FA (total 400 mg m-2) was infused intravenously during the initial and final 2 h. Treatments were given weekly for cycles of 6 weeks' duration. To date, median duration of treatment is 6 months and the median follow-up period is 17 months. The overall response rate was 48% with two complete and 13 partial responses. Predicted median time to progression is 8 months. The site of first progression was hepatic in 10 (42%) and extrahepatic in 14 (58%) patients. Seven patients developed local complications; one required emergency surgery. Side-effects were limited to grade 3 toxicity (four patients) or less. Predicted median survival is 19 months. This approach, which is associated with a high response rate and low systemic toxicity, warrants further evaluation. A phase III study is planned.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged

Intraarterial infusion combination therapy with LV and 5-FU was performed on 8 patients with hepatic metastases from colorectal cancer. Briefly, immediately after administration of LV 30 mg/body, 5-FU was administrated in doses of 750 to 1,250 mg/body over about 2 hours. The therapy was repeated at every weekly visit to the clinic. The number of courses per patient averaged 22. The response rate was 50% (4 PR). Clinical responses were obtained 6 months on average. The 50% survival period was 300 days. Five patients died, 3 due to metastases to other sites. This therapy on an out-patient basis could be continued in all but one patient who was withdrawn from the treatment because of leucopenia. The results of this study suggest that this combination therapy is effective for hepatic metastasis from colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis

To determine the toxicity, response rate, and survival of a regimen of hepatic arterial floxuridine (FUDR) with leucovorin (LV) and dexamethasone (Dec) for the treatment of unresectable hepatic metastases from colorectal carcinoma.. Sixty-two patients with hepatic metastases (33 previously untreated with chemotherapy) were treated with FUDR (0.30 mg/kg/d) and LV (15 mg/m2/d) and Dec (20 mg total dose) as a 14-day hepatic arterial infusion via an implantable pump alternating with 2 weeks of saline.. The complete response (CR) plus partial response (PR) rate was 78% in previously untreated patients, with a median survival duration of 24.8 months; 1- and 2-year survival rates were 91% and 57%, respectively. In the previously treated group, the response rate was 52%, with a median survival duration of 13.5 months. Only 3% of patients (two of 62) developed biliary sclerosis; this was significantly lower than the 21% biliary sclerosis rate observed in our previous trial of hepatic arterial FUDR and LV without Dec (P = .002).. The addition of Dec to hepatic arterial FUDR and LV reduces biliary toxicity while maintaining an excellent response rate and survival. We recommend that this treatment be studied further.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Colorectal Neoplasms; Dexamethasone; Female; Floxuridine; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Survival Analysis

To conduct a pilot trial of hepatic arterial infusion (HAI) of floxuridine (FUDR), leucovorin, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and cisplatin (FLAP) in nonresectable hepatocellular cancer (HCC) confined to the liver and assess the effects of hepatitis B (HBV) and hepatitis C (HCV) viral markers on toxicity, response to treatment, and patient survival.. Of 31 HCC patients, 13 were HBV- and HCV-nonreactive, and 18 had evidence of either current or prior HBV and/or HCV infection. Treatment was delivered through percutaneous hepatic arterial catheters, and Infusaid pumps (Shiley Infusaid, Norwood, MA) were placed in responding patients. Cisplatin (100 mg/m2) and Adriamycin (30 to 35 mg/m2) were administered on day 1, followed by a continuous 24-hour HAI of an admixture of floxuridine (60 mg/m2) and leucovorin (15 mg/m2) daily for 4 days. Treatment was repeated every 5 weeks.. Twelve (41%) of 29 assessable patients had a partial response (PR), with a median time to disease progression of 13 months. Six (50%) of 12 HBV-negative (HBV-)/HCV-negative (HCV-) and six of 17 (35%) HBV-positive (HCV+) and/or HCV-positive (HCV+) patients achieved a PR. Eight patients have been maintained in remission for a median duration greater than 15.5 months. The median survival duration of all 31 patients was 15 months, 7.5 months among HBV+ and/or HCV+ patients, and significantly longer among hepatitis-non-reactive patients (P = .007). (A median has not yet been reached.) Granulocylopenia (< 0.1 x 10(3)/microL), thrombocytopenia (< 25 x 10(3)/microL), and hospitalizations for infectious complications were significantly more common among HBV-HCV-reactive than -nonreactive patients: 56%, 50%, and 67% versus 15%, 15%, and 8%, respectively (P < .05 for all).. HAI of FLAP has induced long-term PR and has palliated extensive nonresectable HCC. Positive hepatitis serology appeared to increase bone marrow susceptibility to myelotoxic drugs. Conceivably, one or both viruses may have a direct inhibitory effect on bone marrow progenitors and thereby contribute to the observed myelotoxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Doxorubicin; Female; Floxuridine; Hepatic Artery; Hepatitis B; Hepatitis C; Humans; Infusion Pumps; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Survival Rate

5-Fluorouracil (5-FU) modulation with either folinic acid (FA) or methotrexate (MTX) has improved 5-FU's potential cytoreductivity. We combined MTX and FA with 5-FU to further augment 5-FU's cytoreductivity. Patients (n = 34) with advanced colorectal carcinoma were first given intravenous MTX (escalated from 30 mg/m2 to 70 mg/m2). FA (100 mg/m2) was infused 17-24 hr later, followed by 5-FU (600 mg/m2). Oral rescue doses of FA were begun 24 hr after MTX. Patients were treated every 2 weeks. No previously treated patient (n = 6) responded. Eight of the remaining 28 (29%) (95% confidence interval, 15-47%) patients achieved a PR. Median survival was 9.3 months. Toxicity (primarily gastrointestinal) necessitated dosage modification in 10 patients (29%). These results, in addition to a literature review, reveal that the manipulation of 5-FU by two modulating agents does not improve the response rate seen with single-agent modulation.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Remission Induction; Survival Rate; Treatment Outcome

We studied three new dose schedules of hepatic arterial infusion of floxuridine (FUDR) and leucovorin and update survival analysis of a previously reported trial using these drugs by hepatic arterial infusion for patients with hepatic metastases from colorectal carcinoma.. Untreated patients with hepatic metastases from colorectal cancer were treated with three dose schedules: Group D, FUDR (0.3 mg/kg/day) and leucovorin (30 mg/m2/day) as a 14-day continuous infusion through an implantable hepatic arterial pump alternating with a 4-week rest period; Group E, a lower dose of FUDR (0.25 mg/kg/day) and leucovorin (30 mg/m2/day) as a 14-day infusion alternating with 2 weeks of saline; and Group F, FUDR (0.3 mg/kg/day) with a lower leucovorin dose (15 mg/m2/day) for 2 weeks followed by a 2-week rest.. In 42 patients with unresectable hepatic metastases, the complete-plus-partial response rate was 56%, with a median survival of 24.2 months. Complete-plus-partial response rates for groups D, E, and F were 30%, 54%, and 75%, respectively. Twelve percent of the 42 patients developed biliary sclerosis; the percentages of patients per group were 17%, 15%, and 6%, respectively. Updated median survival of the original 24 patients treated with FUDR and leucovorin by hepatic arterial infusion and these 42 new patients (66 total) was 28.8 months. One-, two-, three-, four-, and five-year survival rates were 86%, 62%, 31%, 15%, and 7%, respectively.. Hepatic arterial chemotherapy with FUDR and leucovorin for patients with hepatic metastases from colorectal carcinoma yields a high response rate and 1- and 2-year survivals of 86% and 62%, respectively. Although a lower dose of leucovorin (15 mg/m2) with FUDR produces a high response rate with less toxicity, before larger scale trials are initiated, further investigation is needed to reduce toxicity. A study of hepatic arterial dexamethasone with FUDR and leucovorin has been initiated for this purpose.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Drug Administration Schedule; Female; Floxuridine; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Analysis

We report our preliminary results of an ongoing phase-II-study with special regard to local and systemic toxicity, using a combined regimen of high dose Leucovorin and 5-Fluorouracil applicated intra-hepato-arterially. During 24 chemotherapy cycles we saw only mild to moderate systemic toxicity and there was no chemical hepatitis. First results concerning the response rate are encouraging. The modulation of 5-Fluorouracil (5-FU) with folinic acid represents a significant step in the treatment of colorectal cancer. Administration of chemotherapy through the hepatic artery for liver metastases of colorectal cancer allows high local drug concentration with relative low systemic toxicity. Until now there is little information about the local and systemic toxicity of high dose Leucovorin combined with 5-FU applicated intra-hepato-arterially. We describe our experience with this therapy in a running phase-II-study with special regard to local and systemic toxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Prospective Studies

The results of treatment strategies for carcinoma of an unknown primary location have been discouraging. Currently, no chemotherapeutic approach can be considered standard.. We therefore initiated a Phase II study in which fluorouracil (370 mg/m2, day 1 through 5) plus folinic acid (200 mg/m2 day 1 through 5) was administered in a subset of 17 patients (median age, 57 years) affected by histologically diagnosed adenocarcinoma of unknown primary location characterized by liver metastases and elevated CEA of CA 19.9. All of the patients had a performance status of 0-2 (ECOG Scale), and liver involvement was > 30% in 7 cases.. No objective response was observed (4 cases of stabilization and 13 of disease progression). Median survival was 5 months. Toxicity was mild or moderate, and severe diarrhea was observed in only one case.. The proposed regimen is inactive among this subset of patients and confirms that subdiaphragmatic metastases are related to a poor prognosis. Our results, in agreement with data published in the literature, suggest that patients affected by adenocarcinoma of an unknown primary origin metastatic to the liver and with a good performance status should be treated in an investigative setting.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasms, Unknown Primary

25 patients with metastatic colorectal cancer were entered into a phase II trial of combination chemoimmunotherapy using a sequential regimen of 5-fluorouracil (5-FU) and leucovorin and high-dose recombinant human interleukin-2 (rIL-2). Patients initially received three cycles of chemotherapy consisting of 500 mg/m2 of intravenous leucovorin followed by 375 mg/m2 of bolus 5-FU both given daily on days 1-5 of a 21 day cycle. Ten days after the last dose of chemotherapy in cycle 3, patients began high-dose rIL-2 at 720,000 IU/kg intravenously every 8 h to the maximum tolerated number of doses. After 7-10 days of recovery, this rIL-2 treatment was repeated to complete one full course of chemoimmunotherapy. There was no grade IV toxicity associated with 183 cycles of chemotherapy. Other than slight increases in the frequency of diarrhoea, stomatitis and hyperbilirubinaemia, rIL-2 toxicity was similar to that seen in patients given rIL-2 without chemotherapy. Of 23 evaluable patients, the overall response rate (partial + complete response) was 46% with 2 complete responses. Only 3 patients showed major tumour regression during the rIL-2 phase of therapy, but these 3 patients included both complete responders and the 3 most durable responses (15, 16 and 24 months). We conclude that sequential 5-FU/leucovorin and rIL-2 can be given safely without major increases in toxicity over either therapy alone, and although nearly all responses seen are largely attributable to chemotherapy, a contribution of immunotherapy to the minority of patients achieving complete or durable responses cannot be ruled out.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interleukin-2; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

Most patients with colorectal carcinoma metastatic to the liver have relapses after surgical resection of hepatic metastases with failures divided equally between hepatic and extrahepatic sites. A pilot study was begun using a regimen combining intrahepatic floxuridine (FUDR) and systemic 5-fluorouracil (5-FU) and leucovorin (LV) to determine its safety and efficacy.. Because this was a pilot study, 21 patients with unresectable hepatic metastases from colorectal carcinoma were treated to assess the regimen's toxicity. Eight patients had liver metastases that were resected completely; then they received treatment. FUDR was given by hepatic arterial pump through a 14-day continuous infusion at 0.25 mg/kg/day. Systemic therapy consisted of LV 200 mg/m2 and 5-FU 280 mg/m2 using a bolus dose of 5-FU for 5 days with escalation of the 5-FU dose in separate patient cohorts. The maximally tolerated 5-FU dose was 325 mg/m2.. The median survival in the 21 unresectable patients was 16 months with a partial response rate of 56% (10 of 18 evaluable patients; 95% confidence interval, 38-79%). The major systemic toxicity was diarrhea, Grade 3 or 4, in 54% of patients being treated in the 4-week regimen and 19%, in the 5-week regimen. The level of hepatic toxicity was similar to that in previous studies using intrahepatic chemotherapy alone, i.e., 48% of patients had a 200% increase in alkaline phosphatase levels and 10% had bilirubin elevations of more than 3.0 mg/dl (one patient had documented biliary sclerosis). All eight patients treated with adjuvant therapy were alive without disease after a median follow-up of 23 months.. Systemic 5-FU and LV can be combined safely with intraarterial FUDR without loss of efficacy or increased biliary toxicity. Eight patients treated with this regimen as adjuvant therapy after liver metastasis resection were alive and disease-free after a median follow-up of 23 months.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Survival Rate

In September 1987 a phase II study was begun to verify if elderly symptomatic patients affected by advanced gastric cancer could benefit from a combination of 5-fluorouracil (5FU) and leucovorin (LV). We employed Machover's regimen: 5FU 370 mg/m2 i.v. infusion daily for 5 days; LV 200 mg/m2 i.v. bolus daily for 5 days; cycles were repeated every 3 weeks. 23 patients entered the study and 22 were evaluable for response and toxicity. We obtained only one partial response; 9 had stable disease and 12 progressed on therapy. The median duration of survival was 6 months. Symptoms were not affected by treatment. These data reflect the absence of significant improvement in the quality of life, which was further lessened by the presence of treatment side effects. Because of this we think that this regimen cannot be recommended for the treatment of elderly advanced gastric cancer patients.

Topics: Adenocarcinoma; Aged; Aging; Antineoplastic Combined Chemotherapy Protocols; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Stomach Neoplasms

Hepatic regional treatment represents an attempt to improve tumor response by increasing drug concentration with low systemic toxicities. Recently in vitro and clinical studies have shown that the cytotoxicity of 5-fluorodeoxyuridine (FUDR) and 5-fluorouracil (5FU) can be potentiated by high doses of leucovorin (LCV). Two pilot studies with intraarterial FUDR, 5FU, and LCV were initiated. Since 1982, 221 patients with colorectal liver metastases were treated by various forms of long-term monthly continuous regional treatment using implantable ports or pumps. FUDR (0.05 to 1.7 mg/kg/d) was administered alone or combined with 5-FU and leucovorin. In 61 patients curative liver resection was possible and was followed by adjuvant arterial treatment. Overall median survival time (MST) was 15 months and increased to 36 months after liver resection. This was influenced by the following important factors: treatment, number of metastases, extent of infiltration, tumor volume, and minimal intraoperatively diagnosed extrahepatic disease. The response rate varied from 69% to 23%. Time of development of extrahepatic progression was not delayed by additional systemic treatment. Local side effects significantly depended on the duration of arterial infusion. The rate of biliary sclerosis ranged from 19% to 0%. Occurrence of chemical hepatitis was between 7% and 38%. In contrast, after combined intraarterial treatment with LCV, systemic side effects, mainly stomatitis and diarrhea, were dose limiting. Despite the improvement of survival after regional treatment, further randomized trials are mandatory to compare regional with relevant systemic treatment.

Topics: Colorectal Neoplasms; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male

Topics: Antineoplastic Agents; Colorectal Neoplasms; Floxuridine; Fluorouracil; Forecasting; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Liver Neoplasms; Mitomycin; Survival Rate

Treatment results in advanced colorectal cancer have improved during the last decade since the incorporation of agents like folinic acid, PALA, or interferon as active biomodulation of 5-fluorouracil (5-FU), the most potent drug in this disease. But essential prolongation of survival could not be demonstrated. To better define the need to initiate therapy and duration of treatment, a phase II study of high-dose folinic acid and 5-FU was initiated in patients with documented progression or severe tumor-related symptoms prior to start of therapy until best response was observed. The treatment plan was folinic acid 300 mg/m2 as a 10-minute intravenous infusion followed 50 minutes later by 5-FU 600 mg/m2 intravenous bolus days 1 to 3 every 3 to 4 weeks. Thirty-seven consecutive patients were treated during November 1986 and October 1987. Because of severe tumor-related symptoms, immediate treatment was considered mandatory in only eight patients. In the remaining 29 primarily asymptomatic patients, an observational period of a median duration of 8 weeks (range, 1-56) was possible before treatment seemed to be indicated. Most patients experienced some toxicity, mostly leukopenia and gastrointestinal side effects, of World Health Organization grades 3 and 4 during 156 treatment cycles (range, one to eight cycles). The calculated dose intensity was 535 mg/m2 5-FU per week. Of 36 evaluable patients, 14 responded at least with a partial remission (39%; confidence interval, 23% to 55%) of 7 months median duration. An additional 13 patients (36%) had stable disease, giving a rate of tumor stabilization in these progressive patients of 75%, for a median duration of 5.5 months. Median survival since start of therapy was 11 months. Results are comparable to data reported in the literature; survival and remission duration seem not to be mitigated in a patient population in which therapy was withheld until progression or symptoms occur. This patient population might be characterized by more homogeneously distributed risk factors.

Topics: Adult; Aged; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

Patients with advanced colorectal cancer were randomized to receive either fluorouracil (5-FU) 370 mg/m2 IV days 1 to 5 followed by weekly applications of 5-FU 600 mg/m2 or the same doses of 5-FU preceded by folinic acid 200 mg/m2. Because of toxicity, the weekly 5-FU dose in the combination treatment schedule was reduced to 500 mg/m2 in the course of the study. As of November 1990, 135 patients entered the study; 71 have received combination therapy, and 64 monotherapy. Sixty-three and 59 patients, respectively, are included in the present interim analysis. The two groups are well matched for age, performance status, site of disease, number of metastatic sites, and biochemical parameters. Treatment results are evaluable in 118 patients. Thirty percent receiving combination treatment and 20% receiving monotherapy achieved a complete or partial remission. There is no survival time difference between the groups. However, time to progression is superior in the combination treatment group (median 26 weeks compared with 13 weeks). The main toxicity was diarrhea during the weekly therapy. This was especially true for patients receiving combination treatment before the reduction of 5-FU dosage. In contrast to only four of 56 patients with monotherapy, 14 of 39 with the combination treatment at the initial dosage had severe diarrhea with two treatment-related deaths in this latter group. By reduction of 5-FU dosage during the weekly therapy severe diarrhea could be clearly reduced with only one of 18 patients suffering from diarrhea of World Health Organization grade 3. Other toxicity was usually mild. In conclusion, a prolongation of time to progression could be achieved by combination treatment of folinic acid and 5-FU, which was well tolerated when the weekly dose of 5-FU did not exceed 500 mg/m2.

Topics: Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Analysis

Preclinical data suggest that both folinic acid and interferon may enhance the efficacy of 5-fluorouracil (5-FU) in colorectal carcinoma. We therefore initiated a phase I trial evaluating the doses, safety, and pharmacokinetics of the combination of recombinant interferon (IFN) alpha-2b with folinic acid (FA) and 5-FU. Seventeen patients with colorectal cancer who failed local chemotherapy received 5-FU as a 4-hour infusion, preceded by a bolus of FA and IFN. The 5-FU dose was escalated over the range of 400 to 650 mg/m2/d for a period of 7 days. Folinic acid was administered as a bolus in a fixed dose of 200 mg/m2/d and IFN as 5 million U/d subcutaneously on days 1 to 7. A total of 89 courses of therapy were completed for the 17 patients, of which there were 10 paired courses with a combination of 5-FU and IFN or 5-FU alone, being performed to analyze the pharmacokinetics and modulation of 5-FU by IFN. The maximum tolerated dose of 5-FU using this combination and a 4-hour schedule was 600 mg/m2/d for 7 days. The dose-limiting toxicity of this regimen was diarrhea. Mucositis and myelosuppression was not a marked problem at dose levels of 400 and 500 mg/m2/d for 7 days. However, at a dose level of 600 to 650 mg/m2/d for 7 days, grade 3 and 4 (WHO) leukopenia occurred in 50% and mucositis occurred in 33%. At a given dose of 5 million U, IFN did not significantly influence 5-FU serum levels. Mean steady-state serum levels of 5-FU at 500 mg/m2 given as a 4-hour infusion were 16.55 +/- 9.34 mumol/L and 18.23 +/- 12.77 mumol/L with and without IFN, respectively. Mean area under the curve (mumol/L x min) was 4,008 +/- 2,133 and 5,114 +/- 2,567 with and without interferon, respectively. Objective responses were seen in one of 17 of these heavily pretreated patients and stable disease was seen in seven of 17 patients. The recommended dose of 5-FU for use of phase II studies is 500 mg/m2/d for 7 days. We conclude that the toxicity of 5-FU plus FA with and without IFN alpha-2b can be reduced by using a 4-hour infusion instead of a bolus.

Topics: Adult; Colorectal Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Recombinant Proteins

Interferon has been shown to augment the cytotoxic effects of fluorouracil (5-FU) against colon cancer in vitro and possibly in vivo. Therefore a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in colorectal adenocarcinomas refractory to first-line therapy with 5-FU/FA. Eleven patients with rectum cancer and four patients with colon cancer were treated according to the following schedule: 9 million units IFN-alpha subcutaneous three times a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Of 15 patients, one had a minor response, one had a disease stabilization, and three had a mixed response. No complete or partial remissions were seen. Looking at the sensitivity of lung metastases (three of three), the regressions can be explained through the additive effect of IFN-alpha to 5-FU/FA. Although minimal side effects (World Health Organization classification) were observed, most patients experienced a reduction of well-being.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Recombinant Proteins; Rectal Neoplasms

Based on promising results with 5-FU/FA or 5-FU/IFN-alpha in colorectal cancer, a pilot study was initiated to evaluate the effects of the combination 5-FU/FA/interferon alfa (IFN-alpha) in patients with advanced pancreatic cancer. Patients received 9 million units (MU) IFN-alpha subcutaneously three times a week or 6 MU IFN-alpha once a week; 500 mg/m2 5-FU via an intravenous bolus 1 hour after the initiation of a 2-hour infusion of 500 mg/m2 of FA, once a week. Fourteen patients, all previously untreated with chemotherapy, were enrolled; 13 (two females/11 males) were evaluable for response and toxicity (one too early). The median performance status was 80% (range, 60 to 100) and the median age 62 years. Besides the inoperable primary tumor, metastatic sites were liver, lung, and peritoneum. Three of 13 patients had a partial remission, three of 13 patients a minor response, and four of 13 patients no change. Three patients had progressive disease. Until now, no complete remission was seen. Median duration of response was 4+ months; median survival has not been reached yet. Of all patients there were three instances of World Health Organization grade 3 toxicity: fatigue (one of 13), nausea (one of 13), and diarrhea (one of 13); grade 4 toxicity did not occur. Although overall toxicity was moderate, most patients experienced a reduction of well-being. Therefore in all patients the dose of IFN was reduced (from 3 x 9 MU/week to 1 x 6 MU/week). Our preliminary data suggest that biochemical modulation of 5-FU with FA and IFN-alpha (reduced dosage) is effective in pancreatic cancer with moderate toxicity, warranting further study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Infusions, Intravenous; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Recombinant Proteins

A phase I study was undertaken in order to establish the maximum tolerated dose of intra-hepatic arterial 5-fluorouracil (5-FU) when given in combination with systemic folinic acid. Patients with colorectal liver metastases (n = 10) received escalating doses of 5-FU as a 24 h infusion with a fixed dose (400 mg m-2) of intravenous folinic acid once per week. Dose limiting toxicity (WHO grade greater than 2) was encountered at 2 g m-2 5-FU. Principal adverse effects were diarrhoea, vomiting and oral ulceration. The recommended dose for phase II studies is 1.5 g m-2 week-1 24 h 5-FU regional infusion with 400 mg m-2 week-1 intravenous folinic acid.

Topics: Aged; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged

The mechanisms of biochemical modulation of 5-fluorouracil (5-FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha-2a-interferon (rHuIFN-alpha 2a) and 5-FU. Therefore, a Phase I trial of these three agents 5-FU, FA, and rHuIFN-alpha 2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN-alpha 2a or 5-FU. Fifty-five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5-FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN-alpha 2a 4.0 x 10(6) U/m2/d subcutaneously on days 1 to 5. The dose-limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Survival Analysis

Thymic hormones have been shown to exhibit immunorestorative effects in vivo and in vitro, and to enhance the expression of high affinity interleukin-2 (IL-2) receptors on normal human lymphocytes stimulated with phytohemagglutinin. Based on these data, a clinical trial was initiated to determine the effects of the combination of 5-fluorouracil (5-FU) and folinic acid (FA) with thymopentin (TP-5) and interleukin-2 (IL-2) in patients with advanced colorectal carcinoma. Fifteen patients were treated with FA, 200 mg/m2/day by IV bolus, and 5-FU, 400 mg/m2/day as a 30-minute infusion, both given for 5 consecutive days every 28 days. TP-5, 50 mg/day, was administered subcutaneously on days 8-11, and IL-2, 9 million IU/m2 twice daily, was given subcutaneously on days 12-16. Of 8 patients evaluable for response, 4 achieved a response. Two patients had stable disease, and two progressed during treatment. There were no instances of life-threatening toxicity. Two patients developed grade III stomatitis and diarrhea followed by leukopenia and fever, requiring hospitalization. Other toxicities were moderate. These results are only preliminary, and a larger number of patients and longer follow-up are needed to draw meaningful conclusions about the merits of this new approach in cancer treatment.

Topics: Adenocarcinoma; Colorectal Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Interleukin-2; Leucovorin; Liver Neoplasms; Male; Middle Aged; Thymopentin

Thirty evaluable patients were treated with methotrexate (MTX) 200 mg/m2, i.v. infusion over 60 minutes, 24 hours prior to the administration of 5-fluorouracil 600 mg/m2, and folinic acid 200 mg/m2, i.v. infusion over 60 minutes, every 2 weeks. A partial or complete response was achieved in 12 patients (40%), and disease stable in 10 patients (33%). Median actuarial survival was 18 months. Side effects, which were within acceptable limits, included 11 cases of stomatitis (5 Grade 3), 3 cases of leukopenia (Grade 2) and 12 cases of mild nausea and vomiting. We conclude that the present combination is active in metastatic colorectal cancer with mild toxicity. These results are being confirmed and a randomized trial is being carried out to prove that this combination holds therapeutic advantage.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Methotrexate; Middle Aged; Survival Rate

Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU), leucovorin (LV), and cisplatin (CDDP) against human colon cancer cell lines, a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus, followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles, objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits, 26% to 53%). Stable disease occurred in 16 (27%) patients, whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months, with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU, LV, and CDDP is an active, safe, and well-tolerated combination regimen in patients with advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Evaluation; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate

The development of safe arterial access devices and totally implantable or portable infusion pumps for intrahepatic chemotherapy has generated a renewed interest in regional treatment of liver metastases from colo-rectal primaries. Several phase II trials have been carried out, mostly using prolonged infusion of fluorinated pyrimidines showing very high activity for this method of treatment with response rates up to 80%. Randomized trials between systemic and regional therapy have confirmed the higher efficacy of arterial treatment in inducing objective responses but neither of the two studies with a follow-up long enough to assess survival data showed a clear advantage for the patients receiving intraarterial chemotherapy. Gastroduodenitis, ulcers and chemical hepatitis are frequently observed in patients treated with intrahepatic arterial chemotherapy but their incidence can be substantially reduced by a careful surgical procedure during the implant of the arterial catheter and by a close follow-up during chemotherapy. Since toxicity can be serious and no definitive improvement of survival has been shown, this modality of treatment is still applicable only in an investigational setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Floxuridine; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Random Allocation

A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

Topics: Aged; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Random Allocation

Eighty patients with advanced gastrointestinal tumors (64% with colorectal cancer) entered a phase III prospective randomized study with 5-fluorouracil (5-FU) vs 5-FU + folinic acid (FA) The treatment included 5-FU, 600 mg/m2/week for 6 weeks, given as i.v. bolus alone (arm A), or administered by rapid injection half-way through a one-hour infusion of FA, 200 mg/m2/week for 6 weeks (arm B). Partial remission (PR) was achieved in 1 out of 30 (3%) evaluable patients for 6 months in arm A, and in 10 out of 34 (29%) patients in arm B, with a median duration of 8 months (range 6-17) (comparison of the response rate: P = 0.005). In patients with colorectal cancer the response rate was 5% and 27% in arm A and in arm B respectively (P = 0.06). Two patients, who were resistant to 5-FU alone, achieved PR after treatment with 5-FU + FA. Diarrhea was observed in 14/42 patients (33%) in arm B (grade 1-2 in 10 and grade 3 in 4) and in 2/38 patients (5%) in arm A (P = 0.005). Other side effects such as nausea/vomiting, myelosuppression and stomatitis were infrequent and of mild intensity in both arms. No statistical difference in survival was detected when comparing the two groups (estimated median survival 8 months and 11 months for arm A and arm B respectively). These results seem to indicate that the weekly regimen of 5-FU + FA has a superior response rate compared to 5-FU alone, and that it is well tolerated. However, the advantage is not reflected in overall survival.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Pelvic Neoplasms; Prospective Studies; Randomized Controlled Trials as Topic

Chemotherapy with leucovorin (100 to 200 mg) and 5-fluorouracil (30 mg/kg) every 2 wk produced four (three complete) objective responses among a group of eight patients with early metastatic pancreatic primary and unknown cancers. Complete remissions were associated with exceptionally long durations of survival, one in a patient failing prior combination chemotherapy. This treatment warrants testing because of its ease, scientific rationale, and the large population of patients with early metastatic pancreatic cancer for whom there is no accepted treatment. Early metastatic disease is defined as small metastatic lesions not immediately life threatening found in a physiologically intact patient. Controlled trials, demonstrating benefit associated with other 5-fluorouracil-containing regimens for patients with nonmetastatic stages of pancreatic cancer, provide a rationale for extending testing of leucovorin and 5-fluorouracil to other early stages of pancreatic cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Clinical Trials as Topic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasms, Unknown Primary; Pancreatic Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colonic Neoplasms; Doxorubicin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Methotrexate; Rectal Neoplasms; Semustine; Vincristine

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bleomycin; Bone Marrow Transplantation; Carcinoma; Cells, Cultured; Child; Cisplatin; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Cytarabine; Doxorubicin; Drug Therapy, Combination; Fluorouracil; Hepatic Artery; Humans; Hyperthermia, Induced; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Mechlorethamine; Melanoma; Meningeal Neoplasms; Methotrexate; Neoplasms; Osteosarcoma; Peritoneal Cavity; Pleura

Patients with visceral patterns of metastatic breast cancer were stratified according to dominant metastatic site and performance status and then randomized to therapy with cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) or CAF alternating with a "cell-cycle active" regimen including cytosine arabinoside, methotrexate with leucovorin rescue, and oncovin ( CAMELEON ). One hundred eighty-seven patients were randomized; response rate for CAF was 44% and for CAF + CAMELEON , 40%. Durations of disease control and survival were not significantly different. Toxicity of CAF was as anticipated with predominant granulocytopenia, vomiting, and alopecia. Toxicity of CAMELEON was less severe than that of CAF, and CAF toxicity was not worsened by preceding courses of CAMELEON ; however, the CAF- CAMELEON regimen was cumbersome and complex leading to both physician and patient noncompliance. Contrary to the preliminary results of a pilot study, and preliminary reports of the present trial suggesting benefit for the CAF- CAMELEON regimen the present randomized trial does not confirm any significant benefit of CAF- CAMELEON over CAF alone in patients with visceral metastatic breast cancer although this conclusion must be viewed in light of the high inevaluability rate due to patient and physician noncompliance.

Topics: Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Cyclophosphamide; Cytarabine; Doxorubicin; Drug Administration Schedule; Drug Resistance; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Methotrexate; Nausea; Random Allocation; Thrombocytopenia; Vincristine; Vomiting

Thirty patients with advanced measurable colorectal cancer were randomized to receive either methotrexate (MTX) 200 mg/m2 or 40 mg/m2, followed in four hours by 5-fluorouracil (5-FU) 600 mg/m2. Patients receiving the higher dose MTX were given leucovorin rescue 24 hours later. Eight of 13 patients treated with 200 mg/m2 MTX + 5-FU developed severe hematologic toxicity, leading to two toxic deaths. In addition, 9/13 developed mild azotemia, and three patients had severe gastrointestinal toxicity. No patients with prior chemotherapy responded to either regimen. Among those without prior chemotherapy, there were two of six and three of eight partial responses, respectively, in the 200 mg/m2 and 40 mg/m2 MTX regimens. Sequential 200 mg/m2 MTX followed by 5-FU after four hours has unacceptable toxicity. Sequential treatment with standard dose MTX + 5-FU is tolerable and merits further study.

Topics: Aged; Clinical Trials as Topic; Colonic Neoplasms; Digestive System; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Methotrexate; Middle Aged; Rectal Neoplasms; Uremia

Treatments for patients suffering from pancreatic cancer with oligo-hepatic metastasis have always been a cause of certain controversy. Herein, we reported 15 pancreatic cancer patients with oligo-hepatic metastasis who accepted sequential therapy of chemotherapy, radiofrequency ablation (RFA), and radical resection of the primary tumor.. A total of 87 pancreatic cancer patients with synchronous oligo-metastatic hepatic lesions who received treatments in the 2nd Affiliated Hospital of Zhejiang University between January 2017 and July 2020 were enrolled. The chemotherapy regimens included modified folfirinox (54/87) and gemcitabine plus nab-paclitaxel (33/87). Test of blood tumor markers and contrast-enhanced computed tomography (CT) or magnetic resonance (MR) scan was performed at diagnosis and after eight weeks of chemotherapy.. Thirty-five patients received just chemotherapy because of poor reaction to the first round of chemotherapy(Overall survival (OS), 6.47±1.80 months); 15 patients reassessed as stable disease (SD)/partial response (PR) continued chemotherapy (OS, 10.35±3.15); nine patients reassessed as progressive disease (PD) after RFA and continued chemotherapy (OS, 10.90±2.60). The primary tumors in 13 patients were unresectable after chemotherapy and RFA (OS, 12.92±2.47), while 15 patients completed the sequential therapy of chemotherapy, radio-frequency ablation, and radical resection (OS, 16.76±6.55).. Sequential chemotherapy and RFA is a good treatment strategy to select the best candidates for surgical treatment among patients with pancreatic cancer with oligo-hepatic metastasis.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Paclitaxel; Pancreatic Neoplasms; Retrospective Studies

Multikinase inhibitors (MKIs) represent the main treatment options for advanced hepatocellular carcinoma (aHCC). However, accessibility in developing countries is limited. A chemotherapy, Fluorouracil and Oxaliplatin (FOLFOX), offers a less expensive treatment. Therefore, this study sought to compare the clinical effectiveness of FOLFOX with Sorafenib as a first-line treatment for aHCC in real-life practice.. A retrospective aHCC cohort from four Thai hospitals was investigated for patients who received FOLFOX or Sorafenib between 2013-2019. Multiple imputation by chained equations addressed missing covariate data in a treatment effect model using Weight-adjusted-censoring inverse-probability-weighted regression adjustment; overall survival (OS) and progression-free survival (PFS) were estimated.. A total of 504 patients were included, (Sorafenib [n = 382] and FOLFOX [n = 122]). The treatment effect model estimated a median OS for Sorafenib and FOLFOX of 11.38 and 8.22 months, representing a significantly shorter OS (95% confidence interval) of -3.16 (-6.21, -0.11) months for FOLFOX, p = 0.042. A significant shorter median PFS of FOLFOX to Sorafenib of -2.13 (-3.03, -1.24) months, p < 0.001, was reported.. Despite significantly shorter median OS and PFS than Sorafenib, FOLFOX still extended OS by 8.22 months. This evidence may offer clinical utility to physicians considering treatment options for aHCC in low resource settings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Retrospective Studies; Sorafenib; Treatment Outcome

We report 2 cases of transfusion-free treatment for H3 grade of simultaneous liver metastases of the colon which were treated with the chemotherapy followed by R0 liver resection. Case 1 was a 67-year-old woman bearing ascending colon cancer and a metastatic mass occupying the left lobe of the liver with 160 mm in diameter. Laparoscopic ileocecal resection and 30-day left hepatectomy were performed after the 7 courses of FOLFOX plus bevacizumab(BEV). Case 2 was a 72- year-old woman bearing transverse colon cancer with more than 10 foci of liver metastases ranging from 21 mm to 100 mm in diameter. After the transverse colon resection and 12 months of chemotherapy from FOLFOX plus BEV to FOLFIRI plus panitumumab, partial liver resection was performed for each of size-reduced foci. In both patients who declined blood transfusion, optimization of red cells and autologous transfusion with hemodilution contributed to the safe liver resection with no postoperative complications.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms

The patient was 40s male, who underwent laparoscopic low anterior resection for his upper rectal cancer with final pathology results of tub2, pT3(SS), no lymph metastasis and fStage Ⅱ. He was followed up without adjuvant chemotherapy. Half a year after surgery, tumor marker was elevated and CT scan revealed multiple liver metastases. He was treated with oxaliplatin, irinotecan, Leucovorin and 5-fluorouracil(FOLFOXIRI)plus bevacizumab because of RAS mutant type. In the third courses, he has pain in the lower extremities and was diagnosed with acute lower extremity arterial occlusion. Subsequently, chemotherapy was resumed with the exception of bevacizumab, in combination with DOAC, which resulted in tumor shrinkage and allowed resection of the liver metastases.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Oxaliplatin; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Case-Control Studies; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Prognosis; Retrospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Treatment Outcome

Fluorouracil plus leucovorin (5-FU/LV) is a less toxic but mild chemotherapy.. A 63-year-old male patient with rectal cancer and multiple colorectal liver metastases (CRLM, total volume of 1,826 ml) was hospitalized. He had several poor prognostic factors, including elevated levels of tumor markers, with carcinoembryonic antigen and carbohydrate antigen 19-9 levels of 17,119 ng/ml and 7,617 U/ml, respectively. Additionally, the patient had a low body mass index, poor performance status, and a history of apparent weight loss. After capecitabine and oxaliplatin for four cycles, 5-FU/LV has been lasting for nine months. Interestingly, tumor marker levels returned close to normal limits, and the total CRLM volume decreased to 154 ml without any enhancements. The patient's general condition clearly improved after a year of chemotherapy.. Chemotherapy with 5-FU/LV and percutaneous microwave ablation is beneficial to achieve tumor control in patients with highly advanced liver-only CRLM and poor general condition.

Topics: Ablation Techniques; Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Microwaves; Middle Aged; Neoadjuvant Therapy; Treatment Outcome

We investigated the safety and efficacy of circadian chronotherapy via the hepatic artery(chrono-HAI)as a prehepatectomy chemotherapy for initially unresectable colorectal liver metastases. Five-day course of chrono-HAI using 5-FU, l-LV, and L-OHP plus systemic panitumumab with 9-day interval were administered to 24 patients with failure for previous chemotherapy. Response rate and Grade 3 adverse effect(AE) were 63% and 54%, respectively. Among 22 patients( excluding 2 CR patients), conversion surgery could be performed in 10(45%). Two-year overall survival of patients with surgery (58%)was longer in those without(20%, p=0.057). Although incidence of AE was a bit high, chrono-HAI plus systemic panitumumab is an effective prehepatectomy chemotherapy for patients with aggressive colorectal liver metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Treatment Outcome

Chemotherapy is a common treatment for advanced hepatocellular carcinoma, but the effect is not satisfactory. The study aimed to retrospectively evaluate the effects of adding all-trans-retinoic acid (ATRA) to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) for advanced hepatocellular carcinoma (HCC).. We extracted the data of patients with advanced HCC who underwent systemic chemotherapy using FOLFOX4 or ATRA plus FOLFOX4 at the Eastern Hepatobiliary Surgery Hospital, First Hospital of Jilin University, and Zhejiang Sian International Hospital and retrospectively compared for overall survival. The Cox proportional hazards model was used to calculate the hazard ratios for overall survival and disease progression after controlling for age, sex, and disease stage.. From July 2013 to July 2018, 111 patients with HCC were included in this study. The median survival duration was 14.8 months in the ATRA plus FOLFOX4 group and 8.2 months in the FOLFOX4 only group ( P  < 0.001). The ATRA plus FOLFOX4 group had a significantly longer median time to progression compared with the FOLFOX4 group (3.6 months vs. 1.8 months, P  < 0.001). Hazard ratios for overall survival and disease progression were 0.465 (95% confidence interval: 0.298-0.726; P  = 0.001) and 0.474 (0.314-0.717; P  < 0.001) after adjusting for potential confounders, respectively.. ATRA plus FOLFOX4 significantly improves the overall survival and time to disease progression in patients with advanced HCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Disease Progression; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Retrospective Studies; Tretinoin

Intrahepatic cholangiocarcinoma (iCCA) is a primary liver malignancy with a poor prognosis and limited treatment. Cisplatin with gemcitabine is used as the standard first-line chemotherapy regimen; however, there is still no robust evidence for second-line and successive treatments. Although preliminary evidence suggests a vital role of precision therapy or immunotherapy in a subset of patients, the gene alteration rate is relatively low. Herein, we explored the second-line and successive treatments using hepatic arterial infusion chemotherapy (HAIC) based on FOLFIRI after the failure of gemcitabine and platinum combined with target and immunotherapy in refractory CCAs.. Advanced patients with iCCAs confirmed by diagnostic pathology, who progressed at least on a gemcitabine/platinum doublet and/or other systemic chemotherapy combined with target therapy and immune checkpoint inhibitor, were included. All patients received infusional 5-fluorouracil/leucovorin with irinotecan (FOLFIRI) via HAIC until progression or unacceptable toxicity. The primary objective was the feasibility of treatment, with secondary objectives of disease control rate (DCR) and 6-month survival rate.. A total of 9 iCCA patients treated between Dec 2020 and May 2021 were enrolled; 2 patients suffered from distant metastasis, while 7 had local lymph node metastasis and portal vein or hepatic vein invasion. HAIC was delivered as second-line therapy in 6/9 patients, while a third or successive therapy in 3/9 patients. The patients accepted an average of 2.90 ± 1.69 cycles of HAIC. The objective response rate was 22.2%; the disease control rate was 55.5% (5/9); median progression-free survival was 5 months; and 6-month survival rate was 66.7% (6/9).. Our results provide preliminary evidence that HAIC based on FOLFIRI regimen is efficient and safe in some patients progressing after previous treatment. Therefore, HAIC may be a promising and valuable complementary therapy for advanced CCAs as a second-line and successive therapy. Otherwise, the combination of HAIC with precision medicine may improve clinical benefits (clinical registration number: 2021BAT4857).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cisplatin; Fluorouracil; Humans; Immune Checkpoint Inhibitors; Irinotecan; Leucovorin; Liver Neoplasms; Treatment Outcome

The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)].. A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined.. Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly.. Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Computed Tomography Angiography; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Survival Analysis; Treatment Outcome; Tumor Microenvironment

Not all patients with unresectable hepatocellular carcinoma (uHCC) benefit from treatment with immune checkpoint inhibitors and molecular-targeted agents. The aim of this retrospective study was to assess the efficacy and safety of pembrolizumab plus lenvatinib plus hepatic arterial infusion chemotherapy (HAIC) versus pembrolizumab plus lenvatinib in selected populations of patients with treatment-naive uHCC exhibiting programmed cell death ligand-1 (PD-L1) staining.. Consecutive patients with treatment-naive uHCC exhibiting PD-L1 staining who were treated with pembrolizumab plus lenvatinib plus HAIC (PLH) or pembrolizumab plus lenvatinib (PL) were retrospectively identified from our medical centres from 2018 to 2021. HAIC involved oxaliplatin, fluorouracil, and leucovorin (FOLFOX). Follow-up occurred every 3 weeks for 1 year and then every 6 weeks thereafter. The primary endpoints included overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the frequency of key adverse events (AEs).. In total, 248 treatment-naive patients were retrospectively reviewed, 78 of whom were ineligible on the basis of the current criteria. Thus, 170 patients (PLH: n = 84, median age 52 years [range, 42-67]; PL: n = 86, 53 years [range, 43-69]) were eligible for the analysis. The median follow-up was 18.6 months (range, 1-26). At the final follow-up, the median OS was 17.7 months (95% confidence interval [CI], 15.2-18.3) in the PLH group versus 12.6 months (95% CI, 11.1-13.7) in the PL group (hazard ratio [HR] 0.52; 95% CI, 0.36-0.75; p = 0.001). A significant difference was also detected in the median PFS (10.9 months [95% CI, 8.7-11.4] for PLH vs. 6.8 months (95% CI, 5.2-7.4) for PL; HR 0.61, 95% CI, 0.43-0.85; p = 0.001). Significant differences in the rate of the key AEs were noted between groups (79.8% for PLH vs. 62.8% for PL, p = 0.015), but these AEs were controllable.. Among selected populations of patients with treatment-naive uHCC exhibiting PD-L1 staining, the PLH regimen may substantially improve the survival benefits compared with the PL regimen with a controllable safety profile.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Hepatocellular; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Phenylurea Compounds; Progression-Free Survival; Quinolines; Retrospective Studies

A 75-year-old man was diagnosed with advanced rectal cancer infiltrating the bladder and a single metastatic liver tumor. The patient first underwent colostomy followed by 8 cycles of chemotherapy, using a regimen of cetuximab, calcium levofolinate hydrate, fluorouracil and oxaliplatin(Cmab plus mFOLFOX6). This treatment resulted in a partial response(PR). Five months after the first operation, laparoscopic partial hepatectomy(S4), low anterior resection and ileostomy by laparotomy were performed. The pathological findings were T4b, N1b, M1a, H1, ypStage Ⅳa and all surgical margins were negative, so R0 resection was performed for preservation of bladder function. The patient received adjuvant chemotherapy and has survived without recurrence for 10 months after the second operation. The preoperative chemotherapy permitted combined resection of the bladder and urostomy. This is important because a double stoma commonly reduces quality of life. Thus, Cmab plus mFOLFOX6 may be useful as preoperative chemotherapy to preserve bladder function and quality of life.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Quality of Life; Rectal Neoplasms; Urinary Bladder

A woman in her 30s visited our hospital complaining primarily of melena. Colonoscopy revealed the presence of a type 1 tumor in 2 cm from anal verge. Contrast-enhanced CT showed an unresectable massive liver metastasis in the left lobe of the liver and another metastasis in the right lobe. The patient received front-line chemotherapy with Leucovorin, fluorouracil, oxaliplatin, and irinotecan(FOLFOXIRI)plus bevacizumab(BEV). A year later, a marked reduction of liver metastases and primary lesions was confirmed by CT scan imaging. A multidisciplinary team recommended resection of the liver metastases followed by laparoscopic intersphincteric resection for primary lesions. However, after 1 year, a recurrence was diagnosed in the liver; hence, FOLFOXIRI plus BEV was reintroduced for volume reduction. The patient underwent a repeat hepatectomy since enough volume reduction was confirmed. One year later, she experienced a re-relapse of the metastasis in the liver. Currently, she is still undergoing chemotherapy following 7 years since the first visit. Long-term survival can be expected following surgical treatment during chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Organoplatinum Compounds; Rectal Neoplasms

To report the current clinical practice of French physicians for metachronous resectable liver metastasis (LM) occurring after a FOLFOX adjuvant chemotherapy for primary cancer.. Twenty four clinical situations were proposed to a panel of experts via 4 learned societies. Clinical situations varied according time of recurrence (early between 6 and 12 month or > 12 month), extension of LM (limited ≤ 2 or extended > 2 lesions), presence of a neuropathy or not, and of a RAS or BRAF mutation.. A total of 157 physicians participated in this study. A consensus was reached in 17 (71%) clinical situations. For an early limited recurrence, whatever presence of neuropathy, the preferred therapeutic approach (45%) was upfront surgery. For an early extended recurrence, whatever presence of neuropathy, there was a consensus (64%) for a preoperative chemotherapy by FOLFIRI + biologic agent. For a late recurrence without neuropathy, there was a consensus (50%) for a preoperative FOLFOX chemotherapy, whatever the extension of LM. For a late recurrence with neuropathy, upfront surgery was chosen (52%) for limited LM, and preoperative chemotherapy by FOLFIRI + biologic agent (73%) for extended LM. No response was influenced by the RAS mutation status. There was a strong consensus for intensified preoperative chemotherapy in all clinical situations for BRAF-mutated LM.. This national survey provides an overview of the practice patterns in the treatment of LM occurring after adjuvant FOLFOX for primary. It could be a basis to establish expert's recommendations for the clinical practice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Recurrence, Local; Oxaliplatin

FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu.. A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies.. Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice.. This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Carcinoma, Hepatocellular; Cell Line, Tumor; Colorectal Neoplasms; Disease Models, Animal; Drug Compounding; Drug Synergism; Female; Fluorodeoxyuridylate; Fluorouracil; Immunogenic Cell Death; Immunotherapy; Leucovorin; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasm Metastasis; Organoplatinum Compounds; Reactive Oxygen Species; Tissue Distribution

Combination therapy of tegafur/uracil (UFT) and leucovorin (LV) is widely used to treat colorectal cancers. Although this therapy has a significant therapeutic effect, severe adverse effects occur frequently. Therapeutic drug monitoring (TDM) may help to prevent adverse effects. A useful assay that can quantitate plasma levels of 5-FU, uracil, and tegafur simultaneously for TDM has been desired, but such a method is not currently available. In this study, we aimed to develop a sensitive method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma using ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS). After preparing plasma samples by protein precipitation and liquid extraction, 5-FU, uracil, and tegafur were analyzed by UPLC-MS/MS in negative electrospray ionization mode. Validation was performed according to US Food and Drugs Administration guidance. The calibration curves were linear over concentration ranges of 2-500 ng/mL for 5-FU, 20-5000 ng/mL for uracil, and 200-50,000 ng/mL for tegafur. The corresponding average recovery rates were 79.9, 80.9, and 87.8%. The method provides accuracy within 11.6% and precision below 13.3% for all three analytes. Matrix effects of 5-FU, uracil, and tegafur were higher than 43.5, 84.9, and 100.2%, respectively. This assay was successfully applied to assess the time courses of plasma 5-FU, uracil, and tegafur concentrations in two patients with colorectal liver metastasis who received UFT/LV therapy after hepatectomy. In conclusion, we succeeded to develop a sensitive and robust UPLC-MS/MS method for simultaneous quantification of 5-FU, uracil, and tegafur in human plasma. This method is potentially useful for TDM in patients receiving UFT/LV combination therapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Calibration; Chromatography, High Pressure Liquid; Colorectal Neoplasms; Drug Monitoring; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Sensitivity and Specificity; Tandem Mass Spectrometry; Tegafur; Uracil

We herein report a woman who was suffering from type 1 diabetes and hearing impairment and whose mother had mitochondrial disease. Abdominal ultrasound identified a hepatic tumour, and a further examination led to the diagnosis of rectal cancer with synchronous multiple liver metastases. A genetic test led to the diagnosis of mitochondrial disease with a mitochondrial gene 3243A>G mutation. After neoadjuvant chemotherapy, we performed hepatectomy and low anterior resection in one stage. Hepatic vascular exclusion was not performed in order to prevent damage to hepatocytes due to liver ischaemia, and Ringer's lactate solution was not used to prevent lactic acidosis. The postoperative course was uneventful. Only one other case involving hepatectomy being performed in a patient with mitochondrial disease has been reported. Considering the extreme rarity of such cases and the importance of perioperative management, we report this case here.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Diabetes Mellitus, Type 2; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Mitochondrial Diseases; Organoplatinum Compounds; Pedigree; Rectal Neoplasms

The occurrence of colorectal liver metastases (CRLM) impairs prognosis, yet long-term survival can be achieved by enabling liver resection. This study aims to describe factors associated with conversion therapy leading to liver surgery and treatment outcome.. A retrospective cohort study was conducted including all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with conversion therapy and outcome following conversion therapy were analysed with logistic regression and survival analyses.. Out of 1023 patients with CRLM, 100 patients (10%) received conversion chemotherapy, out of whom 31 patients (31%) subsequently underwent liver resection. Patients in whom conversion chemotherapy resulted in liver resection were younger (median age 61 vs. 66 years, p = .024), less likely to have a KRAS/NRAS-mutated primary tumours (25% vs. 53%, p = .039) and more likely to have received anti-EGFR agents (32% vs. 4%, p = .001) than patients progressing during conversion chemotherapy. The median OS for patients treated with conversion chemotherapy leading to liver resection was 24 months, compared to 14 months for patients progressing during conversion chemotherapy, p < .001. The OS for patients progressing during conversion chemotherapy was similar to patients given palliative chemotherapy, approximately 13 months.. Conversion therapy offers a survival benefit in selected patients. Despite treatment advances, the majority of patients undergoing conversion chemotherapy never become eligible for curative treatment.

Topics: Ablation Techniques; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Logistic Models; Male; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Retrospective Studies

Resistance to adjuvant chemotherapy is a major clinical problem in the treatment of colorectal cancer (CRC). The aim of this study was to elucidate the role of an epithelial to mesenchymal transition (EMT)-inducing protein, ZEB2, in chemoresistance of CRC, and to uncover the underlying mechanism. We performed IHC for ZEB2 and association analyses with clinical outcomes on primary CRC and matched CRC liver metastases in compliance with observational biomarker study guidelines. ZEB2 expression in primary tumours was an independent prognostic marker of reduced overall survival and disease-free survival in patients who received adjuvant FOLFOX chemotherapy. ZEB2 expression was retained in 96% of liver metastases. The ZEB2-dependent EMT transcriptional programme activated nucleotide excision repair (NER) pathway largely via upregulation of the ERCC1 gene and other components in NER pathway, leading to enhanced viability of CRC cells upon oxaliplatin treatment. ERCC1-overexpressing CRC cells did not respond to oxaliplatin in vivo, as assessed using a murine orthotopic model in a randomised and blinded preclinical study. Our findings show that ZEB2 is a biomarker of tumour response to chemotherapy and risk of recurrence in CRC patients. We propose that the ZEB2-ERCC1 axis is a key determinant of chemoresistance in CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colorectal Neoplasms; DNA Repair; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endonucleases; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Mice; Organoplatinum Compounds; Transcription, Genetic; Xenograft Model Antitumor Assays; Zinc Finger E-box Binding Homeobox 2

A prognostic benefit of additive chemotherapy in patients following resection of metachronous colorectal liver metastases (CRLM) remains controversial. Therefore, the goal of this retrospective study was to investigate the impact of perioperative chemotherapy on disease-free survival (DFS) and overall survival (OS) of patients after curative resection of metachronous CRLM.. In a retrospective single-centre study, patients after curative resection of metachronous CRLM were included and analysed for DFS and OS with regard to the administration of additive chemotherapy. The Kaplan-Meier method was applied to compare DFS and OS while Cox regression models were used to identify independent prognostic variables.. Thirty-four of 75 patients were treated with additive 5-FU based chemotherapy. OS was significantly prolonged in this patient subgroup (62 vs 57 months; p = 0.032). Additive chemotherapy significantly improved 10-year survival rates (42% vs 0%, p = 0.023), but not 5-year survival (58% vs 42%, p = 0.24). Multivariate analysis identified additive chemotherapy (p = 0.016, HR 0.44, 95% CI 0.23-0.86), more than five CRLM (p = 0.026, HR 2.46, 95% CI 1.16-10.32) and disease recurrence (0.009, HR 2.70, 95% CI 1.29-5.65) as independent risk factors for OS.. Additive chemotherapy significantly prolonged OS and 10-year survival in patients after curative resection of metachronous CRLM. Randomized clinical trials are needed in the future to identify optimal chemotherapy regimens for those patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Rectal Neoplasms; Retrospective Studies; Risk Factors; Survival Rate; Time Factors

The case is a 59‒year‒old woman. A detailed examination of fecal occult blood revealed a diagnosis of cStage Ⅳ sigmoid colon cancer cT3N1M1b(liver H2, hilar liver and celiac artery lymph nodes). After excision of the primary lesion, decided to give chemotherapy. The gene test was RAS gene mutation negative and EGFR positive, and mFOLFOX6 plus panitumumab (pani)was started as the first‒line treatment. Imaging tests at the end of 13 courses showed that the maximum diameter of liver metastases was reduced from 54 mm to 16 mm, and CEA was normalized from 93.9 ng/mL. However, metastasis was found in the hilar lymph nodes, it was judged that hepatectomy is not indicated, radiofrequency ablation therapy was performed. But FOLFIRI plus pani was restarted because metastatic liver tumor relapsed on CT 5 months later. After 6 courses, she felt tired, so I consulted her and changed to TAS‒102 plus bevacizumab. Sudden headache and vomiting appear during 3 courses, head CT revealed subarachnoid hemorrhage. No brain metastases or organic lesions such as cerebral aneurysms and stenotic lesions, the relationship with bevacizumab was strongly suspected.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Sigmoid Neoplasms; Subarachnoid Hemorrhage

To compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) with a modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) regimen with that of transarterial chemoembolization as a locoregional treatment for patients with locally advanced hepatocellular carcinoma (HCC).. This retrospective study included adult patients with locally advanced HCC who received first-line treatment with either HAIC-mFOLFOX or conventional transarterial chemoembolization monotherapy from January 2015 to December 2016. The outcomes, including tumor response rates, evaluated via imaging assessment using the modified response evaluation criteria in solid tumors; overall survival; progression-free survival; and safety, were compared. The propensity score-matching methodology was used to reduce the influence of confounding factors on the outcomes.. The study included 131 patients with locally advanced HCC who underwent transarterial chemoembolization and 101 who received HAIC-mFOLFOX as initial treatment. After propensity score matching (n = 67 in each group), patients who received HAIC-mFOLFOX had a higher objective response rate (43.3% vs 13.4%, P = .001), longer median overall survival (13.9 vs 6.0 months, P < .001), and longer median progression-free survival (6.4 vs 2.8 months, P = .001) than those who underwent transarterial chemoembolization. The survival benefit with HAIC-mFOLFOX was strengthened in patients with HCC with vascular invasion (hazard ratio: 0.379; 95% confidence interval: 0.237-0.607). HAIC-mFOLFOX was associated with lower incidences of severe adverse events (8.9% vs 22.9%) and liver toxicity than transarterial chemoembolization.. Compared with transarterial chemoembolization, HAIC-mFOLFOX is a potentially safer and more effective locoregional therapy for patients with locally advanced HCC.

Topics: Adult; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fluorouracil; Hepatic Artery; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Propensity Score; Retrospective Studies; Treatment Outcome

Over 50% of colorectal cancer patients develop resistance after a transient response to therapy. Understanding tumor resistance from an evolutionary perspective leads to better predictions of treatment outcomes. The objectives of this study were to develop a computational framework to analyze tumor longitudinal measurements and recapitulate the individual evolutionary dynamics in metastatic colorectal cancer (mCRC) patients. A stochastic modeling framework was developed to depict the whole spectrum of tumor evolution prior to diagnosis and during and after therapy. The evolutionary model was optimized using a nonlinear mixed effect (NLME) method based on the longitudinal measurements of liver metastatic lesions from 599 mCRC patients. The deterministic limits in the NLME model were applied to optimize the stochastic model for each patient. Cox proportional hazards models coupled with the least absolute shrinkage and selection operator (LASSO) algorithm were applied to predict patients' progression-free survival (PFS) and overall survival (OS). The stochastic evolutionary model well described the longitudinal profiles of tumor sizes. The evolutionary parameters optimized for each patient indicated substantial interpatient variability. The number of resistant subclones at diagnosis was found to be a significant predictor to survival, and the hazard ratios with 95% CI were 1.09 (0.79-1.49) and 1.54 (1.01-2.34) for patients with three or more resistant subclones. Coupled with several patient characteristics, evolutionary parameters strongly predict patients' PFS and OS. A stochastic computational framework was successfully developed to recapitulate individual patient evolutionary dynamics, which could predict clinical survival outcomes in mCRC patients. SIGNIFICANCE: A data analysis framework depicts the individual evolutionary dynamics of mCRC patients and can be generalized to project patient survival outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Evolution; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Models, Theoretical; Multicenter Studies as Topic; Panitumumab; Prognosis; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Rate

Retrospective studies suggest a survival benefit when platinum-based chemotherapy is administered to patients with pancreatic cancer harbouring a germline mutation in BRCA1, BRCA2 or PALB2 (mut-positive PDAC). However, the objective response rate (ORR) and real-world progression free survival (rwPFS) achieved with such treatment remain ill-defined.. Twenty-six patients with advanced-stage mut-positive PDAC who had been treated with platinum-based therapy were matched by age, race and sex to 52 platinum-treated control PDAC patients. Responses to therapy were determined by RECIST v1.1, performed by blinded radiology review. Measured outcomes included ORR and rwPFS.. The ORR in mut-positive patients was 58% compared to 21% in the control group (p = 0.0022). There was no significant difference in ORR between platinum regimens in mut-positive patients (p = 0.814), whereas in control patients, the only observed responses were to FOLFIRINOX. rwPFS was 10.1 mo. for mut-positive patients and 6.9 mo. for controls (HR 0.43; 95% CI 0.25-0.74; 0.0068).. Mut-positive PDAC has a high ORR and prolonged rwPFS to platinum-based chemotherapy. These findings may have implications particularly in the neoadjuvant setting, and for future clinical trial design, and highlight the importance of early germline testing in patients with PDAC.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; BRCA2 Protein; Carcinoma, Pancreatic Ductal; Case-Control Studies; Cisplatin; Deoxycytidine; Fanconi Anemia Complementation Group N Protein; Female; Fluorouracil; Gemcitabine; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Prognosis; Progression-Free Survival; Retrospective Studies

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease that can be separated into distinct subtypes based on molecular signatures. Identifying PDAC subtype-specific therapeutic vulnerabilities is necessary to develop precision medicine approaches to treat PDAC.. A total of 56 PDAC liver metastases were obtained from the UNMC Rapid Autopsy Program and analyzed with quantitative proteomics. PDAC subtypes were identified by principal component analysis based on protein expression profiling. Proteomic subtypes were further characterized by the associated clinical information, including but not limited to survival analysis, drug treatment response, and smoking and drinking status.. Over 3,960 proteins were identified and used to delineate four distinct PDAC microenvironment subtypes: (i) metabolic; (ii) progenitor-like; (iii) proliferative; and (iv) inflammatory. PDAC risk factors of alcohol and tobacco consumption correlate with subtype classifications. Enhanced survival is observed in FOLFIRINOX treated metabolic and progenitor-like subtypes compared with the proliferative and inflammatory subtypes. In addition, TYMP, PDCD6IP, ERAP1, and STMN showed significant association with patient survival in a subtype-specific manner. Gemcitabine-induced alterations in the proteome identify proteins, such as serine hydroxymethyltransferase 1, associated with drug resistance.. These data demonstrate that proteomic analysis of clinical PDAC liver metastases can identify molecular signatures unique to disease subtypes and point to opportunities for therapeutic development to improve the treatment of PDAC.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Molecular Typing; Oxaliplatin; Pancreatic Neoplasms; Proteome; Proteomics; Survival Rate; Treatment Outcome

Induction of memory T cell response is inefficient in colorectal cancer (CRC) liver metastasis following existing therapies due to abundant stroma and immunosuppressive environment within the metastatic liver, which leads to fast disease progression, high recurrence rate, and short survival. Two fundamental steps are involved to elicit extensive memory T cell response: stimulation of naive T cells with robust and persistent antigen signals; and maintenance of differentiated memory T cells with survival factors. Here, we demonstrate a rational design of triple combination regimen, including relaxin (RLN), FOLFOX (combination of 5-fluorouracil, leucovorin, and oxaliplatin), and IL-12, successfully stimulates central memory T cells and achieves long-term survival in an aggressive experimental CRC liver metastasis model. Sequential administration of FOLFOX and IL-12 gene therapy following stromal deactivation by RLN gene therapy completely cured established CRC liver metastases in ~50% of mice and provided long-lasting protection against tumor recurrence. The study here may highlight the potential of evoking memory response as a curative therapy for the treatment of CRC liver metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Interleukin-12; Leucovorin; Liver Neoplasms; Mice; Neoplasm Metastasis; Organoplatinum Compounds; Relaxin; Treatment Outcome

The authors sought to forecast survival and enhance treatment decisions for patients with liver metastatic colorectal cancer by using on-treatment radiomics signature to predict tumor sensitiveness to irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) alone (F) or in combination with cetuximab (FC).. We retrospectively analyzed 667 metastatic colorectal cancer patients treated with F or FC. Computed tomography quality was classified as high (HQ) or standard (SD). Four datasets were created using the nomenclature (treatment) - (quality). Patients were randomly assigned (2:1) to training or validation sets: FCHQ: 78:38, FCSD: 124:62, FHQ: 78:51, FSD: 158:78. Four tumor-imaging biomarkers measured quantitative radiomics changes between standard of care computed tomography scans at baseline and 8 weeks. Using machine learning, the performance of the signature to classify tumors as treatment sensitive or treatment insensitive was trained and validated using receiver operating characteristic (ROC) curves. Hazard ratio and Cox regression models evaluated association with overall survival (OS).. The signature (area under the ROC curve [95% confidence interval (CI)]) used temporal decrease in tumor spatial heterogeneity plus boundary infiltration to successfully predict sensitivity to antiepidermal growth factor receptor therapy (FCHQ: 0.80 [95% CI = 0.69 to 0.94], FCSD: 0.72 [95% CI = 0.59 to 0.83]) but failed with chemotherapy (FHQ: 0.59 [95% CI = 0.44 to 0.72], FSD: 0.55 [95% CI = 0.43 to 0.66]). In cetuximab-containing sets, radiomics signature outperformed existing biomarkers (KRAS-mutational status, and tumor shrinkage by RECIST 1.1) for detection of treatment sensitivity and was strongly associated with OS (two-sided P < .005).. Radiomics response signature can serve as an intermediate surrogate marker of OS. The signature outperformed known biomarkers in providing an early prediction of treatment sensitivity and could be used to guide cetuximab treatment continuation decisions.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Biomarkers, Tumor; Cetuximab; Cohort Studies; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Image Processing, Computer-Assisted; Irinotecan; Leucovorin; Liver Neoplasms; Male; Molecular Targeted Therapy; Neoplasm Metastasis; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Signal Transduction; Tomography, X-Ray Computed; Transcriptome

The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is more toxic than gemcitabine, but it is a safe regimen with manageable toxicities.. We report a case with steatohepatitis mimicking liver metastasis as toxicity that was not seen in study patient population.. The adverse events of drugs are important predictive factor for treatment management, as important as efficacy. Especially the new lesion and metastasis is the most important factor for changing treatment. The clinicians must be careful about adverse events of regimens.. FOLFIRINOX regimen is the most important combination in pancreas cancer adjuvant setting. This case shows us the different presentation of usual adverse event.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fatty Liver; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Oxaliplatin; Pancreatic Neoplasms

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; BRCA1 Protein; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease Progression; DNA Mismatch Repair; Drug Resistance, Neoplasm; Female; Fluorouracil; Hepatectomy; Humans; Immune Checkpoint Inhibitors; Leucovorin; Liver Neoplasms; Microsatellite Instability; Neoadjuvant Therapy; Nivolumab; Organoplatinum Compounds; Treatment Outcome

Basic and clinical studies on small bowel adenocarcinoma (SBA) are limited due to the rare nature of this cancer. We established a patient-derived xenograft (PDX) model from the tumor tissue of an advanced SBA patient with liver and peritoneal metastasis, and a cell line from the PDX. In the PDX model, compared to the control group, 5-fluorouracil (5-FU) treatment resulted in statistically significant tumor growth inhibition (TGI), while oxaliplatin (OHP) and irinotecan had no significant inhibitory effects. In combination with 5-FU, OHP showed the highest rate of TGI. The IC

Topics: Adenocarcinoma; Aged; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Drug Evaluation, Preclinical; Female; Fluorouracil; Gemcitabine; Heterografts; HT29 Cells; Humans; Inhibitory Concentration 50; Irinotecan; Jejunal Neoplasms; Leucovorin; Liver Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Organoplatinum Compounds; Oxaliplatin; Paclitaxel; Peritoneal Neoplasms; Treatment Failure; Trifluridine; Xenograft Model Antitumor Assays

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cesarean Section; Chemotherapy, Adjuvant; Colectomy; Colon; Colonic Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Live Birth; Liver Neoplasms; Magnetic Resonance Imaging; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Patient Care Team; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Trimester, Second; Treatment Outcome

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Immunotherapy; Leucovorin; Liver Neoplasms; Mice; Organoplatinum Compounds; Oxaliplatin

This study aimed to evaluate the efficacy and the safety of polyethylene glycol conjugated granulocyte colony-stimulating factor (PEG-G-CSF) for preventing neutropenia in metastatic colorectal cancer (mCRC) patients that received fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab (Bev) in clinical practice.. We retrospectively analyzed mCRC patients who received FOLFOXIRI plus Bev between December 2015 and December 2017. We evaluated the efficacy of PEG-G-CSF as preventing or treating grade 3 or 4 neutropenia, the overall response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events of FOLFOXIRI plus Bev based on the Common Terminology Criteria for Adverse Events version 4.0.. A total of 26 patients (median age 53.5 years) were included. The ORR rate was 65.3%, the median PFS was 9.6 months (7.2-16.9), and the median OS was 24.2 months (13.6-NA). Grade 3 or 4 neutropenia occurred in 53.8% of the patients, and febrile neutropenia occurred in 7.7%. PEG-G-CSF was given to 77.0% of the patients, including prophylactically (n = 9) and after the development of grade 3 or 4 neutropenia (n = 11). No patients experienced grade 3 or 4 neutropenia after the administration of PEG-G-CSF. In seven of the nine patients who received PEG-G-CSF prophylactically (77.8%), no dose adjustment was required.. PEG-G-CSF is useful in preventing severe neutropenia in mCRC patients treated with FOLFOXIRI plus Bev.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Oxaliplatin; Peritoneal Neoplasms; Polyethylene Glycols; Prognosis; Retrospective Studies; Survival Rate

Some metastatic colorectal cancer (mCRC) patients receive conversion surgery (CS), including metastasectomy after palliative chemotherapy. Although targeted agents significantly improved the outcomes, the clinical outcome of CS in the targeted agent era has not yet been thoroughly investigated.. We analyzed the clinical data of 96 mCRC patients who initially had unresectable liver- and/or lung-limited metastases and underwent first-line cetuximab or bevacizumab plus FOLFIRI between January 2013 and June 2017.. Liver-limited metastasis was seen in 44 patients (45.8%), lung-limited metastases in 21 patients (21.9%), and both liver and lung metastases in 31 patients (32.3%). Among them, 37 patients (38.5%) received cetuximab, and 59 patients (61.5%) received bevacizumab plus FOLFIRI. Overall response rate was 63.9% and 40.7%, respectively (p = 0.035). After median 8.7 (range 2.5-27.3) months, CS was performed in 11 patients (29.7%) in cetuximab group and 15 patients (25.4%) in bevacizumab group (p = 0.646). Median overall survival has not been reached in R0-resected patients (n = 23), during the median follow-up period of 22.5 (range 9.8-54.5) months. Median disease-free survival was 7.1 (95% CI 2.5-11.7) months: 11.0 (95% CI 3.1-19.0) months in cetuximab group and 3.2 (95% CI 0.0-7.8) months in bevacizumab group (p = 0.422). There was no progression after 18.5 months and disease-free survival reached a plateau at 19.9%.. A substantial proportion of patients could receive CS after cetuximab or bevacizumab plus FOLFIRI chemotherapy. R0-resected patients had excellent overall survival, although 80.1% of them eventually experienced recurrence. Some patients could achieve durable disease-free state.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies

A 73-year-old woman presenting with weight loss was diagnosed as having ascending colon cancer with synchronous liver metastasis. The liver metastasis was solitary but it occupied the medial and anterior segments. The size was over 9 cm in diameter and was located adjacent to the left, middle, and right hepatic veins, making it initially unresectable. Following surgical resection of the primary tumor, she received mFOLFOX6 plus bevacizumab chemotherapy, resulting in a decrease in size of the liver metastasis. During the 15 courses of chemotherapy, an allergic reaction to oxaliplatin occurred and oxaliplatin administration was stopped. Although the liver metastasis was considered to be in a stable disease state according to the RECIST criteria at the time following 32 courses of chemotherapy, we discontinued chemotherapy due to various reasons of the patient. However, the liver metastasis continues to be in the stable disease state, and has not grown for over 5 years since initiating mFOLFOX6 plus bevacizumab chemotherapy and for over 3 years since discontinuing the chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Time Factors

Perioperative chemotherapies are expected to improve prognosis of patients with colorectal liver metastasis(CRLM). In patients with a resectable CRLM, the adjuvant chemotherapy with 5-FU/LV effectively prolongs DFS or RFS. In patients with unresectable CRLM, a neoadjuvant chemotherapy with high response rate and high liver resection rate, such as FOLFOX(or CAPOX, SOX)plus bevacizumab, FOLFOX/FOLFIRI plus cetuximab, or FOLFOXIRI plus bevacizumab, could be an optimal regimen for the conversion therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

Definitive reirradiation using a stereotactic technique is an effective local treatment option for both recurrent liver metastases and recurrent primary liver cancers. The tolerance of the liver, bile ducts, and surrounding gastrointestinal luminal organs must be respected to ensure safe retreatment. The risks associated with retreatment to these organs must be carefully balanced with the probability of clinical benefit. We present 2 cases for consideration of repeat irradiation along with the opinions of 4 experts, along with conclusions about recommendations.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Colonic Neoplasms; Disease Progression; Dose Fractionation, Radiation; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Organs at Risk; Radiotherapy Dosage; Re-Irradiation

Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment.. An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed.. No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role.. The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Time Factors; Treatment Outcome; Tumor Microenvironment

Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection.. We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed.. A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration.. Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Liver Regeneration; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Preoperative Care; Prognosis; Retrospective Studies; Spleen

Topics: Bevacizumab; Colorectal Neoplasms; Humans; Leucovorin; Liver Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds

BACKGROUND Pancreatic adenocarcinoma (PDA) is associated with an 8.6-fold increased risk in Lynch syndrome patients. Here, we report the case of a Lynch syndrome PDA patient with an exceptional response to a single cycle of pembrolizumab immunotherapy. CASE REPORT A 65-year-old male patient with Lynch syndrome mismatch repair (MMR) deficient PDA with metastatic liver disease, received 1 cycle of pembrolizumab (200 mg) after progressing on 2 standard lines of treatment. His initial computed tomography (CT) showed 3×2.5 cm PDA. At that time, the disease was considered borderline resectable, and the patient received 6 cycles of FOLFIRINOX followed by chemoradiotherapy with capecitabine. A follow-up CT scan showed multiple new liver lesions. The biopsy showed metastatic PDA and tumor tissue demonstrated high microsatellite instability with abnormal/lost expression of MLH1 and PMS2 proteins. The patient was started on pembrolizumab. Only 1 cycle was given due to the development of thromboembolic complications: pulmonary embolism and myocardial infarction. His thrombophilia workup was negative. Restaging CT scans at 3, 6, and 9 months after 1 cycle of pembrolizumab revealed an excellent response with shrinkage of liver lesions. Restaging at 11 months showed the eventual resolution of most liver lesions. No new metastatic disease developed. A repeat biopsy of the dominant liver lesion showed no morphological evidence of PDA. CONCLUSIONS Only 1 cycle of pembrolizumab resulted in clinical complete response and pathologic response in metastatic PDA. We emphasize the importance of testing for MMR status and treating with immunotherapy in metastatic PDA patients with MMR deficiency.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colorectal Neoplasms, Hereditary Nonpolyposis; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Oxaliplatin; Pancreatic Neoplasms

Portal vein tumor thrombus (PVTT) is common in hepatocellular carcinoma (HCC). Recent studies indicate that more aggressive treatments, including surgical resection or locoregional treatment, may benefit selected HCC patients with PVTT. External radiation therapy and infusion chemotherapy were found to achieve good outcomes; however, the use of low-energy x-ray radiation system (INTRABEAM), intraoperative radiation therapy, and portal vein infusion chemotherapy for PVTT has not been reported. We present a case of HCC with PVTT. The patient underwent hemihepatectomy and thrombectomy along with intraoperative radiotherapy (IORT) using a portable INTRABEAM radiation system. Subsequently, to treat PVTT, portal vein infusion chemotherapy with FOLFOX (leucovorin [Folinic acid], fluorouracil, and oxaliplatin) regimen was administered. There were no obvious post-operative complications. After 20 months follow-up period, no obvious tumor recurrence had been observed, and PVTT gradually disappeared completely.. IORT using the INTRABEAM radiation system combined with portal vein infusion chemotherapy is promising for select patients with PVTT.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Intraoperative Care; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Portal Vein; Radiotherapy, Adjuvant; Retrospective Studies; Thrombectomy; Venous Thrombosis

Hepatic arterial infusion (HAI) combined with systemic chemotherapy has shown promising results in patients with unresectable colorectal liver metastases (CRLM), even after failure to systemic therapy. Addition of systemic targeted therapies has been investigated with controversial results regarding tolerance, especially with HAI-floruxidine when combined with systemic bevacizumab. Our study aimed to analyse feasibility, safety and efficacy of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies.. Between 2005 and 2016, single-centre consecutive patients with unresectable CRLM who received at least one cycle of HAI-oxaliplatin plus systemic chemotherapy and targeted therapies (cetuximab/panitumumab or bevacizumab) were analysed.. A total of 89 patients (median age 55 years (range, 26-76 years) who previously received a median number of one systemic chemotherapy regimen (range, 0-5) including oxaliplatin in 78% of cases were included. Median number of HAI-oxaliplatin cycles was 9 (range, 1-28) combined with systemic chemotherapy and targeted therapies (LV5FU2 [63%], FOLFIRI [36%]) plus anti-EGFR (30%), or bevacizumab (70%). Grade 3/4 toxicities included neutropenia (40%), HAI-related abdominal pain (43%) and neurotoxicity (12%). The intent-to-treat objective response rate was 42%, and 45% had stable disease, allowing complete CRLM resection/ablation in 27% of patients. After a median follow-up of 72 months, median overall and progression-free survival was 20 and 9 months, respectively.. Addition of targeted therapy to systemic chemotherapy combined with HAI-oxaliplatin is feasible, safe and shows promising activity, even after systemic chemotherapy failure.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin

FOLFOX chemotherapy (CTx) is used for the treatment of colorectal liver metastasis (CRLM). Side effects include rare cardiotoxicity, which may limit the application of FOLFOX. Currently, there is no effective strategy to prevent FOLFOX-induced cardiotoxicity. Glycine has been shown to protect livers from CTx-induced injury and oxidative stress, and it reduces platelet aggregation and improves microperfusion. This study tested the hypothesis of glycine being cardioprotective in a rat model of FOLFOX in combination with CRLM.. The effect of glycine was tested in vitro on human cardiac myocytes (HCMs). To test glycine in vivo Wag/Rij rats with induced CRLM were treated with FOLFOX ±5% dietary glycine. Left ventricle ejection fraction (LVEF), myocardial fibrosis, and apoptosis, also heart fatty acid binding protein (h-FABP) and brain natriuretic peptide levels were monitored. PCR analysis for Collagen type I, II, and brain natriuretic peptide (BNP) in the heart muscle was performed.. In vitro glycine had no effect on HCM cell viability. Treatment with FOLFOX resulted in a significant increase of h-FABP levels, increased myocardial fibrosis, and apoptosis as well as increased expression of type I Collagen. Furthermore, FOLFOX caused a decrease of LVEF by 10% (. Data presented here demonstrate for the first time that dietary glycine protects the heart against FOLFOX-induced injury during treatment for CRLM.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Diet; Disease Models, Animal; Fluorouracil; Glycine; Heart Injuries; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rats

The main drawbacks of neoadjuvant chemotherapy of colorectal liver cancer metastases are related to the toxic liver damage. To determine the degree of biochemical and morphologic liver damage after therapeutic protocol treatment with "bevacizumab plus FOLFOX IV", as well as the correlation between the sex, age, the existence of metabolic syndrome, the length of neoadjuvant therapy treatment and the degree of liver damage.. The study includes the total of 60 colorectal cancer metastases operated patients, divided into two groups of 30 patients: the group of patients who were treated with "bevacizumab plus FOLFOX IV" protocol as a neoadjuvant therapy - prior to liver metastases surgery and the control group, patients with the liver resection done without previous neoadjuvant chemotherapy. The following parameters were examined: biochemical liver function parameters, the presence of metabolic syndrome, pathohistological assessment of the degree of steatosis and SOS syndrome.. The increase in AF was observed in the experimental group (Z = 2.566, p = 0.010), Dbilirubin (Z = 1.970, p = 0.037), LDH (Z = 2.951, p = 0.003) and decrease in albumin values (t = 5.100, p <0.001). The pathohistological examination in only 3.3% showed moderate liver steatosis, while SOS syndrome was recorded in as many as two-thirds (66.66%) of patients in the study group. In 14 patients (46.7%) a mild degree was registered, and in 6 (20.0%) moderate levels of this type of liver damage. Pole (p = 0.13), age (p = 0.09) and length of administration of chemotherapy (p = 0.35), as well as the presence of metabolic syndrome (χ2 = 0.390, p = 0.830), did not have any statistically significant effect on the liver damage degree.. In our study, after the administration of the "bevacizumab plus FOLFOX IV" protocol, a statistically significant increase in AF, Dbilirubin and LDH, as well as a decrease in albumin values, were found. Dominant liver damage was by type of SOS syndrome (66.7%), while steatosis of the liver was recorded in only 3.3% of patients. Gender, age, the presence of metabolic syndrome and the number of chemotherapy cycles did not have any statistic significance on the biochemical parameters and morphological degree of liver damage.. Colorectal cancer metastases, Liver surgery, Oncology, Neoadjuvant chemotherapy, Liver damage.. I principali aspetti negativi della chemioterapia neoadiuvante delle metastasi epatiche da carcinoma del colonretto sono relativi ad un danno tossico del fegato. Questo studio è finalizzato a determinare il grado di danno epatico biochimico e morfologico dopo il trattamento con il protocollo terapeutico di bevacizumab più FOLFOX IV, nonché la correlazione tra sesso, età, esistenza della sindrome metabolica, durata del trattamento neoadiuvante e grado di danno al fegato. Lo studio si è svolto su un totale di 60 pazienti operati per metastasi dal cancro del colon-retto, divisi in due gruppi di 30 pazienti ciascuno: un gruppo di studio, cioè di quelli pretrattati con terapia neoadiuvante secondo il protocollo “bevacizumab più FOLFOX IV”, ed un gruppo di controllo di pazienti trattati direttamente con resezione epatica senza chemioterapia neoadiuvante. Sono stati esaminati i seguenti elementi: parametri biochimici della funzionalità epatica, presenza di sindrome metabolica, valutazione isto-patologica del grado di steatosi e sindrome di SOS. RISULTATI: L’aumento di AF è stato osservato nel gruppo sperimentale (Z = 2.566, p = 0,010), Dbilirubin (Z = 1.970, p = 0,037), LDH (Z = 2.951, p = 0.003) con diminuzione dei valori di albumina (t = 5.100, p <0,001). L’esame isto-patologico solo nel 3,3% ha mostrato steatosi epatica moderata, mentre la sindrome della ostruzione sinusoidale (SOS) è stata registrata in ben due terzi (66,66%) dei pazienti nel gruppo di studio. In 14 pazienti (46,7%) è stato registrato un grado lieve e in 6 (20,0%) livelli moderati di questo tipo di danno epatico. Genere (p = 0,13), età (p = 0,09) e durata della somministrazione della chemioterapia (p = 0,35), nonché la presenza della sindrome metabolica (χ2 = 0,390, p = 0,830), non hanno avuto alcun effetto statisticamente significativo sul grado di danno epatico. CONCLUSIONE: Nel nostro studio, dopo la somministrazione del protocollo “bevacizumab plus FOLFOX IV”, è stato riscontrato un aumento statisticamente significativo di AF, Dbilirubin e LDH, nonché una diminuzione dei valori di albumina. Il danno epatico dominante era del tipo di sindrome SOS (66,7%), mentre la steatosi epatica è stata registrata solo nel 3,3% dei pazienti. Genere, età, presenza di sindrome metabolica e numero di cicli di chemioterapia non hanno avuto alcun significato statistico sui parametri biochimici e sul grado morfologico di danno epatico.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Treatment Outcome

By using the Korean Pancreatic Cancer (K-PaC) registry, we compared the clinical outcomes of FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GNP) in patients with metastatic pancreatic cancer (MPC).. We constructed a web-based database of 3748 anonymized patients diagnosed with pancreatic ductal adenocarcinoma. MPC patients who received first-line FFX or GNP were enrolled. Overall survival (OS), progression-free survival, grade III to IV toxicity, and cross-over treatment were analyzed.. A total of 413 patients (232 vs. 181, FFX vs. GNP; all data are presented in this sequence) were eligible. Median age was 63 years (60 vs. 69 y) with 43% (39% vs. 47%) comprising female individuals. The major metastatic sites were the liver (64%), peritoneum (25%), and distant lymph nodes (18%). The median OS was 11.5 versus 12.7 months (hazard ratio [HR]=0.87, 95% confidence interval [CI]: 0.68-1.12, P=0.286), and median progression-free survival was 7.5 versus 8.1 months (HR=0.92, 95% CI: 0.70-1.20, P=0.517), respectively. The frequency of grade III to IV febrile neutropenia was higher in the FFX group (18% vs. 11%, P=0.040), and that of peripheral neuropathy was higher in the GNP group (8% vs. 14%, P=0.046). The chance to receive second-line chemotherapy was higher in the GNP group (45% vs. 56%, P=0.036). In the cross-over treatment, the median OS of the FFX-GNP group (n=43) and the GNP-FFX group (n=47) was 16.8 versus 17.7 months (HR=0.79, 95% CI: 0.44-1.41, P=0.425).. FFX and GNP showed similar efficacy and comparable toxicity in MPC patients. Although the GNP group had a higher chance to receive second-line chemotherapy, they did not have improved overall survival.

Topics: Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cross-Over Studies; Deoxycytidine; Febrile Neutropenia; Female; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Peripheral Nervous System Diseases; Peritoneal Neoplasms; Progression-Free Survival; Registries; Republic of Korea; Survival Rate; Treatment Outcome

This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection.. Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time-to-organ recurrence.. Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow-up for survivors was 100 (range = 12-185) and 156 months (range = 18-217) for SYS and HAI + SYS, respectively. The 5-year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5-year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS.. Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Incidence; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate; United States

Colorectal cancer (CRC) patients suffer from the second highest mortality among all cancer entities. In half of all CRC patients, colorectal cancer liver metastases (CRLM) can be observed. Metastatic colorectal cancer is associated with poor overall survival and limited treatment options. Even after successful surgical resection of the primary tumor, metachronous liver metastases occur in one out of eight cases. The only available curative intended treatment is hepatic resection, but metachronous CRLM frequently recur after approximately 1 year. In this study, we performed a proteome analysis of three recurrent liver metastases of a single CRC patient by mass spectrometry. Despite surgical resection of the primary CRC and adjuvant chemotherapy plus cetuximab treatment, the patient developed three metachronous CRLM which occurred consecutively after 9, 21 and 31 months. We identified a set of 1132 proteins expressed in the three metachronous CRLM, of which 481 were differentially regulated, including 81 proteins that were associated with the extracellular matrix (ECM). 56 ECM associated proteins were identified as upregulated in the third metastasis, 26 (46%) of which were previously described as negative prognostic markers in CRC, including tenascin C, nidogen 1, fibulin 1 and vitronectin. These data may reflect an ascending trend of malignancy from the first to the third metachronous colorectal cancer liver metastasis. Additionally, the results indicate different ECM phenotypes for recurrent metachronous metastasis, associated with different grades of malignancy and highlights the importance of individual analysis of molecular features in different, consecutive metastatic events in a single patient.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Extracellular Matrix; Extracellular Matrix Proteins; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Mass Spectrometry; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Organoplatinum Compounds; Proteome

Neoadjuvant chemoradiotherapy is a standard mode of therapy for rectal cancer but not colon cancer. A 74-year-old man undergoing treatment for prostate cancer was found to have a tumor in both the sigmoid colon and liver. Colonoscopy showed a type 2 tumor of the sigmoid colon, with a biopsy confirming a diagnosis of well differentiated tubular adenocarcinoma. Computed tomography demonstrated a tumor of the sigmoid colon with metastasis to the liver. As there was a high suspicion of invasion of the left ureter, we decided to administer mFOLFOX6 as neoadjuvant chemotherapy prior to tumor resection. After 8 courses of mFOLFOX6, both the primary lesion and liver metastasis significantly decreased in size. Subsequently, the patient underwent a sigmoidectomy and partial hepatectomy. Histopathological examination revealed pathological complete response(Grade 3). It is important to reveal effective cases of neoadjuvant chemotherapy, the appropriate treatment regime and timing of surgical intervention so as to advance therapeutic strategies for the treatment of colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Sigmoid Neoplasms

The need to remove palliative primary tumors in the incurable Stage Ⅳ colorectal cancer patients remains debatable. Here, we describe the case of a 62-year-old man diagnosed with rectal cancer(cT3N2bM1b, cStage Ⅳb)with both primary tumor and metastatic lesions that were unresectable. Systemic chemotherapy was administered with 5-fluorouracil, Leucovorin, and oxaliplatin(FOLFOX)or FOLFOX with bevacizumab(BEV). After 12 months of treatment, CT scan revealed that both the primary tumor and metastases had shrunk significantly, leading to the conclusion that the primary tumor was resectable. Subsequently, laparoscopic abdominoperineal resection was performed. The patient was discharged 21 days postoperatively, and chemotherapy(FOLFOX plus BEV)was reintroduced 24 days after discharge. The patient was alive 25 months after the first consultation. Palliative primary tumor resection involves risks of operative complications and tumor progression owing to the absence of chemotherapy; however, some recent evidence has shown that primary tumor resection was associated with better prognosis and could be a good option on an individual patient basis. Further studies are required to establish the optimal strategy for patients with Stage Ⅳ colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Proctectomy; Rectal Neoplasms

The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders.. This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial.. A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies.. Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Computational Biology; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Radiographic Image Interpretation, Computer-Assisted; Response Evaluation Criteria in Solid Tumors; Survival Rate; Tomography, X-Ray Computed

A 72-year-old man was admitted to the hospital with fatigue. Colonoscopy revealed a 50 × 50 mm rectal tumor with bleeding. Based on close inspection, he was diagnosed with unresectable advanced rectal cancer with multiple liver metastases. Chemotherapy was administered as 10 cycles of bevacizumab + mFOLFOX6 and 7 cycles of bevacizumab + FOLFIRI. Nine months later, he presented with hematochezia and progression of anemia. It was difficult to stop the bleeding via endoscopy. He underwent radiation therapy (39 Gy in 13 fractions), and hemostasis was confirmed. Then, further chemotherapy was performed with 3 cycles of bevacizumab + FOLFIRI and 2 cycles of TAS102. However 14 months after the initial visit, he presented with right hypochondralgia and abdominal fullness due to the progression of multiple liver metastases. Palliative low-dose whole-liver radiation therapy (WLRT) (30 Gy in 10 fractions) was performed. He developed Grade 2 nausea, but his right hypochondralgia reduced, liver dysfunction improved, and he successfully completed radiotherapy. At approximately the same time his anemia progressed, and colonoscopy revealed recurrent bleeding from the tumor. Re-irradiation (15 Gy in 5 fractions) of the rectal tumor was carried out and a blood transfusion was performed for the bleeding. He was discharged after confirmation the anemia had not progressed. Few reports have been published on the use of both palliative re-irradiation to stop bleeding from rectal cancer and palliative low-dose WLRT. Based on our experience with this case, we believe that palliative radiotherapy can be useful in treating patients with a poor prognosis.

Topics: Abdominal Pain; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Disease Progression; Fluorouracil; Gastrointestinal Hemorrhage; Hemostasis; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Palliative Care; Radiotherapy; Radiotherapy Dosage; Rectal Neoplasms; Treatment Outcome

The safety and feasibility of laparoscopic, two-stage hepatectomy for bilobar colorectal liver metastases is poorly evaluated.. We reviewed retrospectively 86 consecutive patients who underwent complete two-stage hepatectomy (left lobe clearance as the first stage and standard/extended right hepatectomy as the second stage) for bilobar colorectal liver metastases between 2007 and 2017 in 2 tertiary centers. Short- and long-term outcomes were compared between laparoscopic and open two-stage hepatectomy before and after propensity score matching.. Laparoscopic two-stage hepatectomy was performed in 38 patients and open two-stage hepatectomy in 48. After propensity score matching, 25 laparoscopic and 25 open patients showed similar preoperative characteristics. For the first stage, a laparoscopic approach was associated with lesser hospital stays (4 vs 7.5 days; P < .001). For the second stage, a laparoscopic approach was associated with less blood loss (250 vs 500 mL; P = .040), less postoperative complications (32% vs 60%; P = .047), lesser hospital stays (9 vs 16 days; P = .013), and earlier administration of chemotherapy (1.6 vs 2 months; P = .039). Overall survival, recurrence-free survival, and liver-recurrence-free survival were comparable between the groups (3-year overall survival: 80% vs 54%; P = .154; 2-year recurrence-free survival: 20% vs 18%; P = .200; 2-year liver-recurrence-free survival: 39% vs 33%; P = .269). Although both groups had comparable recurrence patterns, repeat hepatectomies for recurrence were performed more frequently in the laparoscopic two-stage hepatectomy group (56% vs 0%; P = .006).. Laparoscopic two-stage hepatectomy for bilobar colorectal liver metastases is safe and feasible with favorable surgical and oncologic outcomes compared to open two-stage hepatectomy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Feasibility Studies; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Laparoscopy; Length of Stay; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Postoperative Complications; Propensity Score; Retrospective Studies

The purpose of this study was to investigate the incidence, origin, and clinical significance of liver atrophy during chemotherapy for colorectal cancer.. This study included 103 patients who underwent chemotherapy before resection for colorectal liver metastases (training set) and 171 patients who underwent adjuvant or first-line chemotherapy without liver resection (validation set). A greater than 10% decrease (atrophy) or increase (hypertrophy) of the liver volume from the baseline was defined as a significant change.. In the training set, the numbers of patients who developed atrophy, no change of volume, and hypertrophy of the liver after chemotherapy were 15 (14.6%), 73 (70.9%), and 15 (14.6%), respectively. Liver atrophy was associated with impaired hepatic function, and the postoperative morbidity rate and refractory ascites/pleural effusion were higher in the patients with liver atrophy than those without (60.0% vs. 31.8%, P = 0.045 and 46.7% vs. 8.0%, P < 0.001, respectively). Histopathological examination revealed a strong association between sinusoidal injury and liver atrophy (P < 0.001). The cumulative incidence of liver atrophy increased with increasing duration of chemotherapy, whereas the incidence of liver atrophy was less frequent in patients who had received bevacizumab than those who had not in both the training set (odds ratio [OR], 0.13; P = 0.001) and the validation set (OR, 0.31; P = 0.007).. Liver atrophy is associated with impaired hepatic functional reserve and observed at an increasing frequency as the duration of chemotherapy increases with frequent histopathological evidence of sinusoidal injury in the liver. Bevacizumab may protect against the development of liver atrophy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Atrophy; Bevacizumab; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Survival Rate

Conversion chemotherapy is often used for borderline or unresectable (B/U) liver metastases from colorectal cancer (CRC) with the aim of achieving resectability. Although intensive and costly regimens are often used, the best regimen in this scenario remains unclear. We aimed to evaluate the outcomes of patients with B/U liver metastases from CRC treated with conversion chemotherapy with the modified fluorouracil, leucovorin, and oxaliplatin (mFLOX) regimen followed by metastasectomy.. We performed a single-center retrospective analysis of patients with B/U liver metastases from CRC treated with chemotherapy with the mFLOX regimen followed by surgery. B/U disease was defined as at least one of the following: more than four lesions, involvement of hepatic artery or portal vein, or involvement of biliary structure.. Fifty-four consecutive patients who met our criteria for B/U liver metastases were evaluated. Thirty-five patients (64%) had more than four liver lesions, 16 (29%) had key vascular structure involvement, and 16 (29%) had biliary involvement. After chemotherapy, all patients had surgery and 42 (77%) had R0 resection. After a median follow-up of 37.2 months, median progression-free survival (PFS) was 16.9 months and median overall survival (OS) was 68.3 months. R1-R2 resections were associated with worse PFS and OS compared with R0 resection (PFS: hazard ratio, 2.65;. Treatment of B/U liver metastases from CRC with conversion chemotherapy using mFLOX regimen followed by surgical resection was associated with a high R0 resection rate and favorable survival outcomes. On the basis of our results, we consider mFLOX a low-cost option for conversion chemotherapy among other options that have been proposed.

Topics: Adult; Aged; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Metastasis; Oxaliplatin; Retrospective Studies; Young Adult

We evaluated the clinical impact of FOLFOXIRI regimen aiming for conversion surgery in patients with unresectable multiple colorectal liver metastasis (CRLM).. A total of 42 patients with unresectable multiple CRLM who received chemotherapy with molecular agents were included in the analysis. The clinical results of FOLFOXIRI with other regimens were compared.. The total conversion rate of 42 unresectable CRLM was 48.1%, and conversion cases had a better prognosis. Clinicopathological characteristics of conversion cases were more frequent in FOLFOXIRI induction, liver limited disease and maximum diameter × number (MDN) over 70. FOLFOXIRI achieved a higher conversion rate compared to other regimens (72.2% vs. 37.5%, p=0.0334), and significantly reduced the medication period until conversion surgery (median 5.8 courses) with a higher tumour necrotic rate. Consequently, the overall survival of conversion cases with FOLFOXIRI was better than that with other regimens (p=0.0055).. FOLFOXIRI plus molecular agents might provide a higher probability of conversion surgery with a prognostic benefit.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Conversion to Open Surgery; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Treatment Outcome; Tumor Burden

It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM.. Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS.. Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16;. Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully.. Se desconoce si la quimioterapia perioperatoria en comparación con la quimioterapia adyuvante sola mejora la supervivencia libre de enfermedad (. Se incluyeron pacientes consecutivos que presentaban hasta cinco CLM resecables en dos centros japoneses y dos centros franceses entre 2008 a 2015. Ambas instituciones francesas favorecían FOLFOX perioperatorio, mientras que los dos grupos japoneses utilizaban sistemáticamente la cirugía de entrada y quimioterapia adyuvante. Se utilizaron la probabilidad inversa del tratamiento ponderado (. Se incluyeron 300 pacientes (grupo de quimioterapia perioperatoria. En comparación con la quimioterapia adyuvante, el FOLFOX perioperatorio no mejora la DFS en CLM resecables siempre y cuando la quimioterapia adyuvante se administre de forma efectiva.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; France; Hepatectomy; Humans; Japan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Perioperative Period; Retrospective Studies; Vitamin B Complex

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; BRCA2 Protein; Carcinoma, Ductal, Breast; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Genetic Testing; Germ Cells; Germ-Line Mutation; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymph Node Excision; Middle Aged; Mutation; Oxaliplatin; Pancreatic Neoplasms; Pancreaticoduodenectomy

A 65-year-old woman was diagnosed with simultaneous hepatic metastasis of rectal cancer with portal venous tumor thrombi(Vp3)that developed in the bifurcation of the portal vein. Four days from the first visit, abdominal dynamic contrastenhanced CT image on the portal venous phase shows that the tumor thrombi progressed in the main trunk of the portal vein (Vp4). We decided that it was a condition of oncologic emergency and initiated FOLFOXIRI plus BV therapy. After 12 courses, tumor shrinkage and regression of the portal venous tumor thrombi were achieved, but conversion surgery was impossible because the collateral circulation of the hepatic portal region remained. The treatment target was changed to the extension of the survival period. The initiation and reinitiation of FOLFOXIRI plus BV therapy and maintenance of 5-FU/l-LV plus BV therapy contributed to disease control in 24 months and survival period of 36months.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Portal Vein; Rectal Neoplasms; Venous Thrombosis

A92 -year-old woman underwent laparoscopic sigmoid colectomy with D3 lymphadenectomy. Histological examination confirmed a pT3(SS), pN0, pM0, pStageⅡ tumor. Abdominal CT 6 months after surgery revealed liver metastasis close to the right branch of the portal vein in the S6 region of the liver. There were no indications for transcatheter arterial embolization, radiofrequency ablation, or hepatectomy. Although she had Grade 3 neutropenia, the patient received 15 courses of oral UFT/LV. Three courses of UFT/LV plus bevacizumab were also administered. She was judged to have achieved stable disease (SD); however, Grade 4 proteinuria was observed. After she was administered 2 courses of TAS-102, we shifted to best supportive care. She died of a sigmoid cancer 32 months after UFT/LV initiation. Careful adaptation of chemotherapy can be used to control a patient's condition during certain periods, even in patients with super-advanced age.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Female; Humans; Leucovorin; Liver Neoplasms; Sigmoid Neoplasms; Tegafur; Uracil

We report 2 cases of advanced colorectal cancer achieving complete response by FOLFOXIRI plus bevacizumab. Case 1 was a 65-year-old male diagnosed with descending colon cancer with multiple liver metastases. Six courses of FOLFOXIRI plus bevacizumab were administered after laparoscopic-assisted left hemicolectomy. Ten partial hepatectomies and 1 radiofrequency ablation were performed as the liver metastases resolved. A pathological complete response was confirmed. Adjuvant chemotherapy was not administered, and recurrence-free survival was 21 months after hepatectomy. Case 2 was a 77-yearold male diagnosed with rectal cancer invading the pelvic wall and sacral foramen with bilateral lateral lymph node metastasis. Additionally, there was a cancer embolism in the right internal iliac vein. Six courses of FOLFOXIRI plus bevacizumab were administered, and the cancer tissue was absent on subsequent CT and MRI. The cancer was scarred by colonoscopy, and the biopsy showed no malignant cells. Six courses of FOLFIRI plus panitumumab were administered as second-line chemotherapy, and the patient survived without any recurrence after 12 months from initiation of chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Recurrence, Local; Organoplatinum Compounds; Rectal Neoplasms

Considering the surgical safety and perioperative complications, simultaneous resection after neoadjuvant therapy is not commonly recommended.. A total of 253 patients were included in study. Comparison of the short-term outcomes was performed after propensity score adjustment in Group A (n = 96) and Group B (neoadjuvant therapy, n = 96).. There was no postoperative mortality. After matching, the differences from surgical confounders were well-balanced. Morbidity (15.6% vs. 15.6%, p = 0.981), and Clavien-Dindo grade of complications (p = 0.710) were similar. No difference was found when the complications were divided according to the origin (general, colorectal and hepatic). Length of the hospital stays also did not differ between the groups (p = 0.482). More importantly, there was no increase in the number of patients with delayed adjuvant treatment after surgery in Group B.. Neoadjuvant treatment did not increase morbidity, length of hospital stays and influence adjuvant treatment after simultaneous resection.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaloacetates; Patient Safety; Proctectomy; Propensity Score; Retrospective Studies; Treatment Outcome

Adenosine has an immunosuppressive and angiogenic modulation of the tumor microenvironment. The present study explored the efficacy of single nucleotide polymorphisms (SNPs) in adenosine-related molecules for patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy.. We analyzed genomic DNA extracted from 451 samples from 3 independent cohorts: a discovery cohort of 107 patients treated with FOLFIRI (5-fluorouracil, leucovorin, oxaliplatin, irinotecan) plus bevacizumab in FIRE-3 (ClinicalTrials.gov identifier, NCT00433927); a validation cohort of 215 patients with FOLFIRI plus bevacizumab in TRIBE (ClinicalTrials.gov identifier, NCT00719797); and a control cohort of 129 patients treated with FOLFIRI plus cetuximab in FIRE-3. The relationship between the selected SNPs and clinical outcomes was analyzed.. In the discovery cohort, patients with any C allele in CD39 rs11188513 had significantly shorter median progression-free survival compared with those with the T/T variant (11.3 vs. 13.1 months; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.04-2.77; P = .022) on univariate analysis. Also, their overall survival (OS) was shorter (27.4 vs. 49.9 months; HR, 2.10; 95% CI, 1.07-4.10; P = .031) on univariate and multivariable analyses. The significant association between CD39 rs11188513 and OS was confirmed in the validation cohort (25.8 vs. 31.6 months; HR, 1.53; 95% CI, 1.09-2.15; P = .013). CD73 rs2229523 and A2BR rs2015353 in the discovery cohort and CD39 rs2226163 in the validation cohort showed significant correlations with OS on univariate and multivariable analyses. None of SNPs were significant in the cetuximab control cohort.. Selected SNPs in the adenosine pathway could affect the clinical outcomes of patients with metastatic colorectal cancer treated with FOLFIRI plus bevacizumab.

Topics: 5'-Nucleotidase; Adenosine; Antineoplastic Combined Chemotherapy Protocols; Apyrase; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cetuximab; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; GPI-Linked Proteins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Receptors, Purinergic P1; Survival Rate

5-Fluorouracil (5-FU) represents the backbone of systemic therapy regimens of colorectal cancer. The current study aims at evaluating the patterns and predictors of cardiac adverse events associated with various 5-FU-based systemic therapy regimens among patients with metastatic colorectal cancer.. This pooled analysis includes de-identified patient-level datasets from 5 randomized studies (NCT00272051, NCT00305188, NCT00115765, NCT00364013, and NCT00384176). In order to evaluate factors predicting the development of all cardiac toxicities, arrhythmias, and ischemic events, univariate logistic regression analysis was conducted. Subsequently, factors with P < .05 in univariate analysis were included in multivariate logistic regression analysis.. A total of 3223 patients were included in the pooled analysis. A total of 255 (7.9%) patients developed some form of a cardiac toxicity, among which 153 (4.7%) patients developed some form of arrhythmia and 62 (1.9%) patients developed an ischemic event. Within multivariate logistic regression analysis for factors predicting cardiac toxicities, only bevacizumab-containing regimens (P = .002) and panitumumab-containing regimens (P < .001) were predictive for the occurrence of cardiac toxicity. Similarly, within multivariate logistic regression analysis for factors predicting cardiac arrhythmias, only panitumumab-based regimens were predictive of the occurrence of arrhythmias (P < .001). Likewise, within multivariate logistic regression analysis for factors predicting cardiac ischemia, only bevacizumab-containing regimens were predictive of ischemic events (P = .004).. Bevacizumab- and panitumumab-containing regimens seem to be associated with a higher risk of cardiac toxicities compared with other 5-FU-based regimens. Bevacizumab-containing regimens seem to increase the risk of 5-FU-related ischemic events, whereas panitumumab-containing regimens seem to increase the risk of arrhythmias.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cardiotoxicity; Cardiovascular Diseases; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Panitumumab; Prognosis; Randomized Controlled Trials as Topic

The phase III VELOUR trial demonstrated efficacy with combined FOLFIRI-aflibercept in patients with metastatic colorectal cancer previously treated with oxaliplatin with or without bevacizumab versus placebo. The effect of FOLFIRI-aflibercept in routine clinical practice was evaluated.. Overall survival (OS), progression-free survival (PFS), response and safety were analysed for 78 patients treated with FOLFIRI-aflibercept at six GITuD institutions. Exploratory analyses of prognostic and predictive markers of efficacy were performed.. Patients had good general status (PS 0-1 96.2%), tumours were mostly RAS-mutant (75.6%), synchronous (71.8%), and left-sided (71.8%). Prior therapy included bevacizumab (47.4%) and anti-EGFR agents (12.8%). PFS was longer for metachronous than synchronous tumours (11.0 vs 5.0 months, P = 0.028), and for left-colon tumours (7.0 vs 3.0 months, P = 0.044). RAS-mutant status, first-line treatment and primary tumour surgery did not impact PFS. The disease control rate was 70.5%. The most common grade 3/4 toxicities were neutropenia (15.3%), asthenia (10.3%), diarrhea and mucositis (6.4% each). Dysphonia was reported in 39.7% of patients, and grade 3 hypertension in 3.8%. Development of hypertension (any grade) was significantly associated with a reduced risk of progression by multivariate analysis (HR = 2.7; 95%CI 1.3-5.4; P = 0.001).. Efficacy with FOLFIRI-aflibercept in a real-life population was in line with results from the pivotal trial and toxicity was manageable with treatment adaptation. Survival outcomes were not impacted by primary tumour location, RAS-mutant status, first-line treatment or primary tumour surgery. Hypertension may be a surrogate marker of efficacy in this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Early Diagnosis; Early Medical Intervention; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Panitumumab; Radiography, Thoracic; Tomography, X-Ray Computed

Although hepatectomy for metastatic colorectal cancer (mCRC) prolongs survival in up to 40% of people, recurrence rates approach 70%. We used a multidisciplinary approach to treat recurrent liver metastases, including chemotherapy, surgery, and palliative care. On the other hand, development of chemotherapeutic agents is remarkable and improves long-term survival. However, whether chemotherapy and repeat hepatectomy combination therapy improve survival or not is still unclear. The aim of this study was to analyze the outcomes of repeat hepatectomy with systemic chemotherapy for mCRC.. Following Institutional Review Board approval, we reviewed the records of all patients who underwent hepatectomy for mCRC between 1974 and 2015 at Fujita Health University Hospital. We used the Kaplan-Meier method to estimate overall survival from the first and last hepatectomy in multi hepatectomy cases after 2005 and compared outcomes between groups using the log-rank test.. A total of 426 liver resections were performed for mCRC; of these, 236 cases were performed after 2005 (late group). In 118 (50%) cases, the site of recurrence was the liver, 59 (50%) underwent repeat hepatectomy, and 14 cases had ≥ 2 repeat hepatectomies. Overall survival (OS) before and after 2005 was 42.2 and 64.1 months, respectively, with the late group having better OS compared to the early (1974-2004) group. OS for single hepatectomy cases was 83.2 months, for two hepatectomies was 42.9 months, and for three hepatectomies was 35.3 months. In total, 59 patients did not undergo surgery after recurrence with an OS of 28.7 months. Mortality of the second and third repeat hepatectomy was 1.7% and 15.3%, respectively.. Repeat hepatectomy with systemic chemotherapy for mCRC is feasible and might achieve improved survival in carefully selected patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Feasibility Studies; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Reoperation; Retrospective Studies; Survival Rate

To compare treatment with hepatic arterial infusion of chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) with both extrahepatic spread (EHS) and intrahepatic tumor and patients with intrahepatic tumor only.. This single-center retrospective study comprised 116 patients with advanced HCC with both intrahepatic tumor and EHS (EHS group; n = 50) or with intrahepatic tumor only (non-EHS group; n = 66) treated with HAIC including oxaliplatin, fluorouracil, and leucovorin between June 2014 and July 2016. Overall survival (OS) and radiologic responses to treatment were determined and compared between the 2 groups.. Both the objective response rate and the clinical benefit rate were higher in the non-EHS group than in the EHS group (37.9% vs 16% objective response rate, P = .010; 81.8% vs 62% clinical benefit rate, P = .017). Median OS was not statistically different between the 2 groups (14.8 months vs 9.8 months, P = .068). Subgroup analysis of OS found that patients with lung metastases survived for a shorter time (OS 7 months) than patients with other metastatic sites (P = .003) and patients free of metastases (P = .001).. HAIC is a potential treatment option for advanced HCC with limited extrahepatic metastases in a population with hepatitis B virus infection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Clinical Decision-Making; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Oxaliplatin; Patient Selection; Retrospective Studies; Time Factors; Treatment Outcome; Young Adult

The array of tools currently available and the aim of treatment make choosing the best therapeutic strategy in metastatic colorectal cancer (CRC) an increasing challenge worldwide. We present the case of a 53-year-old man with metachronous metastases (liver-only metastatic disease) treated with FOLFOXIRI as first-line treatment. In March 2010, a colonoscopy carried out for persistent constipation revealed a neoplastic stenosing mass. After a month, the patient underwent a low anterior rectal resection with colorectal anastomosis; no metastases were found on the computed tomography scan. Histology confirmed adenocarcinoma (pT3N0M0; stage IIA). No adjuvant treatment was given because of the absence of negative prognostic and molecular factors in stage II. After 6 months of follow-up, a computed tomography scan and F-FDG PET showed five focal hepatic lesions. We decided to start a FOLFOXIRI regimen aimed at conversion. The patient had a complete clinical and radiological response to chemotherapy after eight cycles. After 7 years, the patient is currently without any evidence of recurrence or progression of the disease. Few literature reports suggest that chemotherapy alone can cure patients with CRC liver metastases. Although regimens including oxaliplatin have never been reported as potential healing tools, the FOLFOXIRI chemotherapeutic schedule (oxaliplatin, irinotecan, and 5-fluorouracil) showed a high response rate in mCRC and can even cure the metastatic disease in sporadic cases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Remission Induction

To evaluate the pattern of tumor relapse of pathological complete response (pCR) patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME), and to identify predictive factors of distant metastasis in pCR patients after nCRT.. This was a retrospective analysis of 118 LARC patients who achieved a pCR following nCRT and TME from 2008 to 2015. Clinicopathological and therapeutic parameters were evaluated as possible predictors of distant metastasis-free survival (DMFS), and COX regression analysis was performed.. After a median follow-up of 57 months, the 5-year overall and disease-free survival rates were 94.7% and 88.1%, respectively. Overall, 6 patients (5.1%) died, no local recurrence occurred, 13 patients (11%) developed distant metastases, including lung (n = 5), liver (n = 2), bone (n = 3), lung and brain (n = 1), peritoneal (n = 1), and spleen (n = 1) metastasis. On univariate analysis, tumor distance from the anal verge (HR = 0.706, P = 0.039), acellular mucin pools (HR = 6.687, P = 0.002), and MUC1 expression (HR = 8.280, P < 0.001) were independently associated with DMFS. COX regression demonstrated that MUC1 expression (HR = 3.812, P = 0.041) remained to be an independent predictor of DMFS in pCR patients.. Distant metastasis still remained a major concern in pCR patients following nCRT and TME. Tumor distance from the anal verge, acellular mucin pools, and MUC1 expression were associated with distant metastasis in patients with pCR. MUC1 staining remained to be an independent risk factor for DMFS. Such information could facilitate treatment decision in these patients, such as adjuvant chemotherapy and follow-up.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Brain Neoplasms; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Disease-Free Survival; Female; Fluorouracil; Humans; Incidence; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Mesentery; Middle Aged; Mucin-1; Mucins; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Proctectomy; Proportional Hazards Models; Rectal Neoplasms; Remission Induction; Retrospective Studies; Splenic Neoplasms

FOLFIRINOX is a highly effective anticancer treatment, even in advanced pancreatic cancer, which provides a potential cure in patients initially treated with a palliative strategy. A 47-year-old man was found to have an unresectable pancreatic cancer (4 cm in size) surrounding both the superior mesenteric artery and superior mesenteric vein. A simultaneous liver metastasis in Segment 8, with a diameter of 17 mm, was also detected. The pancreatic tumor markers CEA, CA19-9, and DUPAN-2 were significantly elevated to 21.7 ng/mL, 6224 ng/mL, and 1200U/mL, respectively. After 21 courses of FOLFIRINOX, the primary pancreatic tumor diminished in size (partial response) from 42 to 17 mm, and the liver mass almost disappeared. The tumor markers significantly decreased to almost normal levels. Fourteen months after the initial chemotherapy, conversion surgery was performed. Upon surgical resection, the pancreatic tumor was found to be Grade 1b, and a pathologically complete response was observed for the liver metastasis. The patient is still alive 32 months after initial treatment with no recurrence. This is an informative case of a locally advanced pancreatic cancer with a synchronous liver metastasis that had a significant response to FOLFIRINOX, allowing for subsequent curative resection.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome

Many studies have reported radical resection for liver metastasis and the primary tumor could represent an important prognostic factor in patients affected by colorectal liver metastases (CRLM). However, resection of huge liver metastases from colon cancer has been seldom reported.. A 58-year-old man presented with huge liver metastases from colon cancer. Laboratory tests revealed elevated tumor markers and a wild-type mutation in the K-RAS gene. A computed tomography scan demonstrated unresectable liver masses with a 16.5-cm maximum diameter and intrahepatic duct dilatation due to compression by the liver metastases.. The patient was diagnosed with stage IV descending colon carcinoma with multiple huge hepatic metastases.. He was administered 3 treatment courses, including 9 cycles of combined chemotherapy with mFOLFOX6 plus cetuximab (mFOLFOX6 + Cet), and the liver masses reduced. After a preoperative assessment by a multidisciplinary team when the 9 cycles of systemic chemotherapy had been completed, the patient underwent hepatectomy, followed 4 months later by a laparoscopic colectomy. We used a reverse strategy (liver-first) for the patient.. In this case, liver-first treatment (systemic chemotherapy of mFOLFOX6 + Cet) was an effective treatment for unresectable CRLM. No postoperative complications occurred. The patient continued to receive postoperative chemotherapy (mFOLFOX6 + Cet) at the latest follow-up. During the 17 months of follow-up, tumor recurrence was un-noted.. Treating colorectal cancer patients with huge hepatic metastases is possible, and surgeons should consider various treatment options in the management of these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Topics: Carcinoma, Hepatocellular; China; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Topics: Carcinoma, Hepatocellular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Oxaliplatin; Portal Vein; Sorafenib

Spontaneous cancer regression is a rare event, scarcely reported among gastrointestinal malignancies. Pancreatic adenocarcinoma regression has been documented in five previous cases, none of which included liver metastases, and the mechanism by which this occurs is not known. A 56-year-old woman with history of discoid lupus, homocysteinemia and peripheral vascular disease was diagnosed with stage IV pancreatic ductal adenocarcinoma (PDA) metastatic to the liver. She received palliative chemotherapy with 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) for 6 months, complicated by mucositis, diarrhoea, vomiting and two

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lupus Erythematosus, Discoid; Middle Aged; Neoplasm Metastasis; Neoplasm Regression, Spontaneous; Oxaliplatin; Pancreatic Neoplasms

The patient was a 79-year-old man. He had ascending colon carcinoma and multiple hepatic metastases, and right hemicolectomy( D2)was performed in June 2012(SE, N1, P0, M1[H3], Stage Ⅳ). After surgery, 8 courses of mFOLFOX6 plus panitumumab biweekly, then, 5-FU/l-LV biweekly and panitumumab every 4 weeks were administered because he had wild- type KRAS. Before chemotherapy, his serum CEA level was 122 ng/mL, but the value decreased rapidly to a normal level after 7months. The hepatic metastases also decreased, and the lesion was only slightly observed on CT after 7months. Five years after the surgery, images and his CEA level are both normal, and the effectiveness is maintained. Even for right colon cancer, anti-EGFR antibodies might be effective if RAS is wild-type.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colon, Ascending; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Panitumumab

Pancreatic cancers of the tail have an especially poor prognosis due to their late detection. An earlier diagnosis depends on a better understanding of the clinical course of the disease; however, much of the current literature focuses on pancreatic head adenocarcinomas owing to their higher incidence. Thus, we add our case report to the current literature of pancreatic tail cancers in the hope of aiding earlier detection. We present an interesting case of a patient who initially presented with innocuous abdominal pain and a single episode of vomiting who was subsequently diagnosed with metastatic pancreatic tail cancer.. A 56-year-old Hispanic man with a past medical history of alcohol and cocaine abuse was initially evaluated in our clinic after presenting to the emergency department with sudden onset of abdominal pain and one episode of emesis. On further questioning, he stated that he had been experiencing dull, intermittent left back pain for the past 2-3 years. Laboratory tests were performed, which showed that the patient had new-onset diabetes, and imaging revealed a pancreatic tail mass with metastases to the liver. Biopsy confirmed the diagnosis of stage IV metastatic pancreatic tail adenocarcinoma. During follow-up 1 month later, the patient reported that he had been largely asymptomatic since his hospital admission; however, his left back pain had increased in severity. He was then started on a FOLFIRINOX chemotherapy regimen (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin).. There are many pitfalls in the diagnosis of pancreatic cancer, especially pancreatic tail cancer due to its vague symptoms. Thus, pancreatic cancer of the tail often presents late with a very poor prognosis. Because there is currently no widespread screening for pancreatic cancer, it is often difficult for practitioners to identify pancreatic tail cancers. Current research suggests that there is a strong association between new-onset diabetes after the age of 50 and pancreatic cancer, and tumors detected at the onset of diabetes are favorable to resection. Pancreatic cancer has also been shown to be associated with certain risk factors, such as smoking, high body mass index, chronic pancreatitis, and a family history of pancreatic cancer. Thus, when patients with presentations similar to our patient's with new-onset diabetes after the age of 50, along with vague symptoms such as back or abdominal pain as well as the presence of risk factors, we suggest that it is beneficial for practitioners to maintain a high index of suspicion for pancreatic cancer.

Topics: Abdominal Pain; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Diabetes Mellitus; Diagnosis, Differential; Early Detection of Cancer; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Risk Factors

A case of hyperammonemia induced by chemotherapy, including high-dose fluorouracil(5-FU), for advanced unresectable large intestinal cancer has been reported. This case involved an 81-year-old female who was diagnosed with pT4bcN2M1 (multiple hepatic metastases; stage Ⅳ; KRAS: mutant)after emergency surgery for sigmoid colon cancer and diffuse peritonitis. Post-operation, the 4 courses of mFOLFOX6 plus Bmab therapy was started for advanced unresectable recurrent large intestinal cancer; 48 hours later, she developed consciousness disorder(JCS Ⅲ-300). The disorder promptly disappeared after discontinuation of high-dose 5-FU. Because high-dose 5-FU was inferred to be the main cause of hyperammonemia, XELOX plus Bmab therapy was started as a post-treatment. She did not develop hyperammonemia; therefore, 8 courses were administered. The patient is being followed-up now.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Consciousness Disorders; Female; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Liver Neoplasms; Sigmoid Neoplasms

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Capecitabine; Chemoradiotherapy, Adjuvant; Cholangiocarcinoma; DNA Mutational Analysis; Drug Resistance, Neoplasm; Fluorouracil; Humans; Inguinal Canal; Leucovorin; Liver; Liver Neoplasms; Lymphatic Metastasis; Male; Microsatellite Instability; Neoplasm, Residual; Nivolumab; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Programmed Cell Death 1 Receptor; Treatment Outcome

Hepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection.. The nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured.. Based on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection.. The proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Male; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Nomograms; Organoplatinum Compounds; Oxaloacetates; Prognosis; Retrospective Studies; Survival Rate; Tumor Burden

Cytoreductive surgery including liver resection and hyperthermic intraperitoneal chemotherapy provide survival benefit to selected patients but is associated with relevant morbidity and mortality rates. We aimed to report morbidity and mortality rates and parameters linked to increased morbidity.. Retrospective analysis of 37 patients who underwent liver resection and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy between 2006 and 2016. From a prospectively collected database the morbidity and mortality rates and survival data were analyzed.. The mortality rate was 0% and grade III-IV morbidity was 42%. Re-operation rate was 27%. Patients with complications tended to have a higher peritoneal cancer index (16 vs. 13; P=0.23). The performance of rectal resections was statistically significantly associated with morbidity (P=0.02). Neither performance of other type of resections nor the hyperthermic intraperitoneal chemotherapy compound nor the completeness of cytoreduction score was associated with elevated morbidity. No complications related to liver resections were observed. Furthermore, origin of peritoneal metastases did not impact on occurrence of complications. Median overall survival for colorectal primaries was 22 months (range, 9-60 months) and 30 months (range, 12-58 months) for ovarian cancer.. Simultaneous resection of hepatic and peritoneal metastases seems to provide a survival benefit for selected patients and is associated with acceptable morbidity and mortality rates. Knowledge of patients and operative factors linked to morbidity will help to provide a strict selection process and a safer surgical procedure.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Fluorouracil; Hepatectomy; Humans; Hyperthermia, Induced; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Peritoneal Neoplasms; Retrospective Studies

The aim of this study was to investigate the effects of preoperative chemotherapy on the healthy, metastasis-free part of the liver in colorectal cancer patients with liver metastasis, and the relationship between chemotherapy and postoperative complications.. Our study included 90 cases of colorectal cancer liver metastasis resected after preoperative chemotherapy. The patients were divided into three groups according to the received chemotherapy regimen: 20 cases received mFOLFOX6, 54 cases a combination of mFOLFOX6 with bevacizumab, and 16 cases a combination of mFOLFOX6 and cetuximab or panitumumab.. The mean numbers of sinusoidal injuries for each chemotherapy type were compared. The group treated with the combination of mFOLFOX6 and bevacizumab showed a lower extent of sinusoidal injury relative to other groups; this intergroup difference became increasingly remarkable as the number of chemotherapy cycles increased. Complications of various extents were found in all three groups, but no significant differences were observed between the three groups.. In cases where preoperative chemotherapy was extended over a long period, combined use of bevacizumab was thought to be effective because of stabilization of disturbed liver hemodynamics resulting from sinusoidal injury suppression effects, allowing effective distribution of anti-cancer agents to tumors.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Postoperative Complications; Preoperative Period

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

The available data concerning reduced glutathione (GSH) and glutathione S-transferase (GST) levels in colorectal cancer patients during the treatment process are contradictory and insufficient.. Forty patients with metastatic colorectal cancer receiving FOLFOX4 chemotherapy with or without bevacizumab and 40 healthy volunteers were included in the study. Blood samples were taken before treatment, after 2 months and at the end of treatment in the patient group and once in the healthy volunteer group. The levels of GSH and GST in blood serum were evaluated by enzyme-linked immunosorbent assay (ELISA) according to the manufacturer's instructions.. The serum level of GSH was significantly lower in colorectal cancer patients before treatment than in healthy volunteers (37.84 ± 19.39 μg/mL and 52.78 ± 19.39 μg/mL, respectively; p<0.001). After treatment, the level of GSH increased significantly, while the level of GST decreased significantly. These changes were observed only in the groups of patients with partial or complete response, having metastases only in the liver, receiving FOLFOX4 chemotherapy with bevacizumab, or undergoing resection or radiofrequency ablation of liver metastases.. GSH and GST levels change significantly during the treatment process and these changes depend on the response to treatment, treatment type, and site of metastases. Further analysis of the changes in GSH and GST levels during treatment would allow the assessment of the predictive potential of this molecular marker.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Case-Control Studies; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Glutathione; Glutathione Transferase; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Prospective Studies; Young Adult

Topics: Colorectal Neoplasms; Hepatectomy; Humans; Leucovorin; Liver Neoplasms

The patient was a 76-year-old woman who underwent sigmoidectomy in April 2011 for sigmoid colon cancer with multiple concurrent liver metastases. She was treated postoperatively with mFOLFOX6 plus cetuximab but was diagnosed with the progressive disease at the end of course 14. The patient started receiving FOLFIRI plus cetuximab therapy in May 2012. Later in August 2012, she was examined for respiratory distress on the scheduled date of receiving course 7 and was diagnosed with drug-induced interstitial pneumonia resulting from systemic chemotherapy. The patient was administered oxygen, and her symptoms improved temporarily with steroid half-pulse and endotoxin adsorption therapy, but on inpatient day 10, her respiratory condition deteriorated. She was treated with steroid pulse therapy, but died of respiratory failure on inpatient day 17. The main adverse events associated with FOLFIRI plus cetuximab therapy are gastrointestinal symptoms, hematotoxicity, peripheral nerve damage, and dermatological symptoms. However, reports of respiratory conditions such as interstitial pneumonia are rare. Although the incidence is low, interstitial pneumonia can be severe and fatal and therefore requires close attention.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Sigmoid Neoplasms

To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.. This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.. The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001).. HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.. We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; China; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Retrospective Studies; Sorafenib; Survival Rate; Treatment Outcome; Vitamin B Complex; Young Adult

Tumour lysis syndrome (TLS) is a rare oncological emergency in solid tumours. Because it is associated with bad short-term prognosis, early recognition and treatment are mandatory. This case refers to a middle-aged woman who presented with stage IV colon cancer, with massive hepatic involvement. After three cycles of first-line FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin), she developed acute kidney injury and hyperkalaemia that did not respond to standard measures. High suspicion of TLS prompted further corroborating investigations and early intensive care unit admission. With vigorous hydration and allopurinol, TLS completely resolved and the patient was discharged. Prophylaxis of subsequent TLS recurrence was complicated by biopsy-proven neutrophilic vasculitis secondary to allopurinol. Prevention of TLS with hydration and rasburicase was performed prior to each subsequent cycle of chemotherapy. This case report is intended to highlight risk factors for TLS in solid tumours and focus on treatment and secondary prophylaxis of TLS.

Topics: Adenocarcinoma; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diagnosis, Differential; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Palliative Care; Tomography, X-Ray Computed; Tumor Lysis Syndrome

To investigate the short- and long-term outcomes of liver first approach (LFA) in patients with synchronous colorectal liver metastases (CRLM), evaluating the predictive factors of survival.. Sixty-two out of 301 patients presenting with synchronous CRLM underwent LFA between 2007 and 2016. All patients underwent neoadjuvant chemotherapy. After neoadjuvant treatment patients were re-evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Liver resection was scheduled after 4-6 weeks. Changes in non-tumoral parenchyma and the tumor response according to the Tumor Regression Grade score (TRG) were assessed on surgical specimens. Primary tumor resection was scheduled 4-8 weeks following hepatectomy.. Five patients out of 62 (8.1%) showed "Progressive Disease" at re-evaluation after neoadjuvant chemotherapy, 22 (35.5%) showed "Stable Disease" and 35 (56.5%) "Partial Response"; of these latter, 29 (82%) showed histopathologic downstaging. The 5-year survival (OS) rate was 55%, while the 5-year disease-free survival (DFS) rate was 16%. RECIST criteria, T-stage, N-stage and TRG were independently associated with OS. Bilobar presentation of disease, RECIST criteria, R1 margin and TRG were independently associated with DFS. Patients with response to neoadjuvant chemotherapy had better survival than those with stable or progressive disease (radiological response 5-y OS: 65% vs. 50%; 5-y DFS: 20% vs. 10%; pathological response 5-y OS: 75% vs. 56%; 5-y DFS: 45% vs. 11%).. LFA is an oncologically safe strategy. Selection is a critical point, and the best results in terms of OS and DFS are observed in patients having radiological and pathological response to neoadjuvant chemotherapy.

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Cohort Studies; Colectomy; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Margins of Excision; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Radiotherapy; Response Evaluation Criteria in Solid Tumors; Survival Rate; Treatment Outcome

Radiological evaluation of the efficacy of preoperative chemotherapy for colorectal liver metastasis (CRLM) is the most important tool for determining treatment strategies. The aim of this study was to identify a correlation between morphologic appearance on computed tomography (CT) and histologic findings of CRLM after preoperative chemotherapy.. We examined 47 patients who had undergone a first hepatic resection for CRLM after preoperative chemotherapy and had received contrast-enhanced CT scans. We assessed the morphologic appearance of the overall attenuation based on metastases changing from heterogeneous to mixed and homogenous lesions, the tumor-liver interface, and the peripheral rim enhancement on CT. Histologic parameters included usual necrosis (UN), infarct-like necrosis (ILN), three-zonal change, dangerous halo, mucous lake, shape of ILN, dominant type of necrosis, and presence of viable tumor cells. The relationship between morphologic appearance and histologic findings was evaluated.. CT overall attenuation revealed that UN predominance was more common in the heterogeneous group than in the mixed and homogeneous groups (P = 0.011). The frequency of ILN increased sequentially from ill-defined to variable and sharp at the tumor-liver interface (P = 0.038), and the frequency of UN decreased sequentially from present to partially resolved and completely resolved in the peripheral rim enhancement (P = 0.023). The histologic presence of viable tumor cells was closely associated with the tumor-liver interface (P = 0.0003) and the peripheral rim enhancement (P = 0.004).. CT morphologic appearance of CRLM after preoperative chemotherapy is correlated with histologic findings regarding necrosis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Contrast Media; Female; Fluorouracil; Humans; Iohexol; Iopamidol; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Preoperative Care; Tomography, X-Ray Computed

We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Sigmoid Neoplasms

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Ligation; Liver Neoplasms; Neoplasm Staging; Operating Rooms; Organoplatinum Compounds; Portal Vein; Radiography, Interventional

A 50s man receiving dialysis for chronic kidney disease due to IgA nephropathy underwent laparoscopic reversal via Hartmann 's procedure for rectal cancer and multiple liver metastases, followed by chemotherapy for the liver metastases. Following a single course of mFOLFOX therapy, bevacizumab was administered for 8 courses, resulting in tumor shrinkage and a decrease in tumor marker levels. The initial doses were 60mg/m2 oxaliplatin and 280(bolus injection)and 1,680mg/m2 (continuous infusion)of 5-FU. Subsequently, these doses were adjusted to be administered every 3 weeks. No serious adverse events other than neutropenia(Grade3 ), anorexia(Grade1 ), and hiccups(Grade1)were noted.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Fluorouracil; Glomerulonephritis, IGA; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Renal Dialysis

The prevalence of chemotherapy associated liver injuries (CALI), especially SOS (sinusoidal obstruction syndrome) and NRH (nodular regenerative hyperplasia) might be reduced since the introduction of routine use of biological agents with chemotherapy in colorectal liver metastases (CRLM).. One hundred patients with CRLM having undergone at least one liver segment resection were prospectively included, and chemotherapy data recorded. Specimens were reviewed by a single pathologist and CALI were described. Prevalence of CALI was compared to our previous experience published in 2013. NRH diagnosis was performed on reticulin special stain, by contrast to our previous study. Postoperative outcome was analysed.. Bevacizumab was more frequently administrated in patients of the present study: 53/100 (53%) compared to 20/151 (13%), p < 0.0001. Overall, in the present series, SOS was only observed in 28/100 (28%) patients compared to 116/151 (77%) in 2013 (p < 0.001). When looking specifically to patients receiving Bevacizumab with Folfox, we observed a reduced SOS prevalence compared to Folfox alone (p = 0.008). A higher prevalence of NRH was found in the present study, related to increased detection accuracy, but in patients receiving Bevacizumab in association with Folfox, this prevalence was also reduced compared to Folfox alone (p = 0.03). Both SOS and NRH were associated with severe complications (p = 0.008 and p = 0.005, respectively) and postoperative liver insufficiency (p < 0.001 and p < 0.01, respectively).. The routine use of Bevacizumab in association with Folfox significantly reduced CALI prevalence, in turn linked to severe postoperative complications.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Belgium; Bevacizumab; Biological Products; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Postoperative Complications; Prevalence

Few clinical studies have investigated the association between neutrophil-lymphocyte ratio (NLR) and treatment with cetuximab-based chemotherapy in metastatic colorectal cancer (mCRC). The NLR may reflect immune cells modulating specific cytokine signals in the tumor microenvironment; however, which immune-related genes affect the NLR remain unclear.. In 77 patients with KRAS exon2 wild-type mCRC from prospective trials of first-line chemotherapy with cetuximab, expression levels of 354 immune-related genes were measured in tissue samples obtained from all patients by the HTG EdgeSeq Oncology Biomarker Panel. The association between the NLR and clinical outcomes was evaluated using the Spearman rank correlation coefficient. In addition, 2-sample t tests were performed to investigate which genes among the top 100 genes associated with survival had significantly different expression levels between the NLR-low and NLR-high groups among all measured genes.. NLR data were available for 71 patients. The NLR was associated with progression-free survival and overall survival (r = -0.24; P = .040 and r = -0.29; P = .010, respectively). When stratified by the median value of the NLR, the Kaplan-Meier curve of NLR-low versus NLR-high differed significantly for both progression-free survival (median, 11.8 vs. 9.1 months; P = .036) and overall survival (median, 42.8 vs. 26.7 months; P = .029). The 2-sample t test revealed that the expression levels of the LYZ, TYMP, and CD68 genes differed significantly between the NLR-low and NLR-high groups (t test P-value < .005; false discovery rate P-value < .15).. NLR is significantly associated with survival in patients with mCRC treated with first-line chemotherapy with cetuximab. Genes encoding for activities on macrophages may affect the NLR.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Leucovorin; Liver Neoplasms; Lymphocytes; Male; Middle Aged; Neutrophils; Oxaliplatin; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

A 56-year-old woman was diagnosed with rectal cancer and liver metastases(Stage IV), and underwent low anterior resection and laparoscopic partial hepatectomy. The patient received adjuvant chemotherapy(mFOLFOX6 for 24 weeks), but developed multiple lung metastases 11 months later. Before undergoing a pulmonary resection, the patient presented with acute small bowel obstruction. Abdominal computed tomography showed small bowel stenosis due to a tumor, and we suspected peritoneal metastases from the rectal tumor. We performed partial resection of the small intestine, and histopathological examination revealed a primary small bowel tumor. The patient was discharged to her home without complications, and later underwent pulmonary resections for bilateral lung metastases. We usually suspect that small bowel obstruction is due to peritoneal metastases in patients with advanced colorectal tumors, but must consider the rare possibility of a separate primary small bowel tumor, especially in patients with a solitary lesion. We report a rare primary small bowel tumor after FOLFOX treatment in a patient with Stage IV rectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Intestinal Neoplasms; Intestine, Small; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Neoplasms, Multiple Primary; Organoplatinum Compounds; Rectal Neoplasms

To assess and report the efficacy of and tolerance to bevacizumab-based chemotherapy in treatment outcome of metastatic poorly differentiated neuroendocrine tumors.. From 2007 to 2018, 11 consecutive patients with metastatic poorly differentiated neuroendocrine treated in first- or second-line with bevacizumab-based chemotherapies were included in this monocentric retrospective cohort. Tumor response was evaluated by computed tomographic scans.. Administered treatment included 5-fluorouracil and irinotecan (FOLFIRI) bevacizumab, 5-fluorouracil and oxaliplatin (FOLFOX) bevacizumab and 5-fluorouracil, oxaliplatin and irinotecan (FOLFIRINOX) bevacizumab for four, two and five patients, respectively. Three were treated in first-line and eight in second-line after cisplatin-etoposide regimen. Using Response Evaluation Criteria in Solid Tumors, partial response was observed for seven patients, and stable disease for one patient, giving a response rate of 63.6% (95% confidence interval=35.2-92.1%) and disease control rate of 72.7% (95% confidence interval=46.6-99.0%). All patients had died by the time of analysis, median progression-free survival was 14 months, and median overall survival was 15.3 months. Observed toxicity with such protocols was classical with 10 grade 3-4 toxic events, including three of hematological toxicity, three of infection, and three of digestive toxicity.. Bevacizumab-based chemotherapy gave surprising efficacy and safety in first-or second-line treatment for metastatic poorly differentiated neuroendocrine tumor in this retrospective cohort. Prospective randomized trials of such therapy are warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neuroendocrine Tumors; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate; Treatment Outcome

We report a case of effective treatment comprising mFOLFOX6 plus bevacizumab for neuroendocrine carcinoma of the ascending colon. A 60-year-old woman was admitted for diarrhea and abdominal pain. Colonoscopy showed a Type 2 tumor in the ascending colon. She was diagnosed with neuroendocrine cell carcinoma based on biopsy and immunostaining. CT and MRI showed liver metastasis and lymph node #12a metastasis. Right hemi-colectomy, lymphadenectomy, and partial hepatectomy were performed(T4a, N2, M1b, Stage IV). Neuroendocrine cell carcinoma(small-cell type)was finally diagnosed based on a histological examination because the nuclear fission image was 30(/10HPF)and the Ki-67 index was 42%. Three months after the surgery, multiple lymph node metastases were found using CT and MRI. mFOLFOX6 plus bevacizumab was initiated. After 4 courses of the chemotherapy, the metastases responded completely. A total of 10 courses of chemotherapy were administered. About 2 years and 6 months after the surgery, no recurrence is allowed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Neuroendocrine; Colectomy; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds

In order to reduce the frequency and the severity of oxaliplatin-related sensory-neuropathy and preserve antitumor efficacy, we performed alternating 4 mFOLFOX6 and 4 FOLFIRI cycles, in combination with bevacizumab, in patients with metastatic colorectal cancer. The response rate of alternating mFOLFOX6 and FOLFIRI regimens(FIREFOX)plus bevacizumab was 100%. However, during neoadjuvant chemotherapy for colon cancer, we cannot use bevacizumab due to the concern of adverse events, such as bleeding and perforation. Therefore, we used cetuximab in 8 courses of FIREFOX. As a result, the volumes of the rectum cancers and liver metastases decreased. Thereafter, we used bevacizumab in another 8 courses of FIREFOX. A 77- year-old woman suffered from II type rectum cancer, which was localized 7 cm from the anal verge, with multiple liver metastases. We performed 8 courses of FIREFOX plus cetuximab. After observing a decrease in tumor burden, we performed another 8 courses FIREFOX plus bevacizumab. As a result, CEA and CA19-9 decreased to the normal range, and the size of the rectum cancer and liver metastases decreased. She underwent laparoscopic lower anterior and liver resections in the highvolume center. She presently remains alive with no sighs of recurrence, 18 months after resection.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Rectal Neoplasms; Treatment Outcome

Neoadjuvant chemotherapy of colorectal liver metastases can induce hepatotoxicity in noncancerous liver. The aim of the present study was to describe the chemotherapy-induced major changes in the hepatic parenchyma and their prognostic impact. We undertook a retrospective study of 48 cases of colorectal liver metastases treated with neoadjuvant therapy followed by liver resection. These cases were collected at the Pathology Department of Mongi Slim Hospital over a 2-year period (July 2015-February 2018). Our series consisted of 27 men and 21 women with a sex-ratio (M/F = 1.28). The average age of our patients was 57.68 years old with extremes ranging from 30 to 75 years old. All patients received chemotherapy with FOLFOX. From a total of 48 operative specimens examined, we found 24 cases (50%) of non-systematized steatosis, grade 1 sinusoidal obstruction syndrome (n = 12) and grade 2 sinusoidal obstruction syndrome (n = 12), regenerative nodular hyperplasia (n = 3), portal and/or lobular inflammatory infiltrate (n = 6). In three cases, no abnormalities were reported in the liver parenchyma. Surgical margins were < 1 mm in seven cases and were invaded in four cases. Preoperative chemotherapy is associated with regimen-specific liver injury. The presence of such an injury may have a negative impact on the functional reserve of the liver, thereby increasing the risk of surgical morbidity and mortality.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Prognosis; Retrospective Studies

This is the case report of a patient with right-sided, RAS and BRAF wild-type metastatic colorectal cancer, with borderline/potentially resectable liver-limited disease. Following neoadjuvant treatment with FOLFOX plus bevacizumab and radical resection, an early intra-hepatic disease relapse was observed and deemed as potentially resectable. Therefore, treatment with FOLFIRI plus aflibercept was started: a major partial response and radical re-resection were achieved. Following unresectable disease relapse, second-line treatment with FOLFIRI aflibercept was resumed and achieved again a partial response that is still ongoing after more than 9 months. This case report highlights how treatment goals (potentially curative resection vs palliation), molecular status and primary tumor location influence treatment strategies in order to maximize patients' outcomes.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

This is a "best practice" case report of a non-uncommon clinical scenario, referring to an early liver relapse, judged as technically resectable, following adjuvant oxaliplatin-based treatment for left-sided, RAS and BRAF wild-type colon cancer. The choice of aflibercept vs cetuximab/panitumumab relies on the need to counteract an aggressive disease, without loosing the chance of radical surgery, nor loosing treatment options in the third-line setting. Treatment decisions are evidence-based on efficacy data of neoadjuvant anti-angiogenic treatment, as well as on the detrimental effect derived from the addition of cetuximab to perioperative chemotherapy.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oxaliplatin; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

A 35-year-old man was diagnosed with initially unresectable synchronous liver metastases from sigmoid colon cancer. We started FOLFOX plus panitumumab therapy. After 3courses of chemotherapy, the liver metastases became resectable. Sigmoidectomy, extended left lobectomy, and partial hepatectomy were performed. On the final histopathological analysis, all hepatic lesions were fibrotic without viable cancer cells. Nineteen months after the surgery, CT revealed isolated residual liver recurrence in segment 5. After partial hepatectomy, the patient is alive without recurrence. We report a case of pathological complete response with FOLFOX plus panitumumab therapy for initially unresectable colorectal liver metastases with icterus.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Jaundice; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Panitumumab

A 78-year-old man was admitted with diarrhea. Colonoscopy and computed tomography(CT)revealed rectal cancer with multiple liver metastases. Low anterior resection was performed for local control. After the operation, 5 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered as first-line systemic therapy, but CT showed progressive disease with liver metastases. After the first-line systemic therapy, 2 courses of FOLFIRI plus bevacizumab chemotherapy were performed as second-line systemic therapy, but CT also revealed progressive disease with liver metastases. We retrospectively performed comprehensive genomic sequencing with a 415-gene panel and found that the patient had a hypermutation subtype. Interestingly, the panel also revealed that he had mismatch-repair(MMR)deficiency with MSH2 mutation, which is reported as a possible cause of resistance to 5-fluorouracil in colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Mutation; MutS Homolog 2 Protein; Organoplatinum Compounds; Rectal Neoplasms; Retrospective Studies

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dermatitis, Exfoliative; Drug Combinations; Drug Eruptions; Fluorouracil; Hand-Foot Syndrome; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxonic Acid; Pyridines; Tegafur

Hepatic arterial infusion chemotherapy (HAIC) is a treatment used for liver metastases (LM) of colorectal cancer (CRC). Because of its technical conditions, it has been used in only a few experienced centers in France. Our aim was to evaluate its feasibility, efficacy and tolerance in 4 centers.. Clinical, biological, and radiological data of patients treated with HAIC for unresectable LM from CRC in 4 institutions from October 2011 to January 2016 were retrospectively analyzed.. Sixty-one patients with unresectable LM from CRC were included. Patients had previously received systemic chemotherapy in 95% of patients and 82.8% had previous oxaliplatin treatment. Oxaliplatin was administered using an intra-arterial route combined with intravenous (I.V.) Five-fluorouracil (5-FU) with leucovorin alone in 43.3% of patients, or combined with other I.V. chemotherapies or monoclonal antibodies in 56.7% of patients. Grade 3 to 4 clinical toxicities were reported in 16% of patients, including 9.8% of neurotoxicity, and Grade 3 to 4 biological toxicities were reported in 24.6% of patients including 22.2% with neutropenia. Catheter-related complications were observed in 31.1%. Tumor response rate in first- and second-line was 26.5% and third- and fourth-line was 11%. Median overall survival (OS) in first- and second-line was 13.5 months and third- and fourth-line was 8.3 months (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.39-1.12; P = .1729). Median progression-free survival (PFS) in first- and second-line was 9 months and third- and fourth-line were 6 months (HR, 0.53; 95% CI, 0.18-0.659; P = .0037). A secondary R0 resection was possible in 10 cases (16.4%) allowing a 2-year survival of 80%.. These data confirm that in centers that recently developed HAIC using oxaliplatin, this treatment is feasible and has acceptable tolerance. The results, in terms of hepatic PFS, PFS, OS, and the rate of secondary resections of LM, are in the range of published data, and they confirm the interest of HAIC in patients in progression after multiple I.V.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; France; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate

Surgical resection of all sites of disease, in combination with effective systemic chemotherapy, offers the only potential chance for cure for patients with stage IV colorectal cancer (CRC). Coordinated multistage resection using a minimally invasive approach may provide optimal oncologic outcome while potentially offering the benefit of decreased morbidity.. A 66-year-old women presented with transverse colon cancer and synchronous metastasis (CRLM) in segment IV involving the middle hepatic vein and main left portal pedicle, as well as the left adrenal gland. Due to favorable response to neoadjuvant chemotherapy (FOLFOX/bevacizumab), the patient was considered for resection but developed some obstructive symptoms from the primary tumor, necessitating re-coordination of treatment sequencing from the 'liver-first' approach.. The first procedure combined laparoscopic subtotal colectomy (extracorporeal anastomosis) with left adrenalectomy. After restaging, CRLM was removed separately 2 months later via laparoscopic left hepatectomy extending beyond the middle hepatic vein. Successful completion of the two procedures depended on optimal patient/port positioning for the combined colon/adrenal surgery and the second-stage liver resection. Postoperative lengths of stay were 4 and 3 days, respectively, and were without complication. Adjuvant FOLFOX was initiated 21 days following liver surgery, and the patient has been disease-free for 36 months.. This case illustrates the feasibility of the total laparoscopic approach to multivisceral resection for synchronous stage IV CRC in the context of a preplanned, staged multidisciplinary strategy. This approach may offer optimal cancer management, including early return to systemic therapy, shortened time intervals between stages, and minimal postoperative morbidity.1

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Neoplasm Staging; Organoplatinum Compounds

The aim of the study was to evaluate the efficacy of anti-angiogenic therapy with dynamic contrast-enhanced ultrasound (DCE-US) in colorectal cancer (CRC) patients with liver metastasis.A total of 50 CRC patients with liver metastasis who received bevacizumab (BEV)-based chemotherapy (BEV + FOLFOX6 protocol) were recruited into the present study. Before the study (d0), and 3, 7, 14, and 42 days (d3, d7, d14, and d42) after chemotherapy, DCE-US was performed, and tumor perfusion was evaluated quantitatively by retention time (RT), peak enhancement (PE), and wash-in area under the curve (WiAUC) on the basis of a contrast-uptake curve determined with original linear data.Routine ultrasonography was used to evaluate metastatic foci in the liver at baseline. A metastatic focus was selected for dynamic monitoring with ultrasound. The metastatic foci were 1.5 to 8 cm (median: 2.5 cm). The results of hemodynamics monitored at different time points, including RT, PE, and WiAUC, showed that RT at baseline was significantly different between groups (P < .001; Responder group: 10.54 seconds; nonresponder group: 15.33 seconds). The2 groups had opposite changes in RT (continuous increase in the responder group and transient reduction in the nonresponder). The RT of metastatic foci was normalized to that of adjacent normal liver as standard RT-quotient, a similar trend was observed, and no marked difference was noted in the standard RT-quotient between the 2 groups. The median progression-free survival was significantly higher in the increased-RT group (10.8 months) than the decreased-RT group (2.5 months) (P = .002). There were no significant differences in peak intensity and WiAUC between the 2 groups.DCE-US can be used to quantitatively evaluate the hemodynamics of liver metastasis in CRC patients who received bevacizumab-based chemotherapy.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Bevacizumab; Colorectal Neoplasms; Contrast Media; Disease-Free Survival; Female; Fluorouracil; Hemodynamics; Humans; Leucovorin; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Organoplatinum Compounds; Tomography, X-Ray Computed; Treatment Outcome; Ultrasonography

The patient was a 66-year-old woman with a history of right breast cancer 20 years prior. Her chief complaint was hematochezia, and she was diagnosed as having rectal cancer. She underwent laparoscopic high anterior resection. We made a diagnosis of moderately differentiated adenocarcinoma, type 2, 25×20 mm, pMP, pN0, Stage I, KRAS being wild-type. Multiple liver metastases were detected 6 months after the surgery. Tumor contacted with grison. The tumor was not completely resected as evidenced by the small liver remnant volume. Conversion therapy was administered, and the patient received 6 courses of FOLFIRI plus cetuximab therapy. Alopecia and grade 1 eruption were observed as adverse effects of the chemotherapy. The tumor size was reduced, and we resected the tumor by performing right lobectomy and partial hepatectomy. At 1 year 3 months after surgery, no recurrence was observed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colectomy; Combined Modality Therapy; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Rectal Neoplasms; Treatment Outcome

Analysis of K- and N-RAS mutations is mandatory before planning treatment of metastatic colorectal cancer, because only RAS wild-type (WT) patients can benefit from treatment with anti-EGFR monoclonal antibodies (cetuximab and panitumumab).. Here we report the case of a 69-year-old male patient affected by metastatic sigmoid cancer. He underwent left hemicolectomy, and histology diagnosed a well-differentiated, pT4, node-positive adenocarcinoma; KRAS analysis performed with direct sequencing identified a mutation in exon 2 of the KRAS gene (GGT->GTT). After first-line chemotherapy with FOLFOX6 plus bevacizumab, the patient underwent surgical resection of residual liver metastases. Histology showed metastatic deposits from colic adenocarcinoma with extensive coagulative necrosis. Mutational analysis of the KRAS gene was also performed on liver metastases by pyrosequencing assay, and no mutation was identified. Due to the discordant results (GGT->GTT exon 2 KRAS mutation in the primary tumor, and KRAS-WT in the liver metastases), mutational analysis on liver metastasis was repeated using next-generation sequencing and enriching the sample in tumor cells by manual microdissection; the same type of mutation of the primary tumor (GGT->GTT exon 2 KRAS gene) was confirmed.. Accurate tissue sampling and adequately sensitive assays are essential to correctly identify colorectal cancer patients who can be treated with an anti-EGFR monoclonal antibody.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Exons; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Mutation; Neoplasm Metastasis; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); ras Proteins

To test the effects of enhanced intracellular oxygen contents on the metastatic potential of colon cancer.. Colorectal cancer is the commonest gastrointestinal carcinoma. Distant metastases occur in half of patients and are responsible for most cancer-related deaths. Tumor hypoxia is central to the pathogenesis of metastases. Myo-Inositoltrispyrophosphate (ITPP), a nontoxic, antihypoxic compound, has recently shown significant benefits in experimental cancer, particularly when combined with standard chemotherapy. Whether ITPP protects from distant metastases in primary colon cancer is unknown.. ITPP alone or combined with FOLFOX was tested in a mouse model with cecal implantation of green fluorescent protein-labeled syngeneic colorectal cancer cells. Tumor development was monitored through longitudinal magnetic resonance imaging-based morphometric analysis and survival. Established serum markers of tumor spread were measured serially and circulating tumor cells were detected via fluorescence measurements.. ITPP significantly reduced the occurrence of metastases as well as other indicators of tumor aggressiveness. Less circulating tumor cells along with reduction in malignant serum markers (osteopontin, Cxcl12) were noted. The ITPP benefits also affected the primary cancer site. Importantly, animals treated with ITPP had a significant survival benefit compared with respective controls, while a combination of FOLFOX with ITPP conferred the maximum benefits, including dramatic improvements in survival (mean 86 vs 188 d).. Restoring oxygen in metastatic colon cancer through ITPP inhibits tumor spread and markedly improves animal survival; an effect that is enhanced through the application of subsequent chemotherapy. These promising novel findings call for a clinical trial on ITPP in patients with colorectal cancer, which is under way.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colonic Neoplasms; Enzyme-Linked Immunosorbent Assay; Fluorouracil; Immunohistochemistry; Inositol Phosphates; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neoplastic Cells, Circulating; Organoplatinum Compounds; Real-Time Polymerase Chain Reaction

Colonic inflammation seen in inflammatory bowel disease (IBD) predisposes to the development of colorectal adenocarcinoma. In contrast, colorectal neuroendocrine carcinomas (NECs) have rarely been reported in the setting of IBD, and no definitive relationship between these tumours and IBD has been established. Dysplasia from chronic inflammation leading to neuroendocrine cell differentiation may be responsible for NEC development, though this finding has not been seen consistently. We present a case of large-cell neuroendocrine carcinoma of the sigmoid colon in a 65-year-old woman with long-standing ulcerative colitis. Although she underwent regular endoscopic follow-ups and was receiving the tumour necrosis factor alpha inhibitor infliximab, her tumour was large and aggressive, with metastases to the liver discovered at time of diagnosis. This case highlights the aggressive nature and poor prognosis of NECs and stresses the need to identify patients at high risk of developing NECs and develop improved surveillance guidelines for detecting them.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Carcinoma, Neuroendocrine; Colitis, Ulcerative; Fatal Outcome; Female; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Precancerous Conditions; Risk Factors; Sigmoid Neoplasms; Tomography, X-Ray Computed

To evaluate accuracy and reliability of three-dimensional ultrasound (3D US) for response evaluation of hepatic metastasis from colorectal cancer (CRC) using a personalized 3D-printed tumor model.. Twenty patients with liver metastasis from CRC who underwent baseline and after chemotherapy CT, were retrospectively included. Personalized 3D-printed tumor models using CT were fabricated. Two radiologists measured volume of each 3D printing model using 3D US. With CT as a reference, we compared difference between CT and US tumor volume. The response evaluation was based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria.. 3D US tumor volume showed no significant difference from CT volume (7.18 ± 5.44 mL, 8.31 ± 6.32 mL vs 7.42 ± 5.76 mL in CT, p>0.05). 3D US provided a high correlation coefficient with CT (r = 0.953, r = 0.97) as well as a high inter-observer intraclass correlation (0.978; 0.958-0.988). Regarding response, 3D US was in agreement with CT in 17 and 18 out of 20 patients for observer 1 and 2 with excellent agreement (κ = 0.961).. 3D US tumor volume using a personalized 3D-printed model is an accurate and reliable method for the response evaluation in comparison with CT tumor volume.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Imaging, Three-Dimensional; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome; Tumor Burden; Ultrasonography

Optimal margin size when resecting colorectal liver metastases (CRLM) remains unclear, particularly in the setting of perioperative chemotherapy. We evaluated the prognostic significance of margin size in patients who received neoadjuvant FOLFOX and/or FOLFIRI prior to resection of CRLM.. Clinicopathologic factors were collected for patients who underwent curative liver resections for CRLM between 4/2004-1/2016 and received neoadjuvant oxaliplatin and/or irinotecan and 5-FU (FOLFOX, FOLFIRI). Margins were categorized as < 1, ≥ 1-< 5, ≥ 5-< 10, or ≥ 10 mm and evaluated for association with overall survival (OS) and disease-free survival (DFS) by Cox multiple regression analysis. Margin status was classified as positive (< 1 mm) or negative (≥ 1 mm) and similarly evaluated.. Of 227 patients, the median age was 58 years and most had synchronous (80%) lesions. The majority had colon cancers (75%). Margin sizes were 13% < 1 mm, 27% ≥ 1-< 5 mm, 23% ≥ 5-< 10 mm, 36% ≥ 10 mm. Most (63%) received chemotherapy post-liver resection. Five-year OS and DFS were 54% (95% CI 46-62%) and 22% (95% CI 16-28%), respectively. Positive margins significantly increased the risk of death without post-liver resection chemotherapy (HR = 3.32, p = 0.0077), but not with post-liver resection chemotherapy (HR = 1.00, p = 0.99). Negative margin sizes of ≥ 1-< 5, ≥ 5-< 10, and ≥ 10 mm were not significant predictors of OS (p > 0.05).. Patients undergoing liver resection for CRLM should receive post-resection chemotherapy if negative margins (≥ 1 mm) cannot be achieved. For patients receiving FOLFOX and/or FOLFIRI chemotherapy, wider margins did not improve OS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Margins of Excision; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Prognosis; Treatment Outcome

In patients with malignancy who receive aflibercept based chemotherapy, gastrointestinal perforation is among the reported adverse events with a prevalence of 1.9%. This complication may lead to mortality up to 10.8%. We here report a case of small bowel perforation that occurred fifteen days after the first cycle of aflibercept in a 58-year old female who had metachronous colorectal liver metastases. Emergency laparotomy was performed and revealed a small bowel perforation without any anastomotic dehiscence. Surgery was followed by uneventful outcome. The use of aflibercept in patients with malignancy may be associated with very early gastrointestinal perforation and this should be known by oncologist and surgeons.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colectomy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Intestinal Perforation; Intestine, Small; Leucovorin; Liver Neoplasms; Middle Aged; Pancreaticoduodenectomy; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

Case report presents the successful treatment of unresectable liver metastasis in a patient with colon cancer. A 44-year-old male underwent right hemicolectomy followed by capecitabine for a moderately differentiated adenocarcinoma of the colon. 2 years later, a liver metastatic lesion was detected and had increased in size despite chemotherapy with capecitabine plus oxaliplatin (XELOX). Curative liver resection was conducted after conversion of unresectable tumor to resectable by transarterial chemoembolization followed by chemotherapy - irinotecan with fluorouracil and folinic acid (FOLFIRI). No recurrence was observed during 22-month follow-up after hepatectomy.

Topics: Adenocarcinoma; Adult; Biomarkers; Camptothecin; Capecitabine; Chemoembolization, Therapeutic; Colectomy; Colonic Neoplasms; Fluorouracil; Hepatectomy; Humans; Inflammation Mediators; Irinotecan; Leucovorin; Liver Neoplasms; Male; Microspheres; Organoplatinum Compounds; Oxaliplatin; Remission Induction

Topics: Humans; Leucovorin; Liver Neoplasms

We experienced 2 cases in which ramucirumab plus FOLFIRI as second-line treatment was beneficial. Case 1 was a 67-yearold man, underwent panitumumab plus mFOLFOX6 as first-line treatment for unresectable rectal cancer with ureteral invasion and multiple liver metastases, but the disease became worse at 9.3 months. We changed to ramucirumab plus FOLFIRI as second-line treatment. After 2 courses, a grade 3 febrile neutropenia was observed, but treatment was beneficial and continued administration for 9 months or more. Case 2 was a 73-year-old man who underwent panitumumab plus mFOLFOX6 as first-line treatment after cytoreductive surgery of the primary lesion for sigmoid colon cancer with intestinal obstruction and liver metastasis, but the disease became worse at 4.7 months. Upon entering ramucirumab plus FOLFIRI therapy, the metastatic lesions shrinked remarkably. Adverse events of grade 3 or higher were not observed and finally continued administration for 7.9 months. It was suggested that ramucirumab plus FOLFIRI combination therapy for metastatic colorectal cancer could be an effective as second-line treatment.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Disease Progression; Drug Resistance, Neoplasm; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Ramucirumab; Rectal Neoplasms; Sigmoid Neoplasms

FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria.. Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics.. A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%).. Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.

Topics: Activities of Daily Living; Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Camptothecin; Eligibility Determination; Female; Fluorouracil; Humans; Hyperbilirubinemia; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Peritoneal Neoplasms; Renal Insufficiency; Retrospective Studies

Metastatic colorectal cancer (mCRC) combined with hyperbilirubinemia is typically considered a contraindication to irinotecan-based therapy, a proven first-line treatment of mCRC. Herein, we present 6 consecutive patients with mCRC combined with hyperbilirubinemia who underwent UGT1A1 genotyping before receiving FOLFIRI plus bevacizumab. Dose escalation of irinotecan was performed according to the results of UGT1A1 genotyping in all patients. Improvement in the serum total bilirubin level to a normal range was noted in all 6 patients. Disease control was 100%. The median progression-free survival was 7.5 months and the median overall survival was 8.5 months. FOLFIRI plus bevacizumab as a first-line chemotherapy may achieve effective disease control and be safe in patients with mCRC and hyperbilirubinemia based on UGT1A1 genotyping. More prospective clinical studies are necessary to evaluate the clinical benefits and safety of this treatment approach.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bilirubin; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prospective Studies; Survival Rate

Secondary resection is a chance of cure for a subgroup of metastatic colorectal cancer (mCRC) patients with unresectable liver-limited disease. Medical treatment has a dual goal: to induce tumour shrinkage and to prevent disease relapse. The aims of the present analysis were to assess the efficacy of FOLFOXIRI plus bevacizumab in this setting, and to investigate whether this regimen could revert the poor prognosis of high-risk patients defined by clinical and molecular factors. We performed a pooled analysis of patients with unresectable and liver-limited mCRC, treated with first-line FOLFOXIRI plus bevacizumab in three prospective clinical trials by Gruppo Oncologico del Nord Ovest. 205 (37.9%) patients with liver-limited disease were selected, out of 541 treated patients. Liver metastases were synchronous, ≥4 and bilobar in 90%, 61%, and 79% of cases, respectively. The largest diameter was >5 cm in 42% of cases, and ≥6 segments were involved in 25%. Seventy-four patients (36.1%) underwent R0 or R1 resection of metastases. R2 resections were performed in 17 cases (8.3%). Having <6 involved segments (p < 0.001) and achieving RECIST response (p = 0.019) were associated with higher chances of resection. R0/R1 resected patients had significantly longer median progression-free survival (PFS) (18.1 versus 10.7 months, HR: 0.48 [0.35-0.66], p < 0.001) and overall survival (OS) (44.3 versus 24.4 months, HR: 0.32 [0.22-0.48], p < 0.001) compared with other patients, both in the univariate and multivariate analyses (PFS p = 0.025; OS p < 0.001). The 5-year PFS and OS rate in R0 resected patients were 12% and 43%, respectively. Neither negative baseline characteristics nor high clinical risk scores or RAS/BRAF mutations were associated with poor post-resection outcomes. In conclusion, FOLFOXIRI plus bevacizumab demonstrates efficacy in the conversion setting with considerable long-term outcome results independent of clinical and molecular prognostic factors (NCT00719797, NCT01163396 and NCT02271464).

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Prospective Studies; Young Adult

HER2 gene amplifications and activating mutations in the HER2 receptor tyrosine kinase are present in 4% of metastatic colorectal cancers (mCRCs). HER2-targeted therapy is not standard of care, although preclinical and clinical data suggest that patients with HER2 amplifications and/or HER2-activating mutations may benefit from HER2-directed therapy. HER2 amplifications and activating mutations have also been implicated in resistance to anti-epidermal growth factor receptor-based therapy. This report describes a patient with KRAS, NRAS, and BRAF wild-type mCRC who experienced disease progression on first-line treatment with FOLFIRI and cetuximab after only 5 months, and subsequently experienced progression on second-line treatment with capecitabine and oxaliplatin plus bevacizumab after 2 months with significant functional decline. Next-generation sequencing of the primary tumor identified HER2 amplification, and we were able to obtain trastuzumab-DM1 for off-label use. The patient had symptomatic clinical benefit from trastuzumab-DM1 and had radiographic disease control for 7 months. On progression, therapy was changed to trastuzumab and pertuzumab, but the patient's disease progressed 3 months later. Treatment with the trastuzumab-DM1 resulted in a sustained response that was longer than his prior responses in the first and second lines of treatment, with a dramatic improvement in the patient's functional status. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-amplifed CRC with trastuzumab-DM1. Clinical trials targeting patients with HER2-mutated and -amplified metastatic colon cancer are currently underway. Molecular insights from investigating HER2 activation and the impact of HER2-directed therapies in a wide variety of solid tumors will create the needed evidence base to more broadly inform patient care.

Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Chemoradiotherapy, Adjuvant; Colorectal Neoplasms; Disease Progression; DNA Mutational Analysis; Drug Resistance, Neoplasm; Fluorouracil; Gene Amplification; High-Throughput Nucleotide Sequencing; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Male; Maytansine; Middle Aged; Molecular Targeted Therapy; Off-Label Use; Palliative Care; Proto-Oncogene Proteins c-myc; Receptor, ErbB-2; Tomography, X-Ray Computed; Trastuzumab; Tumor Suppressor Protein p53; Ultrasonography

Preoperative neoadjuvant therapy for colorectal liver metastases (CRLM) is increasing in use and can lead to chemotherapy-induced damage to sinusoidal integrity, namely sinusoidal obstruction syndrome (SOS). SOS has been associated with an increased need for intraoperative blood transfusions, increased length of hospitalization post-surgery, decreased tumor response, and a shorter overall survival after resection due to liver insufficiency. It is critical for clinicians and pathologists to be aware of this type of liver injury, and for pathologists to include the status of the background, non-neoplastic liver parenchyma in their pathology reports. In this study, expression of CD34 by sinusoidal endothelial cells (SECs), increased expression of smooth muscle actin (SMA) by hepatic stellate cells (HSCs), and aberrant expression of glutamine synthetase (GS) by noncentrizonal hepatocytes were semiquantitatively evaluated in liver resection or biopsy specimens from patients with CRLM to determine their diagnostic value for assessing chemotherapy-induced sinusoidal injury (CSI).. The expression of each marker was compared among 22 patients with CRLM with histologically evident SOS (SOS+) and 8 patients with CRLM who had not undergone chemotherapy. Each case was given a histologic grade using the sinusoidal obstruction syndrome index score (SOS-I) to assess the likelihood of SOS. Cases were also given an immunohistochemical grade using the total CSI score calculated as the sum of CD34, SMA, and GS scores.. Abnormal staining patterns for CD34 and SMA were significantly more frequent and extensive in SOS+ cases than in the controls (81.8% vs. 25%, P < 0.01; 72.7% vs. 25%, P = 0.03). Aberrant GS expression in midzonal and periportal hepatocytes was only observed in SOS+ cases (31.8% vs. 0%), but this difference did not reach statistical significance. The CSI score was significantly higher in the SOS+ cases when compared to controls (P < 0.01), and was associated with a higher SOS histologic grade (P = 0.02).. The CSI score, calculated using an immunohistochemical panel consisting of CD34, SMA, and GS, may serve as an objective marker of chemotherapy-induced sinusoidal injury and could help diagnose this peculiar form of liver injury.

Topics: Actins; Adult; Aged; Aged, 80 and over; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Glutamate-Ammonia Ligase; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin-eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; CD3 Complex; CD56 Antigen; CD8 Antigens; Cetuximab; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Inflammation; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaloacetates

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

The management of disappearing colorectal liver metastases in the postadjuvant chemotherapy setting is challenging. We describe a novel technique that facilitates laparoscopic resection of disappearing metastatic liver lesions with great precision. Details of this new technique are described in 2 patients with colorectal cancer synchronously metastatic to the liver. Both patients had small indistinct intraparenchymal liver lesions after adjuvant chemotherapy. A video displays the steps of the procedure. Both patients presented with colorectal cancer with synchronous liver metastasis. They received FOLFOX regimen after resection of their primary. They both responded to adjuvant chemotherapy. On repeat posttreatment imaging, the liver lesions became smaller and indistinct. With laparoscopic ultrasound, subtle parenchymal heterogeneities were identified. The lesions were initially ablated with a wide radiofrequency ablation zone. Then, without removing the needle, the prongs were deployed to the borders of the parenchymal heterogeneity. Using an ultrasonic vessel sealer, the lesions were resected. Final pathology identified 1 viable focus of cancer in each patient. Both patients were discharged home uneventfully on their second postoperative day. There were no complications. We have described a novel technique that could facilitate precise resection of intraparenchymal small indistinct or disappearing liver metastases of colorectal origin. This option should be kept within the armamentarium of the laparoscopic liver surgeon managing patients with malignant liver tumors.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Catheter Ablation; Cecal Neoplasms; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Ultrasonography, Interventional

To evaluate safety, efficacy of drug-eluting beads with irinotecan (DEBIRI) on local response and survival of patients affected by colorectal liver metastases (CRLM) progressing during or after second line was evaluated. Sixty-two patients, with colorectal liver metastases, not suitable for surgery or thermal ablation treatments, progressing during or within 6 month from the end of second-line chemotherapy, were treated with DEBIRI chemoembolization between February 2009 and July 2014. CRLM were histologically confirmed. Exclusion criteria were considered. The DEBIRI technique consists in intrahepatic embolization of metastases with non-absorbable beads (75-150 μm and 100-300 μm) preloaded with irinotecan, carried near tumour using a selective catheterization of the right or of the left hepatic artery. To control pain associated with treatment, we use a specific schedule. Efficacy of treatment, defined as lack of disease progression and reduction in size of metastasis according to RECIST 1.1 criteria, was evaluated after two treatments with contrast-enhanced computed tomography (CT) at 4 months. If necessary, more treatments are repeated. A total of 191 procedures were performed. No intra-/peri-procedural death occurred. Pain and post-embolization syndrome were generally controlled by medications. Overall, the efficacy of treatment, evaluated in terms of stability and remission of the disease, was 37.1%. In our experience, DEBIRI technique results as a safe and effective procedure, with good intra- and peri-procedural tolerability.

Topics: Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoembolization, Therapeutic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies

Cetuximab combined with chemotherapy is one of the first-line treatments of metastatic colorectal cancer. Although disease progression inevitably occurs, rechallenge and maintenance therapies using cetuximab-based regimens may be beneficial, particularly for patients with wild-type (WT) KRAS.. A 47-year-old female patient who underwent right hemicolectomy presented with an ulcerative adenocarcinoma (grade 2) revealed by histopathological analysis. The patient received three cycles of adjuvant chemotherapy, but disease recurred 15 months later. Cetuximab and a FOLFOX-4 regimen were administered, followed by surgery and adjuvant chemotherapy that was administered for approximately one year. Three years after completing adjuvant therapy, her serum carcinoembryonic antigen levels rapidly increased, and enhanced computed tomography showed widespread metastases. Rechallenge with cetuximab and the FOLFIRI regimen was then initiated, and after 12 cycles, lesions in the lung and liver shrank significantly, and serum CEA levels dramatically declined. Maintenance therapy with cetuximab and capecitabine was then administered for 10 months until the metastatic lesions in the lung and liver enlarged.. Rechallenge and maintenance therapy with cetuximab-based chemotherapy were relatively effective for managing a female patient with WT KRAS. Optimization of this strategy requires further in-depth investigations of more patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Cetuximab; Colorectal Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Maintenance Chemotherapy; Middle Aged; Organoplatinum Compounds; Treatment Outcome

Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy.. We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed.. We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months).. Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Survival Rate; Transcriptome; Treatment Outcome

To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients. : Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors.. There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively).. Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients.

Topics: Adult; Aged; Ampulla of Vater; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Common Bile Duct Neoplasms; Disease-Free Survival; Dose Fractionation, Radiation; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Pancreaticoduodenectomy; Retrospective Studies; Survival Rate; Tegafur; Treatment Failure

Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients.. Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells.. Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, -42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly.. Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; DNA; Female; Fluorouracil; Genotyping Techniques; Glutathione S-Transferase pi; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Leukocytes, Mononuclear; Liver Neoplasms; Male; Matrix Metalloproteinase 9; Middle Aged; Nitric Oxide Synthase Type III; Organoplatinum Compounds; Platelet Count; Polymorphism, Single Nucleotide; Retrospective Studies; Sequence Analysis, DNA; Splenomegaly; Thrombocytopenia; Tomography, X-Ray Computed; Treatment Outcome; Vascular Endothelial Growth Factor A

A 75-year-old woman presented with right upper quadrant abdominal pain and anorexia. She was diagnosed with descending colon cancer with lymph node and liver metastases. She was treated with preoperative chemotherapy consisting of levofolinate/5-fluorouracil/oxaliplatin (mFOLFOX6). After the completion of 7 courses of chemotherapy, the tumor shrunk remarkably. A left-sided colectomy with radical lymphadenectomy and an extensive posterior segment resection of the liver were performed. Postoperatively, pathological analysis revealed no cancerous cells in the primary tumor, lymph node metastases, or liver metastases. She is currently receiving mFOLFOX6 therapy as adjuvant chemotherapy. In a patient with advanced colon cancer, a complete response of not only the primary tumor but also the lymph node and liver metastases to preoperative chemotherapy is rare. This case demonstrates that mFOLFOX6 therapy is safe and effective as preoperative chemotherapy for advanced colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colon, Descending; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Organoplatinum Compounds; Treatment Outcome

Patients who undergo liver resection for metastatic colorectal cancer (mCRC) have reported 5-year survivals ranging from 25% to 50%. The current study updated long-term survival for patients with resected liver metastases treated with adjuvant hepatic arterial infusion (HAI) and systemic (SYS) chemotherapy.. Updated survival and recurrence free survival for patients treated on four consecutive adjuvant protocols with HAI and SYS from 1991 to 2009. Patients were divided into two groups: those treated on protocols before 2003 and after 2003. Median follow-up for all patients was 11 years.. All 287 patients enrolled in four prospective protocols after liver resection are included. Patients treated before 2003 had a median follow-up of 15 years, 5 and 10-year survivals of 56% [95%CI: 49-64%] and 40% [95%CI: 32-47%], respectively, and median survival of 71 months. Patients treated after 2003 had a median follow-up of 9 years, 5 and 10-year survivals of 78% [95%CI: 70-84%] and 61% [95%CI: 51-70%], respectively, and median survival has not been reached.. Survival is improving for patients with mCRC who undergo liver resection. These data support the durability of long-term survival in patients who undergo resection followed by adjuvant HAI and SYS therapy. J. Surg. Oncol. 2016;113:477-484. © 2016 Wiley Periodicals, Inc.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dexamethasone; Disease-Free Survival; Female; Floxuridine; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Survival Rate; Young Adult

We evaluated the impacts of a series of novel histopathological factors on clinical-surgical outcomes and survival of patients who underwent surgery for colorectal cancer liver metastasis, with and without neoadjuvant chemotherapy.. A prospective database including 150 consecutive patients who underwent 183 hepatic resections for metastatic colorectal cancer was evaluated. Among them, 74 (49.3%) received neoadjuvant chemotherapy before surgery. The histopathological factors studied were: a) microsatellitosis, b) type and pattern of tumour growth, c) nuclear grade and the number of mitoses/mm(2), d) perilesional pseudocapsule, e) intratumoural fibrosis, f) lesion cellularity, g) hypoxic-angiogenic perilesional growth pattern, and h) the tumour normal interface.. Three or more metastatic lesions, R1 resection margins, and <50% tumour necrosis were prognostic factors for a worse OS, but only the former was confirmed to be an independent prognostic factor in the multivariate analysis. Furthermore, tumour fibrosis <40% and cellularity >10% were predictive of a worse neoadjuvant therapy response, but these findings were not confirmed in the multivariate analysis. Finally, tumour necrosis <50%, cellularity >10%, and TNI >0.5 mm were prognostic factors for a worse DFS and AS in the univariate but not in the multivariate analysis.. Several factors seem to influence the outcomes of surgery for colorectal cancer liver metastasis, especially the number of the lesions, the margins of resection, the percentage of necrosis and fibrosis, as well as the cellularity and the TNI.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Databases, Factual; Deoxycytidine; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Metastasectomy; Mitotic Index; Multivariate Analysis; Necrosis; Neoadjuvant Therapy; Neoplasm Grading; Organoplatinum Compounds; Oxaloacetates; Panitumumab; Prognosis; Retrospective Studies; Tumor Burden

A 61-year-old man was admitted to our hospital because of a complaint of blood in stool. He was diagnosed with advanced colon and gastric cancers. Computed tomography (CT) revealed a sigmoid tumor with invasion to the bladder, a metastatic tumor in the lateral segmental branch of the left hepatic lobe, and ascites. He was diagnosed with initially unresectable double cancer. Ileostomy was performed immediately, and he was treated with modified (m) FOLFOX6 regimen (oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin). After 6 courses of the mFOLFOX6 regimen, CT revealed that the primary lesion of the sigmoid colon and liver metastasis had reduced in size, and the ascites had disappeared. Gastroscopy revealed that the gastric cancer had disappeared. Biopsy results were negative. Accordingly, his gastric cancer was diagnosed as treatment effect Grade 3. After 8 courses of mFOLFOX6 therapy, sigmoidectomy, partial resection of the bladder, and partial resection of the liver were performed. Gastric cancer was not resected in accordance with his will. Although 40 months has passed after the radical resection, neither the sigmoid colon cancer nor the gastric cancer recurred.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Sigmoid Neoplasms; Stomach Neoplasms

The benefit of preoperative chemotherapy for patients with liver metastases from colorectal cancer remains unclear. We evaluated the efficacy of preoperative chemotherapy with bevacizumab in such patients, and attempted to identify clinical predictors of recurrence.. Between February 2007 and December 2013, a total of 65 liver resections for colorectal metastases were performed at our Institution; 47 patients underwent preoperative chemotherapy, which consisted of modified FOLFOX6 (mFOLFOX6) in 42 cases. The last clinical follow-up was in December 2014. Demographic and clinicopathological factors were reviewed for each patient, and potential predictors of recurrence after liver resection were evaluated. Disease-free survival (DFS) and overall survival (OS) were compared with respect to clinicopathological factors.. The 3- and 5-year OS rates were 73.9% and 62.5%, respectively. The time at which metastases appeared, and the extent of metastasis according to the Japanese classification did not significantly affect OS or DFS. However, mFOLFOX6 plus bevacizumab significantly improved DFS compared to mFOLFOX6 alone. Patients did not experience worsening of hepatic dysfunction during preoperative chemotherapy, and tolerated surgical stress well.. Preoperative chemotherapy with bevacizumab appears to be an effective treatment modality for liver metastases from colorectal cancer, and results in prolonged DFS.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Preoperative Period; Survival Analysis

The response rate of patients with unresectable liver-limited metastases of colorectal cancer can be improved by converting inoperable disease to operable disease. However, the benefits of conversion chemotherapy for survival are still controversial.Patients considered to have technically inoperable disease by a multidisciplinary team were retrospectively analyzed. Patients were stratified based on the treatment they received, into the chemotherapy only (G1), chemotherapy plus bevacizumab (G2), or chemotherapy plus cetuximab (G3) groups. The primary endpoint was the resection rate. The secondary endpoint was the overall survival (OS), according to both the treatment received and liver surgery status.In total, 104 patients were included: 30 in the G1, 39 in the G2, and 35 in the G3 groups. All G3 patients had the wild-type KRAS exon 2. The surgical resection rates for patients in the G1, G2, and G3 groups were 43.3% (13/30), 30.7% (12/39), and 51.4% (18/35), respectively. Disease-free survival did not show significant differences among the 3 groups. The median OS was 35.2 months in the G1, 28.8 months in the G2, and 42.1 months in the G3 (P = 0.25) groups. The OS was significantly higher in patients who underwent surgical resection than those who did not. The median OS was 28.4 months in patients who did not undergo resection, whereas it had not been reached after a median follow-up period of 37.5 months for patients who underwent surgical resection (events: 21/43).Our data confirmed that the conversion of initially inoperable disease to operable disease conferred a survival benefit, even in patients who relapsed after surgery. The addition of cetuximab to chemotherapy improved the objective response and resection rates, conferring a potential survival benefit even in patients whose diseases were not converted to operable disease, compared to chemotherapy alone or in combination with bevacizumab.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Proto-Oncogene Proteins p21(ras); Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Survival Rate

We report a case of advanced colon cancer that was effectively treated with mFOLFOX6 plus panitumumab combination chemotherapy. The patient was a 54-year-old man who had type 2 colon cancer of the rectum. An abdominal CT scan demonstrated rectal cancer with bulky lymph node metastasis and 1 hepatic node (rectal cancer SI [bladder retroperitoneum], N2M0H1P0, cStage IV). He was treated with mFOLFOX6 plus panitumumab as neoadjuvant chemotherapy. After 4 courses of chemotherapy, CT revealed that the primary lesion and regional metastatic lymph nodes had reduced in size (rectal cancer A, N1H1P0M0, cStage IV). Anterior rectal resection with D3 nodal dissection and left lateral segmentectomy of the liver was performed. The histological diagnosis was tubular adenocarcinoma (tub2-1), int, INF a, pMP, ly0, v0, pDM0, pPM0, R0. He was treated with 4 courses of mFOLFOX6 after surgery. The patient has been in good health without a recurrence for 2 years and 5 months after surgery. This case suggests that induction chemotherapy with mFOLFOX6 plus panitumumab is a potentially effective regimen for advanced colon cancer.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Panitumumab; Rectal Neoplasms

Nestin expression has been reported to be associated with the prognosis of many solid tumors including human hepatocellular carcinoma (HCC). The present study aimed to identify the role, if any, of Nestin in the chemotherapeutic treatment of HCC.. We determined Nestin expression in nine HCC cell lines and 220 tissue samples of advanced HCC patients (retrospectively registered) treated with FOLFOX regimens. We examined the correlations between Nestin expression and clinicopatholgical variables and HCC prognosis. Also, we used in vitro and in vivo methods to determine the effects of Nestin expression on HCC cell invasion, migration and chemosensitivity.. Nestin expression was significantly increased in HCC tissues and drug-resistant cell lines, and the presence of high levels of Nestin was associated with poor survival. We also showed that drug-resistance occurred in HCC cells with epithelial-mesenchymal transition (EMT), which in turn enhanced invasion ability. Nestin depletion reversed drug-resistance in the Bel-7402/5-FU and Bel-7402/ADM cell lines. Nestin knockdown enhanced chemotherapeutic efficacy in nude mice. Moreover, Nestin up-regulation in Bel-7402 was associated with the activation of Wnt/β-catenin signaling.. Our findings suggest that Nestin inhibitors may be useful for the chemotherapy of HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Movement; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Leucovorin; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Nestin; Organoplatinum Compounds; Prognosis; Up-Regulation; Wnt Signaling Pathway

Chemotherapy-induced liver injury after potent chemotherapy is a considerable problem in patients undergoing liver resection. The aim of this study was to assess the relationship between the fractal dimension (FD) of Tc-99m diethylenetriaminepentaacetic acid (DTPA) galactosyl human serum albumin (GSA) and pathologic change of liver parenchyma in liver cancer patients who have undergone chemotherapy.. We examined 34 patients (10 female and 24 male; mean age, 68.5 years) who underwent hepatectomy. Hepatic injury was defined as steatosis more than 30 %, grade 2-3 sinusoidal dilation, and/or steatohepatitis Kleiner score ≥4. Fractal analysis was applied to all images of Tc-99m DTPA GSA using a plug-in tool on ImageJ software (NIH, Bethesda, MD). A differential box-counting method was applied, and FD was calculated as a heterogeneity parameter. Correlations between FD and clinicopathological variables were examined.. FD values of patients with steatosis and steatohepatitis were significantly higher than those without (P > .001 and P > .001, respectively). There was no difference between the FD values of patients with and without sinusoidal dilatation (P = .357). Multivariate logistic regression showed FD as the only significant predictor for steatosis (P = .005; OR 36.5; 95 % CI 3.0-446.3) and steatohepatitis (P = .012; OR, 29.1; 95 % CI 2.1-400.1).. FD of Tc-99m DTPA GSA was the significant predictor for fatty liver disease in patients who underwent chemotherapy. This new modality is able to differentiate steatohepatitis from steatosis; therefore, it may be useful for predicting chemotherapy-induced pathologic liver injury.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemical and Drug Induced Liver Injury; Fatty Liver; Female; Fluorouracil; Fractals; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Predictive Value of Tests; Radionuclide Imaging; Radiopharmaceuticals; Risk Factors; ROC Curve; Technetium Tc 99m Aggregated Albumin; Technetium Tc 99m Pentetate

This study aimed to investigate the pharmaco-economic implications of FOLFOX4 or sorafenib for advanced hepatocellular carcinoma in China.. To conduct the analysis, we performed a Markov model to simulate the process of advanced HCC treated with sorafenib or FOLFOX4. Clinical data were obtained from the ORIENTAL trial and the EACH trial. Incremental cost-effectiveness ratio was regarded as the primary outcome in the analysis. One-way sensitivity analysis as well as probabilistic sensitivity analysis was performed to explore the impact of essential variables on the results of the analysis.. Treatment with sorafenib provided an effectiveness gain of 0.3935 quality-adjusted life year at an average cost of $18,748.00, whereas chemotherapy of FOLFOX4 brought 0.3808 quality-adjusted life year at a cost of $6876.02. The incremental cost-effectiveness ratio of FOLFOX4 versus sorafenib was $934,801.57/QALY. In a probabilistic sensitivity analysis based on a Monte Carlo simulation of 1000 items, the probabilities of FOLFOX4 and sorafenib being cost-effective were 100% and 0% using a willingness-to-pay threshold of $20,301.00 per quality-adjusted life year.. FOLFOX4 chemotherapy is likely to be a cost-effective option compared with sorafenib in the treatment of advanced hepatocellular carcinoma in China.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; China; Cohort Studies; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Monte Carlo Method; Niacinamide; Organoplatinum Compounds; Phenylurea Compounds; Quality-Adjusted Life Years; Sorafenib

Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.. We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.. Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. ©2016 AACR.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Colonic Neoplasms; Disease Models, Animal; Fluorouracil; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inositol Phosphates; Leucovorin; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organoplatinum Compounds; Oxygen; Tumor Burden; Vascular Endothelial Growth Factor A

Hepatic artery infusion (HAI) chemotherapy is an effective regional therapy for unresectable colorectal liver metastases (U-CRLM).1. A 62-year-old male presented with a symptomatic ascending colon cancer and multiple bilobar unresectable liver metastases. He underwent laparoscopic right colectomy followed by six cycles of FOLFOXIRI and bevacizumab with stable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and also underwent robotic HAI pump placement.. The patient was placed supine on a split-leg table, and four robotic and two laparoscopic assistant ports were placed as shown. Use of the robot allowed for precise dissection of the common hepatic artery (CHA) and gastroduodenal artery (GDA), as well as a portal lymphadenectomy. A standard cholecystectomy was performed and the GDA was dissected for a distance of 2-3 cm from its takeoff from the CHA. The robotic scissors were used to create a precise transverse GDA arteriotomy, and the HAI pump catheter tip was advanced to the CHA/GDA junction and secured with two silk ties. Finally, a methylene blue dye injection test was performed to ensure uniform distribution within the liver. Operative time was 147 min, estimated blood loss was 20 ml, and the postoperative course was uneventful. The first dose of HAI with floxuridine was administered on postoperative day 4 (day of discharge) and systemic chemotherapy was administered 2 weeks later.. The robotic platform allows for minimally invasive HAI pump placement. Fig. 1 Port placement for robotic-assisted hepatic artery infusion pump placement using the DaVinci Si platform. Illustration depicts a 12 mm periumbilical port for the robotic camera (upper green port), three 8 mm (purple) robotic working ports (the left MCL, right MCL, and right AAL for robotic arms R1, R2, and R3, respectively), and 12 mm (lower green) and 5 mm (red) laparoscopic assistant ports in the right and left lower quadrants, respectively. The pump pocket is created in the left lower quadrant just below the 5 mm (red) port site.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Robotic Surgical Procedures; Vascular Surgical Procedures

A 68-year-old man was diagnosed with rectal cancer on colonoscopy and liver metastasis of rectal cancer on abdominal computed tomography(CT). He underwent resection of the primary lesion, and the final diagnosis was A, N1, H1, P0, M0, fStage IV. After resection of the primary lesion, he received chemotherapy with mFOLFOX6 plus cetuximab. After 6 courses of the treatment, CT revealed partial response of the liver metastasis. Then, he underwent resection of the liver metastasis. The pathological finding revealed that the resected specimen had no cancer cells. After resection of the liver metastasis, he received 6 courses of chemotherapy with the same regimen, and relapse-free survival continues until the time of this writing.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms

To determine whether baseline CT texture analysis of hepatic metastasis from colorectal cancer (CRC) is predictive of therapeutic response after cytotoxic chemotherapy.. 235 patients with liver metastasis from CRC who underwent CT and cytotoxic chemotherapy using FOLFOX and FOLFIRI were divided into derivation cohort (n=145) and validation cohort (n=90). The CT texture of the hepatic metastasis was quantified using baseline CT. We analyzed the independent predictor for the response from derivation cohort and validated it using validation cohort. We also compared texture features between included four CT scanners.. 89 responding and 146 non-responding patients were evaluated. In the derivation cohort, lower skewness (OR, 6.739) in 2D, higher mean attenuation (OR, 2.587), and narrower standard deviation (SD) (OR, 3.163) in 3D were independently associated with response to chemotherapy. However, only lower skewness (P=0.213) on 2D and narrower SD on 3D analysis (P=0.097) did not show a significant difference on either CT scanner. When applied to the validation set, the lower skewness on 2D (AUC=0.797) and narrower SD on 3D (AUC=0.785) showed good performance.. CT texture analysis is useful for prediction of therapeutic response after cytotoxic chemotherapy in patients with liver metastasis from colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome

The impact of perioperative chemotherapy on patients with multiple colorectal liver metastases (CRLM) remains unclear. We attempted to examine whether the introduction of modern chemotherapies has improved the prognosis of patients that undergo liver resection for ≥4 CRLM.. Between January 1990 and December 2013, 194 patients underwent liver resection for CRLM at our institution. The outcomes of the patients with ≥4 and 1-3 CRLM were compared before and after 2005, when modern chemotherapies were introduced to Japan.. There were 50 and 144 patients with ≥4 (Group 1) and 1-3 (Group 2) CRLM, respectively. The overall survival (OS) rate of Group 1 was significantly worse than that of Group 2 (P = 0.0007). The OS rate of Group 2 was significantly better after 2005 than before 2004 (P = 0.039), while no such differences were observed in Group 1. Multivariate analysis identified three prognostic factors in Group 1: a serum carcinoembryonic antigen level of ≥20 ng/ml (P = 0.018), a serum cancer antigen 19-9 level of ≥100 U/ml (P = 0.018), and a primary colorectal cancer N factor of ≥N2 (P = 0.023).. The prognosis of patients with ≥4 CRLM that undergo liver resection has not improved despite the development of modern chemotherapies. J. Surg. Oncol. 2016;114:959-965. © 2016 Wiley Periodicals, Inc.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome; Tumor Burden

Recent evidence indicates that inflammatory parameters could be useful to predict metastasis from colorectal cancer. However, their roles in predicting chemotherapy response and prognosis in patients with synchronous colorectal liver metastasis (CLM) are unknown.. The clinical data and baseline laboratory parameters of 55 patients with synchronous CLM were retrospectively reviewed. All patients underwent palliative resection of the primary tumor and oxaliplatin-based chemotherapy. Two indices of systemic inflammation were reviewed-neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)-preoperatively and before the second cycle of chemotherapy. Associations between prognostic variables and tumor response, progression, and survival were investigated.. NLR < 4 and PLR < 150 were correlated with better disease control (p = 0.024 and 0.026, respectively). In univariate analysis, elevated NLR and PLR were significant prognostic factors for poor overall survival (OS) and progression-free survival (PFS). In multivariate analysis, PLR (p = 0.027), age (p = 0.018), resection of liver metastases (p = 0.017), and lactate dehydrogenase level (p = 0.011) were independent predictors of PFS, while resection of liver metastases was the only independent predictor of OS (p = 0.002). In addition, when patients were divided into groups according to changes in NLR and/or PLR, reduced NLR and PLR were associated with improved disease control (p = 0.038 and 0.025, respectively). Normalization of NLR also was associated with improved PFS.. NLR and PLR are potentially useful clinical biomarkers to predict chemotherapy response in patients with synchronous CLM. PLR also may be useful to predict PFS in these patients.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Blood Platelets; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphocyte Count; Lymphocytes; Male; Middle Aged; Neutrophils; Organoplatinum Compounds; Oxaloacetates; Platelet Count; Prognosis; Retrospective Studies; Treatment Outcome

There are diverse protocols to manage patients with recurrent disease after primary cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. We describe a case of metachronous liver metastasis after CRS and HIPEC for colorectal cancer, successfully treated with a selective metastectomy and partial graft of the inferior vena cava. A 35-year-old female presented with a large tumour in the cecum and consequent colonic stenosis. After an emergency right colectomy, the patient received adjuvant chemotherapy. One year later she was diagnosed with peritoneal carcinomatosis, and it was decided to carry out a CRS/HIPEC. After 2 years of total remission, an isolated metachronous liver metastasis was detected by magnetic resonance imaging surveillance. The patient underwent a third procedure including a caudate lobe and partial inferior vena cava resection with a prosthetic graft interposition, achieving an R0 situation. The postoperative course was uneventful and the patient was discharged on postoperative day 17 after the liver resection. At 18-mo follow-up after the liver resection the patient remained free of recurrence. In selected patients, the option of re-operation due to recurrent disease should be discussed. Even liver resection of a metachronous metastasis and an extended vascular resection are acceptable after CRS/HIPEC and can be considered as a potential treatment option to remove all macroscopic lesions.

Topics: Adenocarcinoma; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cecal Neoplasms; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Cytoreduction Surgical Procedures; Female; Fluorouracil; Hepatectomy; Humans; Hyperthermia, Induced; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Metastasectomy; Organoplatinum Compounds; Peritoneal Neoplasms; Vena Cava, Inferior

We report 2 cases of metastatic rectal cancer patients who received chemotherapy with FOLFOXIRI plus bevacizumab(Bev). Case 1: A 54-year-old woman diagnosed with advanced rectal cancer with synchronous liver metastasis underwent a laparoscopic low anterior resection. After the operation, she received FOLFOXIRI plus Bev treatment, and experienced Grade 4 adverse events, including dyspnea and ventricular fibrillation(Vf). After chemotherapy, no other metastasis was detected except a liver metastasis, and partial resection of the liver was performed. Histopathological evaluation revealed that the effect of the chemotherapy was Grade 1a. After liver resection, FOLFOXIRI plus Bev was administered, and a recurrence of the rectal cancer was not detected. Case 2: A 44-year-old woman was diagnosed with advanced rectal cancer with synchronous liver metastasis, distant lymph nodes metastasis, and vaginal invasion. First a colostomy was performed and FOLFOXIRI plus Bev treatment was administered. Grade 3 adverse events, including tremor, neuralgia, and anemia occurred, and chemotherapy was stopped for 3 months. Her adverse events were not under control when progression of the disease was detected, and her treatment was changed to another chemotherapy regimen.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Treatment Outcome

A 75-year-old man was diagnosed with sigmoid colon cancer with multiple liver metastases at our hospital in May 2010. He underwent mFOLFOX6 and panitumumab chemotherapy for 6 months. He then underwent sigmoidectomy, lymphadenectomy D3, partial resection of 2 parts of S6, and cholecystectomy in January 2011. However, he underwent partial resection of the liver an additional 4 times in the 5 years followingthe primary operation. Despite multiple liver metastases, he is alive 5 years after the primary operation, havingsurvived 5 hepatectomies for multiple resectable liver metastases.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Panitumumab; Sigmoid Neoplasms; Treatment Outcome

A 63-year-old man underwent low anterior resection for rectal cancer.A synchronous liver metastasis located in segment 8 was 12 cm in diameter and unresectable due to its proximity to the inferior vena cava(IVC).The postoperative pathological findings revealed a T3(SS), N0, M1(liver)Stage IV tumor, and wild type K-RAS was expressed.We chose FOLFIRI plus cetuximab(Cmab)for first-line chemotherapy.After 6 courses, we changed the molecular target drug from Cmab to bevacizumab( Bmab)because the liver metastasis remained unresectable.The patient had long-term stable disease(SD)for approximately 30 months with the FOLFIRI-based regimen.We then changed the regimen to mFOLFOX6 plus Bmab for second-line, Cmab for third-line, and trifluridine/tipiracil hydrochloride for fourth-line chemotherapy to treat progressive disease(PD).After treatment with these chemotherapies, the patient wished to continue treatment.We restarted FOLFIRI plus Bmab for fifth-line chemotherapy as his general condition was still good.Consequently, his tumor markers levels decreased with stabilization of the disease on CT scans, and he continued therapy for 6 months while maintaining a good quality of life.This case suggested that rechallenge with anti-cancer agents could be effective and improve the prognosis of colorectal cancer patients after using all key drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Rectal Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

Whether hepatic arterial infusion (HAI) of oxaliplatin influences the rates of complete pathologic response (CPR) and severe oxaliplatin-related lesions (SOxL) in patients with colorectal liver metastases (CRLM) is unknown. This study aimed to compare the incidence of CPR and SOxL between systemic (intravenous, IV) and HAI administration.. All patients with initially unresectable CRLM who had undergone hepatic resection in two expert centers between 2004 and 2010 after at least 6 cycles of oxaliplatin-based chemotherapy administered either via HAI (n = 18) or IV (n = 50) were included. The presence of CPR and SOxL were evaluated by two pathologists. A 1:2 case match using a propensity score was used.. A CPR was observed significantly more often after HAI (33 vs. 10 %, P = 0.03). However, SOxL had occurred more frequently in patients in the HAI group versus the IV group, 66 and 20 %, respectively (P < 0.001). On a well-balanced cohort, HAI was associated with higher chance of CPR (odds ratio 9.33, 95 % confidence interval 1.59-54.7) but also higher risk of SOxL (odds ratio 13.7, 95 % confidence interval 3.08-61.3). A CPR markedly enhanced overall survival (OS) and disease-free survival (median OS of 114 vs. 42 months, P = 0.02; median disease-free survival of 51 vs. 12 months, P = 0.002). Patients with SOxL did not experience different outcome (median OS of 42 vs. 50 months, respectively; P = 0.92) CONCLUSIONS: HAI of oxaliplatin increases the likelihood of a CPR at the cost of a higher incidence of SOxL in patients with initially unresectable CRLM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

The aim of the present study was to evaluate a single center experience with hepatic arterial infusion (HAI) in patients with hepatocellular carcinoma.. A retrospective analysis of 20 patients treated for hepatocellular carcinoma between 1994 and 2007.. Most patients were treated with an HAI of doxorubicin and cisplatin combined with 5-fluorouracil and folinic acid. The response was not evaluable in the majority of patients, predominantly because of associated surgical procedure or because only one cycle of HAI was administered. The median progression-free survival was 7.7 months. The median survival of all patients was 12.2 months (5-year survival 5%). Serious adverse events were observed in 5 patients, and one patient died of liver failure in association with the administration of HAI.. The data show the limited efficacy of HAI in patients with hepatocellular carcinoma.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Hepatocellular; Cisplatin; Czech Republic; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Immunosuppressive Agents; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pregnancy; Retrospective Studies; Survival Rate; Treatment Outcome; Vitamin B Complex

Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Pseudo-Obstruction; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Parenteral Nutrition; Peripheral Nervous System Diseases; Treatment Outcome

In this case report we detail the treatment of a patient with pancreatic ductal adenocarcinoma and a solitary liver metastasis who received nine cycles of FOLFIRINOX therapy with favourable response. The patient subsequently underwent synchronous distal pancreatectomy and hepatectomy with an R0 resection followed by three further cycles of FOLFIRINOX. At the last follow-up, 2 years from operation and 28 months from the diagnosis of metastatic pancreatic adenocarcinoma the patient remains disease free.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

Our aim was to analyze the potential role of chemokine receptors CXCR2 and CXCR4 signalling pathways in liver metastatic colorectal cancer (CRC) relapse. CXCR2, CXCR4, and their chemokine ligands were evaluated in liver metastases of colorectal cancer in order to study their correlation with overall and disease-free survival of patients having received, or not received, a neoadjuvant chemotherapy regimen. Quantitative RT-PCR and CXCR2 immunohistochemical staining were carried out using CRC liver metastasis samples. Expression levels of CXCR2, CXCR4, and their ligands were statistically analyzed according to treatment with neoadjuvant chemotherapy and patients' outcome. CXCR2 and CXCL7 overexpression are correlated to shorter overall and disease-free survival. By multivariate analysis, CXCR2 and CXCL7 expressions are independent factors of overall and disease-free survival. Neoadjuvant chemotherapy increases significantly the expression of CXCR2: treated group 1.89 (0.02-50.92) vs 0.55 (0.07-3.22), P = 0.016. CXCL7 was overexpressed close to significance, 0.40 (0.00-7.85) vs 0.15 (0.01-7.88), P = 0.12. We show the involvement of CXCL7/CXCR2 signalling pathways as a predictive factor of poor outcome in metastatic CRC. 5-Fluorouracil-based chemotherapy regimens increase the expression of these genes in liver metastasis, providing one explanation for aggressiveness of relapsed drug-resistant tumors. Selective blockage of CXCR2/CXCL7 signalling pathways could provide new potential therapeutic opportunities.

Topics: Antineoplastic Combined Chemotherapy Protocols; beta-Thromboglobulin; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Receptors, CXCR4; Receptors, Interleukin-8B; Signal Transduction

This retrospective analysis investigated the effectiveness of combination therapy with bevacizumab and chemotherapy in the first-line treatment of patients with KRAS wild-type metastatic colorectal cancer.. Patients with KRAS wild-type metastatic colorectal cancer in the CORECT registry who initiated treatment with bevacizumab between 2008 and 2012 were enrolled. Overall survival and progression-free survival were the main effectiveness end points.. A total of 981 patients were enrolled. Median progression-free survival was 11.3 months (95% CI: 10.7-11.8) and median overall survival was 28.4 months (95% CI: 26.2-30.6). The most common adverse events were thromboembolic disease (4%) and hypertension (3.5%).. This retrospective analysis shows the effectiveness of bevacizumab with chemotherapy in patients with KRAS wild-type metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Young Adult

A 40-year-old woman visited her primary care physician because she had pain in the upper right part of the abdomen. She was diagnosed with descending colon cancer with multiple liver metastases, and was referred to our department. After a laparoscopic abdominal colectomy for removal of the original lesion, chemotherapy was initiated with a modified combination of folinic acid, 5-fluorouracil, and oxaliplatin (mFOLFOX6) + panitumumab. After 12 courses of treatment with the mFOL FOX6 + panitumumab combination, followed by 13 courses of the simplified biweekly 5-fluorouracil and Leucovorin (sLV5FU2) + panitumumab combination, her liver tumors had regressed to about 90% of their original size. A laparoscopic partial hepatectomy was successfully performed. Histopathological examination indicated a Grade 2 regression of the tumor in response to chemotherapy. This report highlights the effectiveness of "conversion therapy" after chemotherapy with the mFOLFOX6+panitumumab combination, especially in those patients with multiple liver metastases from colorectal cancer.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Colectomy; Colon, Descending; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Panitumumab

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Metastasis; Organoplatinum Compounds

A 72-year-old woman with a sigmoid colon cancer and a synchronous colorectal liver metastasis (CRLM), which involved the right hepatic vein (RHV) and the inferior vena cava (IVC), was referred to our hospital. The metastatic lesion was diagnosed as initially unresectable because of its invasion into the confluence of the RHV and IVC. After she had undergone laparoscopic sigmoidectomy for the original tumor, she consequently had 3 courses of modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus cetuximab. Computed tomography revealed a partial response, and the confluence of the RHV and IVC got free from cancer invasion. After 3 additional courses of mFOLFOX6 plus cetuximab, preoperative percutaneous transhepatic portal vein embolization (PTPE) was performed to secure the future remnant liver volume. Finally, a right hemihepatectomy was performed. The postoperative course was uneventful. The patient was discharged from the hospital on postoperative day 13. She had neither local recurrence nor distant metastasis 18 mo after the last surgical intervention. This multidisciplinary strategy, consisting of conversion chemotherapy using FOLFOX plus cetuximab and PTPE, could contribute in facilitating curative hepatic resection for initially unresectable CRLM.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cetuximab; Chemotherapy, Adjuvant; Cholecystectomy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds; Oxaliplatin; Tomography, X-Ray Computed; Treatment Outcome

We present the case of a 43-year-old-man with wild-type KRAS and BRAF colorectal adenocarcinoma that was metastatic to the liver and lung. The patient initially received neoadjuvant chemotherapy with FOLFOX and bevacizumab, followed by surgical resection of the primary tumor and hepatic metastases. His disease recurred shortly after surgery and he was treated with FOLFIRI plus the anti-EGFR antibody cetuximab. After this regimen failed to arrest his disease progression, treatment with FOLFIRI in combination with another anti-EGFR antibody, panitumumab was started. While on this therapy, the patient's lung nodules remained largely stable but metastatic lesions within the liver continued to progress. Our case highlights the differences between panitumumab and cetuximab, and contemplates the possible explanations for this patient's apparently heterogeneous disease progression within the liver despite stabilization of multiple pulmonary nodules.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Panitumumab

The high objective response rate to cetuximab along with chemotherapy in patients with colorectal liver metastases makes it an effective downsizing protocol to facilitate surgery in those with initially unresectable disease. Adoption of this strategy has been variable in the UK. A retrospective observational study was conducted in 7 UK specialist liver surgical centres to describe the liver resection rate following a downsizing protocol of cetuximab and chemotherapy and to evaluate the quality and efficiency of processes by which the treatment was provided.. Data were collected in 2012 by reviewing medical records of patients with colorectal metastases confined to the liver, defined as unresectable without downsizing therapy at first review by a specialist Multi Disciplinary Team (MDT).. Sixty patients were included; 29 (48%) underwent liver resection following cetuximab and chemotherapy. Of the 29, 17 (59% or 28% of all patients) achieved R0 resection and 7 (24% or 12% of all patients) R1 resection. All treated patients were KRAS wild-type.. In specialist liver surgical centres, where patients are evaluated for liver resection, optimal management by MDT using KRAS testing, cetuximab and chemotherapy results in a 28% R0 resection rate in patients with initially unresectable colorectal cancer liver metastases.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm, Residual; Organoplatinum Compounds; Outcome and Process Assessment, Health Care; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Survival Rate; Tumor Burden; United Kingdom

In recent decades, the management of rectal cancer has been significantly improved by optimizing the surgical treatment with the total mesorectal excision and the development of neoadjuvant radiotherapy with or without chemotherapy. In this study, we investigated the impact of changes in practice over a period of 15 years in an expert centre.. A monocentric study was conducted retrospectively on cT3-resectable T4 patients who received chemoradiotherapy for a locally advanced rectal adenocarcinoma between 1993 and 2008. We studied sphincter preservation, pathological complete response (ypT0), survival, and toxicities by different concomitant chemotherapy and treatment period.. Among the 179 patients who had a chemoradiotherapy, 56.4% were received concomitant 5-fluoro-uracil-leucovorin, 28.5% with concomitant capecitabine, and 15.1% with concomitant oxaliplatin and capecitabine. The average dose of radiotherapy was 45 Gy (25×1.8 Gy). Five-year disease-free survival was 74.3% and overall survival 68.8%. The rate of local recurrence and distant metastases were 6.1 and 23.6%. In multivariate analysis, concomitant chemotherapy oxaliplatin and capecitabine improved the pathological complete response rate (ypT0; capecitabine: 6%, 5-fluoro-uracil-leucovorin: 10.3%, capecitabine-oxaliplatin: 22.2%), but not significantly (P=0.12) and with more toxicities, and treatment interruptions. Sphincter preservation rate was not improved significantly during the study period (1993-2004 vs. 2005-2008), but disease-free survival improved from 72.2% up to 87.5% (P=0.03).. Our results are consistent with those published in the literature. Concomitant chemotherapy with 5-fluoro-uracil or capecitabine remains the standard scheme. Upfront chemotherapy, before chemoradiotherapy, should be investigated with regard to the predominance of metastasis.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Anal Canal; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Retrospective Studies; Treatment Outcome

This case report describes a patient whose persistent hiccups significantly improved with the use of vinegar.. A patient with an adenocarcinoma of the colon and hepatic metastases developed hiccups the day following chemotherapy with FOL-FOX (folinic acid (leucovorin), 5-fluorouracil, oxaliplatin). Hiccups continued for seven days with no improvement from a number of commonly used pharmacological agents (chlorpromazine, metoclopramide, haloperidol, and baclofen). Relief was finally obtained after sipping vinegar. CASE MANAGEMENT AND OUTCOME: Hiccups occurred several times during the following chemotherapy cycles but the patient completed the treatment using vinegar when they recurred without stopping any drugs. Hiccups stopped or decreased in intensity or in rate per minute after sipping vinegar.. Hypotheses have been developed for the molecular and physiological mechanisms underlying sour compounds' effectiveness in relieving hiccups. Further studies should explore the potential role of vinegar in relieving hiccups in advanced heavily treated cancer patients.

Topics: Acetic Acid; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Hiccup; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

Repeating a prior chemotherapy (rechallenge therapy) is an option for selected patients with metastatic colorectal cancer, but there is very little evidence in the literature for this approach. Thus, we reviewed our registry to evaluate prognostic factors and survival of patients who received irinotecan and oxaliplatin- based regimens as rechallenge third and fourth-line therapy.. Patients who received irinotecan-based or oxaliplatin-base regimen as first-line had been rechallenged with third-line or fourth-line therapy. These patients were selected from the database of Turkish mCRC registry archives between October 2006 and June 2013 and evaluated retrospectively for factors effecting progression free survival (PFS) and overall survival (OS) by the Kaplan-Meir and Cox-regression methods.. Thirty-nine patients were enrolled. The median duration of follow-up was 36 months (14-68 months). Thirty-one patients (76%) died during follow-up. In terms of rechallenge treatments, 29 patients had received third-line and 10 patients had received fourth-line. Response rate (RR) was found to be 12.9%, with stable disease in 19 (48.7%) patients. The median PFS was 6 months (95%CI=4.64-7.35 months) and the median OS was 11 months (95%CI=8.31-13.7 months). The factors effecting survival (PFS and OS) were only being PFS after first-line chemotherapy≥12 months (p=0.007, 95% CI=1.75-35.22 and p=0.004, 95%CI=1.44-7.11), both in univariate and multivariate analyses.. This study indicates that rechallenge treatment could be a good option as a third or later line therapy in patients who had ≥12 months PFS on receiving first line therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Prognosis; Retreatment; Retrospective Studies; Survival Rate; Turkey

Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis and over-expression of VEGF has been detected in hepatocellular carcinoma (HCC). The aim of the present study was to clarify the usefulness of VEGF for monitoring the response to intra-arterial chemotherapy in patients with HCC.. Seventy-three patients with liver cirrhosis (LC) and advanced HCC (aHCC) received hepatic arterial infusion chemotherapy (HAIC: leucovorin (LV) at 12 mg/h, cisplatin (CDDP) at 10 mg/h and 5-fluorouracil (5-FU) at 250 mg/22 h) via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneous drug delivery system.. i) Serum VEGF levels were higher in patients with progressive disease than those in patients with a partial response or stable disease. ii) VEGF levels were higher in patients with alcoholic LC than those in patients with hepatitis C-related or hepatitis B-related LC. iii) VEGF levels were higher in stage IVB patients than those in patients with stage III or IVA disease. iv) VEGF levels were significantly higher in patients with giant or confluent multinodular tumors than those in patients with multiple discrete nodules. v) Serum VEGF levels were higher in patients with vascular invasion than in patients without vascular invasion.. Monitoring the serum VEGF level is useful for predicting the response of aHCC to HAIC, as well as for predicting metastasis, tumor type and vascular invasion.

Topics: Aged; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Treatment Outcome; Vascular Endothelial Growth Factor A

Irreversible electroporation (IRE) is a non-thermal injury tissue ablation technique that uses electrical pulses to cause cell death. IRE damages the endothelial cells of blood vessels; however these cells re-grow, and thus IRE does not result in permanent damage to blood vessels. We report the novel use of IRE for ablation of microscopically positive margins after resection of colorectal liver metastases (CRLM) impinging on hepatic veins.. A 68-year-old female was found to have colon cancer and synchronous bilateral unresectable liver metastases. Chemotherapy with FOLFOX and cetuximab was initiated, with subsequent conversion to resectability of the CRLM. The patient underwent colectomy followed by right liver posterior sectionectomy with wedge resection of segment 5. Resection of tumor impinging on the left and middle hepatic veins would have required left hepatectomy, with insufficient remnant liver volume. The CRLM were meticulously dissected off the hepatic veins leaving a microscopically positive margin, and IRE was then used for margin ablation, leaving intact hepatic veins and venous blood flow. The patient is alive and without recurrent disease now 30 months after resection. Herein we review the IRE technology and its use in ablation of liver metastases.. Use of IRE margin ablation for microscopically-positive CRLM resection may lead to long-term patient survival; further prospective randomized trials are needed to confirm this finding.

Topics: Ablation Techniques; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colorectal Neoplasms; Electroporation; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Treatment Outcome

The aim of the present retrospective study was to analyze clinical outcome and risk factors associated with treatment outcomes according to KRAS status in patient with metastatic colorectal cancer (mCRC) treated with bevacizumab (bev) plus chemotherapy in the first-line setting.. We performed observational study on 1622 patients with mCRC treated with bev plus oxaliplatin- or irinotecan-based chemotherapy, and correlated treatment outcomes with KRAS mutation status. The primary endpoint was progression-free survival (PFS) and additionally overall survival (OS). Adverse events of bevacizumab and risk factors including location of metastases were evaluated.. Mutation in KRAS was present in 40.6% of mCRC cases. The median PFS in patients with wild-type KRAS (wtKRAS) vs mutant KRAS was 11.5 vs 11.4 months, respectively. The median OS was 30.7 vs 28.4 months (p = 0.312). Patients with KRAS mutation had lung metastases more frequently than wtKRAS individuals (32.0% vs 23.8%; p = 0.001). We observed no difference in clinical outcome between hepatic and extrahepatic metastatic disease.. KRAS mutation does not interfere with clinical benefit from first-line treatment with bevacizumab plus chemotherapy in mCRC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Survival Rate; Young Adult

The combination of surgery and chemotherapy (CTx) is increasingly accepted as an effective treatment for patients with colorectal liver metastases (CRLM). However, controversy exists whether all patients with resectable CRLM benefit from perioperative CTx. We investigated the impact on overall survival (OS) by neo-adjuvant CTx in patients with resectable CRLM, stratified by the clinical risk score (CRS) described by Fong et al.. Patients who underwent surgery for CRLM between January 2000 and December 2009 were included. We compared OS of patients with and without neo-adjuvant CTx stratified by the CRS. The CRS includes five prognosticators and defines two risk groups: low CRS (0-2) and high CRS (3-5).. 363 patients (64% male) were included, median age 63 years (IQR 57-70). Prior to resection, 219 patients had a low CRS (neo-adjuvant CTx: N = 65) and 144 patients had a high CRS (neo-adjuvant CTx: N = 88). Median follow-up was 47 months (IQR 25-82). In the low CRS group, there was no significant difference in median OS between patients with and without CTx (65 months (95% CI 39-91) vs. 54 months (95% CI 44-64), P = 0.31). In the high CRS group, there was a significant difference in OS between patients with and without CTx (46 months (95% CI 24-68) vs. 33 month (95% CI 29-37), P = 0.004).. In our series, patients with a high CRS benefit from neo-adjuvant CTx. In patients with a low risk profile, neo-adjuvant CTx might not be beneficial.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Digestive System Surgical Procedures; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Oxaliplatin; Predictive Value of Tests; Prognosis; Propensity Score; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome

To retrospectively compare the efficacy of two irinotecan-based chemotherapy regimens combined with bevacizumab in first-line therapy of metastatic colorectal cancer (mCRC).. The data of 558 patients with mCRC treated with first-line bevacizumab plus irinotecan-containing regimen were obtained from the national CORECT registry that collects data of all patients with mCRC treated with targeted-agents. The treatment outcomes of patients treated with bevacizumab plus irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) were compared to patients treated with bevacizumab plus irinotecan and capecitabine (XELIRI).. Among 4,312 patients with CRC treated with bevacizumab, only 13% (558) received irinotecan-based chemotherapy. No significant differences were observed in terms of progression-free survival and overall survival between FOLFIRI and XELIRI groups. Moreover, the toxicity of both regimens was also comparable.. This retrospective analysis confirms the comparable activity of FOLFIRI and XELIRI regimens when combined with bevacizumab.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Czech Republic; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Retrospective Studies; Treatment Outcome

Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report (5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Carcinoma, Pancreatic Ductal; Chemotherapy, Adjuvant; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Positron-Emission Tomography; Remission Induction; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden

Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis.. Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups.. There were significant differences in tumor differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage (P < 0.001), metachronous liver metastasis (P < 0.001), metachronous lung metastasis (P < 0.001), and ERCCI expression (P < 0.001) between the seven groups. Both 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) exhibited significant differences (both P < 0.001) with survival gradually decreasing from cecum to sigmoid colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS.. Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cecal Neoplasms; Chemotherapy, Adjuvant; Colon; Colonic Neoplasms; Disease-Free Survival; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Thymidylate Synthase

Colon cancer in pregnancy is uncommon. Only a small number of case reports have been published in the literature on the use of chemotherapeutic drugs during pregnancy. Reports of such cases assist clinicians in further investigating the use of chemotherapy in pregnancy.. FOLFOX-6 was administered to a pregnant, 33-year-old Saudi woman with metastatic colon cancer from 22 to 30 weeks of gestation. Her cancer was diagnosed during her pregnancy. She tolerated the chemotherapy well and delivered a full-term baby girl with no obvious harm, and normal development was documented at her 2-year follow-up examination.. Colon cancer during pregnancy is not easily detected and is difficult to manage. A detailed history and high clinical suspicion are needed in patients who present with symptoms and signs suggestive of malignancy. A multidisciplinary approach with patient involvement is needed to decrease morbidity and mortality caused by both treatment and the cancer in the mother and to limit side effects for the fetus. Further data and long-term follow-up are needed to better understand the potential long-term side effects of chemotherapeutic drugs on offspring.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Ovarian Neoplasms; Ovariectomy; Oxaliplatin; Pregnancy; Pregnancy Complications, Neoplastic

Most liver metastases from colorectal cancer (CRC) are unresectable at diagnosis. Systemic chemotherapy allows secondary surgical resection in 10 to 20% of patients. Hepatic intra-arterial treatments could enhance response and resection rate. We therefore designed a prospective phase II trial testing the transarterial chemoembolization (TACE) using drug-eluting beads loaded with irinotecan (DEBIRI) with concomitant systemic FOLFOX regimen, the FFCD 1201 trial, in patients with liver limited metastatic CRC.. A 48-year old patient was operated from an occlusive sigmoid adenocarcinoma. Magnetic resonance imaging showed 6 bilobar liver metastasis. The patient was considered as non-eligible for surgery initially. Patient was included in the FFCD 1201 trial and received 5 cycles of FOLFOX and 2 sessions of DEBIRI, with a quite good tolerability. Post-treatment evaluation showed a partial response and sufficient tumor shrinkage to make liver metastasis resectable. Right hepatectomy associated with wedge resection in the left liver was performed and pathological findings showed a complete pathological response (CPR).. Combination of DEBIRI with FOLFOX could increase tumor shrinkage leading to secondary resection of liver metastases from CRC. This combination may also, as shown here for the first time in a patient with unresectable LM, induce CPR of all LM, known to be associated with better outcome. Our case also emphasizes the difficulty to morphologically assess pathological response and the need for new tool to better select patients who should be resected. Further results of the FFCD 1201 trial will bring more information on this new combination therapy.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemoembolization, Therapeutic; Colorectal Neoplasms; Drug Carriers; Fluorouracil; Hepatic Artery; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Organoplatinum Compounds; Prospective Studies; Remission Induction

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Positron-Emission Tomography; Tomography, X-Ray Computed

We report a case of a 59 years old man affected by an adenocarcinoma of the rectum RAS wild type with synchronous liver metastases, diagnosed on October, 2011. The patient underwent a left hemicolectomy with left hepatic lobectomy. In view of the recurrence of the disease from 18.01.2012 to 13.7.2012 we practiced first line chemotherapy with FOLFOX plus bevacizumab for 12 total cycles, obtaining a complete response, so the patient underwent clinical follow-up controls that proved negative until January, 2013, when, following the appearance of pain in the pelvis to the left, a total body PET with 18FDG was performed that documented the presence of bone metastases (left hemipelvis), confirmed histologically. Therefore from 03.18.2013 to 29.03.2013 the patient underwent a left ischium radiotherapy (for a total of 30 Gy). On May, 2013, a CT scan showed a progression of disease in the liver and so the patient started a II line chemotherapy with FOLFIRI and aflibercept, treatment still ongoing. At 46 months after diagnosis, the patient is in good general condition, presenting a complete response of the disease, demonstrated by a total body CT scan, performed in April 2015, completely negative.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Colorectal Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

We report a case of radical resection of rectal cancer with multiple liver and lung metastases after preoperative chemotherapy. A 54-year-old woman presented with abdominal pain and loss of body weight due to rectal cancer with multiple liver and lung metastases. Therefore, the patient received 14 courses of bevacizumab+mFOLFOX6, and 7 courses of panitumumab+FOLFIRI. After the chemotherapy, the size of the distant metastases reduced by 62% on computed tomography, according to RECIST. Due to the reduction in size, a conversion surgery was attempted. First, an abdominal operation with laparoscopy was performed, and 2 months later an operation to resect the lung metastases via thoracoscopy was performed. Currently, 3 months after surgery, the patient is alive, without recurrence.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Panitumumab; Rectal Neoplasms

It is generally believed that the plasma concentration of 5-fluorouracil (5-FU) is constant when 5-FU is continually administered for chemotherapy. The aim of the present study was to verify whether this is true.. Nine patients with colorectal cancer were enrolled in this study. All patients received chemotherapy; four patients received FOLFIRI (leucovorin, 5-fluorouracil, irinotecan) and five received FOLFOX (leucovorin, 5-fluorouracil, oxaliplatin). 5-FU was administered continuously (2400 mg/m(2)) for 46 h. Serum was collected at 12 points after the start of administration. The concentration of 5-FU was evaluated using a new immunoassay method and gas chromatography-mass spectrometric (GC/MS) method.. The concentrations of 5-FU fluctuated dramatically over time, with greater than 3-fold changes in each individual, and the pattern was not constant.. Because the serum concentration of 5-FU fluctuates and displays various patterns, the dosage should not be based on body surface area. A new individualized method for determining the 5-FU dosage should be developed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Humans; Immunoassay; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate

To assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM) of Diffusion-weighted imaging (DWI) in the assessment of liver metastases treated with targeted chemotherapy agents.. 12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI) were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST) as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC) analysis were performed.. 24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp) values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively.. IVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Diffusion Magnetic Resonance Imaging; Early Detection of Cancer; Female; Fluorouracil; Humans; Image Processing, Computer-Assisted; Leucovorin; Liver Neoplasms; Male; Middle Aged; Motion; Neoplasm Metastasis; Perfusion; ROC Curve; Spleen; Tomography, X-Ray Computed; Whole Body Imaging

Primary colorectal choriocarcinoma is a rare neoplasm. Only 19 cases have been reported worldwide, most of which involved adenocarcinomas. The prognosis is usually poor, and the standard therapy for this tumor has not been established. A 61-year-old woman presented with constipation and lower abdominal discomfort. She was diagnosed with primary adenocarcinoma with focal choriocarcinomatous differentiation in the sigmoid colon and liver metastasis. Because the serum beta-human chorionic gonadotropin level was not significantly elevated, and because only focal choriocarcinomatous differentiation was diagnosed, we selected the chemotherapy regimen that is used for the treatment of metastatic colorectal adenocarcinoma. The patient survived for 13 months after the initial diagnosis. This is the first case in Korea to assess the suppressive effects of the standard chemotherapy for colorectal adenocarcinoma against coexisting colorectal choriocarcinoma and adenocarcinoma.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Chorionic Gonadotropin, beta Subunit, Human; Colon, Sigmoid; Colonic Neoplasms; Colonoscopy; Constipation; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Prognosis; Tomography, X-Ray Computed

The SCAN colorectal cancer systemic therapy workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for colorectal cancer in Singapore.. The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.. Five international guidelines were evaluated-those developed by the National Comprehensive Cancer Network for colon (2014) and rectal (2014) cancer, the European Society of Medical Oncology for advanced (2012) and early (2013) cancer and the National Institute of Clinical Excellence (2011). Recommendations on systemic therapy in colorectal cancer were produced.. These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of colorectal cancer.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Metastasectomy; Microsatellite Instability; Organoplatinum Compounds; Oxaliplatin; Panitumumab; Singapore

We describe a case of a man affected by colon adenocarcinoma with metachronous nodes and liver metastases (resected), exposed to first line therapy with FOLFOX-cetuximab. After disease progression, a second line based on FOLFIRI-aflibercept was started achieving an initial partial response followed by a long-lasting disease stability with a good tolerability.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Disease Progression; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Treatment Outcome

We performed laparoscopic liver resection in a patient with synchronous liver metastasis from advanced sigmoid colon cancer after induction with S-1 plus oxaliplatin (SOX) plus bevacizumab (BV) chemotherapy. A 61-year-old woman underwent laparoscopy-assisted sigmoidectomy for locally advanced sigmoid colon cancer with synchronous liver metastasis. SOX plus BV chemotherapy was initiated. After 3 courses, the liver tumor was downsized, and metastasectomy was performed laparoscopically with R0 resection. The postoperative course was uneventful and the patient was discharged on the 11th postoperative day. She has been free from recurrence. Induction with SOX plus BV chemotherapy is considered to be not only effective, but also beneficial for maintaining the quality of life (QOL) in patients with advanced colorectal cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Drug Combinations; Female; Hepatectomy; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Middle Aged; Oxonic Acid; Sigmoid Neoplasms; Tegafur

A 70s-year-old man was referred to our hospital because of sigmoid colon cancer. Computed tomography (CT) revealed a large mass in the right lobe of the liver and small masses in Couinaud segments Ⅳ and Ⅵ. We started systemic chemotherapy with mFOLFOX6 and panitumumab. After 6 courses of the treatment, the size and number of the liver metastases was remarkably reduced on CT. We performed a simultaneous laparoscopic resection for the primary tumor and synchronous liver metastases. The postoperative course was uneventful and he had no signs of recurrence 12 months after surgery.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Panitumumab; Sigmoid Neoplasms; Treatment Outcome

The case is of a 62-year-old man with no medical history and no family history.A type 2 tumor was found in the entire circumference of the sigmoid colon by colonoscopy after a positive result on a fecal occult blood test, and 5 liver metastases were recognized in both lobes of the liver by using contrast-enhanced CT.He was first treated by primary tumor resection. Subsequently, 5-fluorouracil/l-leucovorin/oxaliplatin (mFOLFOX6) plus bevacizumab (BV) was started 1 month after the surgery and a total of 8 cycles of mFOLFOX6 plus BV were administered without any adverse events.On CT assessment after the chemotherapy, the patient was diagnosed with stable disease according to RECIST guidelines since the size of the tumor only showed a slight reduction.However, it was considered to be an optimal response based on the morphologic criteria. Thereafter, a medial segmentectomy and partial resection of the liver was performed.A mucus reservoir was found in the tumor site, and no viable tumor cells were detected pathologically, which confirmed the pathological complete response with mFOLFOX6 plus BV.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colectomy; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Sigmoid Neoplasms

A 58-year-old woman was diagnosed with a sigmoid colon cancer and synchronous liver metastasis. Because an obstruction of the sigmoid colon was identified, the patient underwent sigmoidectomy. Computed tomography(CT)findings suggested possible vena cava and hepatic vein invasion. Therefore, the decision was made to offer systemic chemotherapy. The patient underwent 6 courses of chemotherapy with 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX6). After 4 courses of chemotherapy, CT scans showed a significant reduction of the liver metastasis (reduction rate of 5 0%; a partial response) and demonstrated improved exclusion of the inferior vena cava and hepatic vein. After 6 courses of chemotherapy, we performed right trisegmentectomy of the liver and resection of the inferior vena cava and diaphragm. Postoperative pathological findings revealed negative margins, and no invasion of the inferior vena cava. The pathological response grade of the tumor after chemotherapy was determined to be Grade 2. Adjuvant chemotherapy was not performed because of the patient 's poor performance status. The patient was alive with no recurrence 8 years after resection of the liver metastasis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Invasiveness; Organoplatinum Compounds; Sigmoid Neoplasms; Time Factors; Vena Cava, Inferior

A patient in his 70s was diagnosed with rectal cancer (pT3, pN1, cM0, and pStage IIIa) for which he underwent low anterior resection of the rectum and received adjuvant therapy with UFT/LV. Multiple liver, lung, and para-aortic lymph node metastases were detected after 6 months, and the patient then received a total of 24 courses of FOLFOX4 plus bevacizumab instead of UFT/LV. The liver and para-aortic lymph node metastases showed a complete response (CR), and the lung metastases markedly diminished. Therefore, the patient completed the FOLFOX4 plus bevacizumab chemotherapy regimen. After 2 years, a recurrence of the initial liver metastases was detected. A CR on radiological imaging does not correspond to a pathological CR. Therefore, a careful follow-upis required even when a CR on radiological imaging is achieved.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Aorta; Bevacizumab; Chemotherapy, Adjuvant; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Organoplatinum Compounds; Rectal Neoplasms; Recurrence

Colorectal cancer is the fourth most common cancer diagnosed in the United States, and the third most common cause of death from cancer. Approximately 20% of the patients with colorectal cancer have distant metastasis during diagnosis. Primary tumor resection is controversial in unresectable metastatic colorectal cancer (CRC). We studied the survival effect of primary tumor resection in unresectable metastatic CRC according to kirsten ras (KRAS) mutation status.. Seventy eight CRC cases with unresectable metastasis were included in the study. The KRAS status was known in all patients. 34 patients had undergone primary tumor resection before 1st chemotherapy.. ThE median time from primary tumor resection to first chemotherapy was 6 (3-17) weeks. The survival was better in the unresectable metastatic colon patients with resected primary tumor, but it was statistically non-significant (P = 0.07). The median OS was similar (P = 0.91) in the KRAS wild patients with or without primary tumor resection. The median OS was 28 months in KRAS mutant patients with primary tumor resection, 14 months in KRAS mutant patients without primary tumor resection (P = 0.002).. Primary tumor resection offers survival advantage in KRAS mutant patients, but randomized prospective studies are required.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Cohort Studies; Colectomy; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins p21(ras); Retrospective Studies; Survival Rate

We aimed to investigate the efficacy of second line treatment with modified FOLFOX6 (mFOLFOX6) following cisplatin- plus 5-fluorourasil (CF) chemotherapy in patients with metastatic esophagus cancer (mEC).. In our oncology clinic, between March 2011 and September 2014, we reviewed patients admitted with progressive mEC following first line CF chemotherapy and those with >60 kanofsky performance status performed second line mFOLFOX6 regimen.. A total of 242 patients with mEC were evaluated. 94 of 242 patients (38.8%) had received second-line chemotherapy treatment. All of these patients had received mFOLFOX6 regime. Median age was 53 years (range: 28-71). The received median number of chemotherapy cycles was 6 (2-12). Objective response rate (ORR) was obtained in 39 of 94 (41.4%) patients, 6 (6.3%) of these had complete response (CR) and 33 (35.1%) had partial response (PR). Stable disease (SD) was obtained in 20 (21.3%) patients and progression was observed in 35 (37.3%) patients. Grade ¾ toxicity was observed in 67 (71.2%) patients. The hematologic toxicity was found as the most common toxicity (69.1%).. mFOLFOX6 regimen as a second line treatment can be applied to the mEC patients with progressive disease following CF chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Squamous Cell; Cohort Studies; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Treatment Outcome

The clinical benefits of conversion chemotherapy followed by liver resection for initially unresectable colorectal liver metastases are still controversial. The criteria for unresectability vary from one team to another. To clarify this issue, we retrospectively assessed the survival and characteristics of metastatic colorectal cancer (mCRC) patients with liver-limited disease (LLD) who underwent conversion therapy.. Our criteria for resectability depended on the size of the remnant liver volume (>30 %) and expected function after removal of all metastases. Between December 2007 and September 2011, a total of 115 patients were diagnosed as having mCRC with LLD and received chemotherapy. Among them, 47 had tumors that were initially diagnosed as resectable. They underwent hepatic resection after chemotherapy (resected group). Of the 67 tumors were initially diagnosed as unresectable, 12 became resectable after chemotherapy (conversion group), leaving 55 tumors that remained unresectable after chemotherapy (unresected group).. The median follow-up was 25.2 months. Hepatic resection was more invasive in the conversion group than in the resected group. Median disease-free survival was significantly higher in the resected group than in the conversion group (p = 0.013). Overall survival (OS) was also higher in the resected group, but the difference was not significant (p = 0.36). However, OS was significantly higher in the conversion group than in the unresected group (p = 0.034). Multivariate analysis of the resected and conversion groups showed that OS was significantly negatively influenced by abnormal carcinoembryonic antigen levels at surgery (p = 0.037) and a hospital stay >30 days (p = 0.009).. Our results showed that conversion chemotherapy could contribute to longer OS in mCRC patients with LLD.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaloacetates; Retrospective Studies; Survival Analysis; Treatment Outcome

Stereotactic radiotherapy is a minimally invasive technique for delivering highly focused ionizing radiation with extreme precision. This technique was initially developed in neurosurgical practice and applied to extracranial lesions in the 1990s, and was termed stereotactic body radiotherapy (SBRT). Studies have reported that the resection of distant metastases from colorectal cancer (CRC) contributes to relatively long-term survival. However, the resection of pulmonary and liver metastases is not possible for various reasons. SBRT offers a therapeutic alternative to unresectable metastatic lesions. The present study describes three cases of distant metastasis from CRC that exhibited a complete response (CR) to SBRT. Case 1 is a 70-year-old man with recurrent liver metastases after surgery for rectal cancer with liver metastasis (S3: diameter 1.8 cm and volume 3.0 ml; S6: diameter 1.3 cm and volume 1.2 ml). Cases 2 and 3 were 65-year-old and 70-year-old men, respectively. Both patients had pulmonary metastasis after surgery for rectal and cecum cancer (Case 2: diameter 1.2 cm and volume 0.9 ml; Case 3: diameter 0.8 cm and volume 0.27 ml). All cases were moderately differentiated adenocarcinomas. No serious adverse side-effects were observed during the therapy. CR was obtained in all patients on the basis of computed tomography 15-33 months after radiotherapy. Our experience supports that SBRT is a safe and alternative technique for resection in patients with distant metastasis from CRC who have small metastatic tumor volume.

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Organoplatinum Compounds; Radiosurgery; Treatment Outcome

The aim of this study was to investigate the relationship between the use of bevacizumab (Bmab) in addition to oxaliplatin (OX), the development of sinusoidal obstruction syndrome (SOS) and the changes in splenic volume as an indicator of the protective effect of Bmab against OX-induced SOS.. Seventy-nine patients who received OX-based chemotherapy with (OX + Bmab group: n = 48) or without Bmab (OX group: n = 31) for colorectal liver metastases were included in this study. The changes in splenic volume after chemotherapy were evaluated in the two groups. Furthermore, the relationship between the changes in splenic volume and SOS were analyzed in the 55 patients who underwent hepatectomy.. A significant increase in the splenic volume was observed in the OX group, but not in the OX + Bmab group. The increase in the splenic volume relative to baseline was significantly higher in the OX group than in the OX + Bmab group (39.1% vs. 2.3%, p < 0.0001). The incidence of moderate or severe SOS was significantly higher in the OX group than in the OX + Bmab group (50.0% vs. 16.0%, p = 0.0068), and the increase in the splenic volume was significantly higher in the patients with SOS than in those without SOS (42.9% vs. 9.9%, p = 0.0001). A multivariate analysis identified the increase in the splenic volume as an independent predictor of the development of SOS.. This study demonstrated that the inhibition of splenic volume enlargement might be a useful indicator of the protective effect of Bmab against OX-induced SOS.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organ Size; Organoplatinum Compounds; Oxaliplatin; Radiography; Retrospective Studies; Spleen; Treatment Outcome

The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies.. Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM.. The CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ≤4 cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55).. Local recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30 mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease.. LR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Catheter Ablation; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Treatment Outcome

Complete pathological response occurs in 10-20% of patients with rectal cancer who are treated with neoadjuvant chemoradiation therapy prior to pelvic surgery. The possibility that complete pathological response of rectal cancer can also occur with neoadjuvant chemotherapy alone (without radiation) is an intriguing hypothesis.. A 66-year old man presented an adenocarcinoma of the rectum with nine liver metastases (T3N1M1). He was included in a reverse treatment, aiming at first downsizing the liver metastases by chemotherapy, and subsequently performing the liver surgery prior to the rectum resection. The neoadjuvant chemotherapy consisted in a combination of oxaliplatin, 5-FU, irinotecan, leucovorin and bevacizumab (OCFL-B). After a right portal embolization, an extended right liver lobectomy was performed. On the final histopathological analysis, all lesions were fibrotic, devoid of any viable cancer cells. One month after liver surgery, the rectoscopic examination showed a near-total response of the primary rectal adenocarcinoma, which convinced the colorectal surgeon to perform the low anterior resection without preoperative radiation therapy. Macroscopically, a fibrous scar was observed at the level of the previously documented tumour, and the histological examination of the surgical specimen did not reveal any malignant cells in the rectal wall as well as in the mesorectum. All 15 resected lymph nodes were free of tumour, and the final tumour stage was ypT0N0M0. Clinical outcome was excellent, and the patient is currently alive 5 years after the first surgery without evidence of recurrence.. The presented patient with stage IV rectal cancer and liver metastases was in a unique situation linked to its inclusion in a reversed treatment and the use of neoadjuvant chemotherapy alone. The observed achievement of a complete pathological response after chemotherapy should promote the design of prospective randomized studies to evaluate the benefits of chemotherapy alone in patients with stages II-III rectal adenocarcinoma (without metastasis).

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemotherapy, Adjuvant; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Rectum

To retrospectively evaluate findings of chemotherapy-induced focal hepatopathy (CIFH) on gadoxetic acid-enhanced magnetic resonance (MR) and diffusion-weighted (DW) images and to determine imaging features that are most helpful in differentiating CIFH from metastasis.. This retrospective study was approved by the institutional review board, and informed consent was waived. MR images, including DW images and gadoxetic acid-enhanced images, from 12 patients (four men, eight women; age range, 25-64 years) with 15 CIFHs were reviewed independently and in consensus by two radiologists and were compared with those obtained in 20 control patients (12 men, eight women; age range, 32-84 years) with 30 hepatic metastasis who were matched for tumor size, primary organ, and chemotherapy regimen. Interobserver agreement was assessed with κ statistics, and univariate analysis was performed for comparisons. For quantitative analyses, apparent diffusion coefficients (ADCs) and lesion-to-liver contrast ratios (CRs) were measured. Histopathologic examinations were performed for CIFHs.. Histopathologic examination revealed that the development of CIFHs was attributable to accentuated manifestations of sinusoidal obstruction syndrome. Interobserver agreement was excellent (κ > 0.85). An ill-defined margin on hepatobiliary phase (HBP) images was the most discriminating independent variable in the differentiation of CIFH from metastasis (odds ratio, 16; P = .009). ADC and CR values in CIFH group were significantly higher than those in metastasis group (P < .001 and P = .041).. CIFH should be considered a mimicker of metastasis in patients with gastrointestinal malignancy during chemotherapy. CIFH can be differentiated from metastasis on the basis of gadoxetic acid-enhanced MR and DW imaging findings; an ill-defined margin on HBP images was especially characteristic.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Chemical and Drug Induced Liver Injury; Contrast Media; Diffusion Magnetic Resonance Imaging; Female; Fluorouracil; Gadolinium DTPA; Gastrointestinal Neoplasms; Humans; Image Interpretation, Computer-Assisted; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies

Bevacizumab is a widely used agent for treatment for colorectal cancer. Though it relates to several adverse events, a few cases have been reported of drug-induced interstitial lung damage in bevacizumab-based chemotherapy for advanced colorectal cancer. In this study, we retrospectively reviewed a consecutive series of 72 patients with advanced colorectal cancer who received bevacizumab-based chemotherapy and identified five cases (6.9%) who developed interstitial pneumonia (IP). The median age was 68 years, all five were male, and four of five patients were smokers. Three cases were asymptomatic, and they immediately recovered by withdrawal of chemotherapeutic drugs. On the other hand, two severe cases were required high-dose infusion of corticosteroid. It is suggested that early diagnosis of IP contributes to prevent exacerbation of the event and results in better outcomes. IP may have been associated with systemic chemotherapy, suggesting that a caution should be raised for pulmonary damage by bevacizumab-based chemotherapy.

Topics: Adult; Aged; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prednisolone; Prognosis; Radiography, Thoracic; Retrospective Studies

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colectomy; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Neoadjuvant Therapy; Positron-Emission Tomography

Both 5-FU and oxaliplatin have been used as single agents in patients with colorectal cancer and severe liver dysfunction, but the combination of these drugs has not yet been investigated. A 67-year-old man diagnosed with colorectal cancer in 2008 presented in April 2011 to Appalachian Regional Healthcare Cancer Center with obstructive jaundice and weight loss. Imaging studies were compatible with a liver mass and dilatation of the intrahepatic bile ducts. A liver biopsy confirmed metastatic colorectal cancer. Because his total bilirubin level was 23.1 mg/dL, a percutaneous catheter was placed in May 2011. His total bilirubin level decreased to 5.9 mg/dL, but then increased to 9.4 mg/dL in June 2011. He was started on a FOLFOX regimen, with a 50% dose reduction of 5-FU bolus (200 mg/m(2)) and continuous infusion (1200 mg/m(2)) over 46 hours, and a 15% dose reduction of oxaliplatin (75 mg/m(2)) every 2 weeks. He tolerated this regimen very well, with normalization of his bilirubin level, a significant decrease in his tumor markers, and a partial response seen on PET/CT scan. His only significant toxicity was a grade 2 stomatitis. He received 21 cycles of FOLFOX, and was later switched to cetuximab treatment after disease progression. These findings suggest that FOLFOX might be effective in metastatic colon cancer with severe liver dysfunction, with minimal toxicity, and deserves further investigation.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Function Tests; Liver Neoplasms; Magnetic Resonance Imaging; Male; Neoplasm Metastasis; Organoplatinum Compounds; Treatment Outcome

Biological characteristics of colorectal cancer liver metastases (CRCLM) are increasingly recognized as major determinants of patient outcome. The purpose of this study was to evaluate the prognostic value of metabolic response to preoperative chemotherapy as quantified by (18)F-FDG positron emission tomography (PET) for patients undergoing liver resection of CRCLM.. All patients (n = 80) who had staging PET before liver resection for CRCLM at Austin Health in Melbourne between 2004 and 2011 were included. Thirty-seven patients had PET and CT imaging before and after preoperative chemotherapy. Semiquantitative PET parameters-maximum standardized uptake variable (SUVmax), metabolic tumour volume (MTV), and total glycolytic volume (TGV)-were derived. Metabolic response was determined by the proportional change in PET parameters (∆SUVmax, ∆MTV, ∆TGV). Prognostic scores, CT RECIST response, and tumour regression grading (TRG) were also assessed. Correlation to recurrence-free (RFS) and overall survival (OS) was assessed using Kaplan-Meier survival and multivariate analysis.. Semiquantitative parameters on staging PET before chemotherapy were not predictive of prognosis, whereas all parameters after chemotherapy were prognostic for RFS and OS. Only ∆SUVmax was predictive of RFS and OS on multivariate analysis. Patients with metabolically responsive tumours had an OS of 86 % at 3 years vs. 38 % with nonresponsive or progressive tumours (p = 0.003). RECIST and TRG did not predict outcome.. Tumour metabolic response to preoperative chemotherapy as quantified by PET is predictive of prognosis in patients undergoing resection of CRCLM. Assessing metabolic response uniquely characterizes tumour biology, which may allow future optimization of patient and treatment selection.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorodeoxyglucose F18; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; ROC Curve; Survival Rate; Tomography, X-Ray Computed; Young Adult

Whether the survival benefit of perioperative FOLFOX in patients with liver metastases of colorectal cancer (LMCRC) is provided by preoperative chemotherapy (CT), postoperative CT, or both remains unclear. This study aimed to evaluate, in patients with resectable LMCRC, the survival impact of preoperative and postoperative separately.. Between 2000 and 2010, the 179 patients (126 men, age 61 ± 11 years) with initially resectable LMCRC, who underwent liver resection (LR) and were offered pre- and/or postoperative FOLFOX were included. Twenty-four (13%) patients did not receive CT, 27(15%) patients received only preoperative CT, 71 (40%) patients received only postoperative CT, and 57 (32%) patients received both pre- and postoperative CT.. Operative morbidity and mortality rates were 19 and 0.6%, respectively. At 1, 3, and 5 years, OS and DFS rates were 97, 66, 46 and 60, 32, and 24%, respectively. Postoperative FOLFOX was an independent predictor of increased OS (HR = 0.55 [95% CI, 0.35-0.87] p = 0.01) and DFS (HR = 0.54 [0.36-0.82] p = 0.0017), whereas the synchronous onset of the metastasis and the presence of radiographically occult liver metastases were independent predictors of poorer OS. Alternatively, preoperative FOLFOX had no significant influence on OS (HR = 0.96 [0.57-1.60] p = 0.83) or DFS (HR = 1.05 [0.66-1.66] p = 0.87).. The survival benefit of FOLFOX in patients with resectable LMCRC may be provided by postoperative rather than preoperative administration.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Evaluation; False Negative Reactions; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Postoperative Care; Preoperative Care; Radiography; Retrospective Studies; Treatment Outcome

Despite introduction of effective chemotherapy protocols, it has remained uncertain, if patients with colorectal cancer (CRC) liver metastases should receive adjuvant therapy. Clinical or molecular predictors may help to select patients at high risk for disease recurrence and death who obtain a survival advantage by adjuvant chemotherapy.. A total of 297 patients with potentially curative resection of CRC liver metastases were analyzed. These patients had no neoadjuvant therapy, no extrahepatic disease and negative resection margins. The primary endpoint was overall survival. Patients' risk status was evaluated using the Memorial Sloan-Kettering Cancer Center clinical risk score (MSKCC-CRS). Multivariable analyses were performed using Cox proportional hazard models.. A total of 137 (43%) patients had a MSKCC-CRS > 2. Adjuvant chemotherapy was administered to 116 (37%) patients. Patients who received adjuvant chemotherapy were of younger age (p = 0.03) with no significant difference in the presence of multiple metastases (p = 0.72) or bilobar metastases (p = 0.08). On multivariate analysis adjuvant chemotherapy was associated with improved survival in the entire cohort (Hazard ratio 0.69; 95% confidence interval 0.69-0.98). It improved survival markedly in high-risk patients with a MSKCC-CRS > 2 (HR 0.40; 95% CI 0.23-0.69), whereas it was of no benefit in patients with a MSKCC-CRS ≤ 2 (HR 0.90; 95% CI 0.57-1.43).. The MSKCC-CRS offers a tool to select patients for adjuvant therapy after resection of CRC liver metastases. Validation in independent patient cohorts is required.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Prospective Studies; Survival Analysis; Treatment Outcome

Hepatic resection of metastatic colorectal cancer (CRC) has become the treatment of choice for patients after resection of the primary CRC. However, some patients do not benefit from immediate resection because of rapidly progressive disease. The aim of this study was to examine the prognostic value of extracapsular invasion (ECI) of lymph node (LN) metastasis of CRC with liver metastases following liver resection.. All patients who underwent resection for CRC with liver metastases between 1995 and 2011 were reviewed. All of those with metastasis from primary CRC were included in this study. Preoperative, intraoperative, and postoperative data, including primary tumor pathology results, were retrospectively reviewed. All resected LNs from primary CRC were re-examined to assess ECI. Associations between clinicopathologic factors, survival, and the nodal findings were evaluated.. ECI was identified in 47 (48%) patients. ECI was correlated with the number of positive LNs (p = 0.0022), timing of liver metastasis (p = 0.0238), and number of liver metastases (p = 0.0001). Univariate analysis indicated that the number of positive LNs (p = 0.0014), ECI (p = 0.0203), and adjuvant chemotherapy (p = 0.0423) were significant prognostic factors. Patients with ECI had a significantly worse survival (p = 0.0024) after liver resection than patients with LN-negative and ECI-negative groups.. In patients with hepatic CRC metastases, ECI in regional LNs reflects a particularly aggressive behavior, such as a greater number of liver metastases. In CRC patients with liver metastases, ECI in regional LNs might be correlated with poor prognosis following liver resection.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Rate

Peri-operative chemotherapy is recommended for the management of colorectal liver metastases (CRLM). The aim of this study was to examine the impact of peri-operative bevacizumab on survival in patients with resected CRLM.. A multicentre retrospective cohort of patients with resected CRLM was analysed from the LiverMetSurvey Registry. Patients who received peri-operative FOLFOX (group A) were compared with those who received peri-operative FOLFOX and bevacizumab (group B).. In total, 501 patients were compared (A, n = 384; B, n = 117). Group A was older (68.3 versus 62.5 years, P < 0.01), had more rectal cancers (30.7 versus 18.8%, P < 0.01) and higher carcinoembryonic antigen (CEA) levels at diagnosis (17.0 versus 9.7 ng/ml, P = 0.043). No difference was observed regarding primary tumour stage, synchronicity and the number or size of metastases. Post-operative infections were more frequent in group B (4.7% versus 12.8%, P < 0.01). Peri-operative bevacizumab had no effect on 3-year overall survival (OS) (76.4% versus 79.8%, P = 0.334), or disease-free survival (DFS) (7.4% versus 7.9%, P = 0.082). DFS was negatively associated with primary tumour node positivity (P = 0.011) and synchronicity (P = 0.041).. The addition of bevacizumab to standard peri-operative chemotherapy does not appear to be associated with improved OS or DFS in patients with resected CRLM.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Proportional Hazards Models; Registries; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

To report a metastatic colorectal cancer patient with hyperbilirubinemia treated with a combination of bevacizumab and FOLFIRI (5-fluorouracil, leucovorin, and irinotecan) using uridine diphosphate glucuronosyl transferase (UGT1A1) genotyping.. A 46-year-old male was diagnosed with rectosigmoid colon cancer with liver metastases and hyperbilirubinemia presenting with severe jaundice. UGT1A1 genotyping was used before therapy to ascertain whether genotype-adjusted dosages of irinotecan plus bevacizumab could alleviate the toxicity. Then, the patient was treated with FOLFIRI.. The FOLFIRI regimen was successfully used in this patient without concerns regarding toxicity.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Leucovorin; Liver Neoplasms; Male; Middle Aged

Weekly cetuximab plus irinotecan-based regiments are standard first- and second-line chemotherapy for patients with KRAS wild-type metastatic colorectal cancer (mCRC). However, the chemotherapy regimens are given every 2 weeks, which is asynchronous with cetuximab weekly administration. This study investigated the efficacy and safety of biweekly cetuximab administration in patients with mCRC. Twenty-six patients with KRAS wild-type mCRC, who received biweekly cetuximab plus FOLFIRI/irinotecan as first/second-line chemotherapy, at least three cycles of cetuximab and once CT evaluation in West China Hospital from May 2010 to February 2013, were retrospectively analyzed. The median number of cetuximab administrations was 8.3 (range 3-20). Fourteen patients received FOLFIRI as first-line therapy; response rate was 50.0%; median PFS was 8.8 months (95% CI 4.9-12.7). Ten patients received FOLFIRI and two patients received irinotecan as second-line therapy; response rate was 33.3%; median PFS was 4.6 months (95% CI 0.9-8.3). The toxicity was similar to weekly cetuximab combination schedules. Rash was observed in 69.2% of evaluable patients (grade 3 in 7.7%). Overall, our results show that biweekly cetuximab plus FOLFIRI/irinotecan may be as effective and safe as the standard weekly schedule.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Asian People; Camptothecin; Cetuximab; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Salvage Therapy; Survival Rate

Molecular markers for predicting or monitoring the efficacy of bevacizumab in patients with metastatic colorectal cancer (mCRC) remain to be identified. We have now measured the serum concentrations of 25 angiogenesis-related molecules with antibody suspension bead array systems for 25 mCRC patients both before and during treatment in a previously reported phase II trial of FOLFIRI chemotherapy plus bevacizumab. The serum concentration of vascular endothelial growth factor-A (VEGF-A) decreased after the onset of treatment (P < 0.0001), whereas that of placental growth factor increased (P < 0.0001). Significant differences in the levels of several factors (such as VEGF-A, soluble VEGF receptor-2, and interleukin-8) were apparent between responders and nonresponders during treatment. The rapid and pronounced decrease in serum VEGF-A level after treatment onset was apparent in all subjects and was independent of the baseline concentration. However, four of nine nonresponders showed a subsequent early increase in the serum VEGF-A level. Our results thus suggest that an early increase in the serum VEGF-A concentration after the initial decrease is a potential predictive marker of a poor response and reactive resistance to bevacizumab plus chemotherapy.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Neovascularization, Pathologic; Prognosis; Survival Rate

A 58-year-old man underwent low anterior resection for type 2 rectal cancer with liver metastasis. An abdominal computed tomography (CT) scan showed multiple hepatic tumors (in S2, S3, S4, and S6) and a filling defect in the left portal vein. Pathological examination revealed a moderately differentiated adenocarcinoma, pSS, pN0, ly0, v3, with a tumor thrombus in the portal vein. After surgery, the patient was treated with combined chemotherapy of bevacizumab/Leucovorin and fluorouracil with oxaliplatin (FOLFOX4). After 11 courses of chemotherapy, tumor marker levels normalized, and the sizes of the liver metastases and thrombus in the left portal vein remarkably decreased. Resection of the left hepatic lobe and a partial resection of S6 were performed. Pathological examination revealed no residual cancer cells and indicated that the histological classification due to the chemotherapy regimen was Grade 3. The patient was alive for 5 years after the initial surgery, without recurrence.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Sigmoid Neoplasms; Thrombosis

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Hepatitis B virus; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Virus Activation

There is a paucity of data on the current management and outcomes of liver-directed therapy (LDT) in older patients presenting with stage IV colorectal cancer (CRC). The aim of the study was to evaluate treatment patterns and outcomes in use of LDT in the setting of improved chemotherapy.. We used Cancer Registry and linked Medicare claims to identify patients aged ≥66 y undergoing surgical resection of the primary tumor and chemotherapy after presenting with stage IV CRC (2001-2007). LDT was defined as liver resection and/or ablation-embolization.. We identified 5500 patients. LDT was used in 34.9% of patients; liver resection was performed in 1686 patients (30.7%), and ablation-embolization in 554 patients (10.1%), with 322 patients having both resection and ablation-embolization. Use of LDT was negatively associated with increasing year of diagnosis (odds ratio [OR] = 0.96, 95% confidence interval [CI] 0.93-0.99), age >85 y (OR = 0.61, 95% CI 0.45-0.82), and poor tumor differentiation (OR = 0.73, 95% CI 0.64-0.83). LDT was associated with improved survival (median 28.4 versus 21.1 mo, P < 0.0001); however, survival improved for all patients over time. We found a significant interaction between LDT and period of diagnosis and noted a greater survival improvement with LDT for those diagnosed in the late (2005-2007) period.. Older patients with stage IV CRC are experiencing improved survival over time, independent of age, comorbidity, and use of LDT. However, many older patients deemed to be appropriate candidates for resection of the primary tumor and receipt of systemic chemotherapy did not receive LDT. Our data suggest that improved patient selection may be positively impacting outcomes. Early referral and optimal selection of patients for LDT has the potential to further improve survival in older patients presenting with advanced colorectal cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Embolization, Therapeutic; Female; Fluorouracil; Humans; International Classification of Diseases; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Medicare; Neoplasm Staging; Proportional Hazards Models; Registries; United States; Vitamin B Complex

The NCCN Guidelines for Colon Cancer address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease,and survivorship. This portion of the guidelines focuses on the use of systemic therapy in metastatic disease. The management of metastatic colorectal cancer involves a continuum of care in which patients are exposed sequentially to a variety of active agents, either in combinations or as single agents. Choice of therapy is based on the goals of treatment, the type and timing of prior therapy, the different efficacy and toxicity profiles of the drugs, the mutational status of the tumor, and patient preference.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Colonic Neoplasms; Deoxycytidine; Disease Progression; Fluorouracil; GTP Phosphohydrolases; Humans; Leucovorin; Liver Neoplasms; Membrane Proteins; Organoplatinum Compounds; Oxaloacetates; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome

We aimed to investigate the efficacy and tolerability of a FOLFOX7 regimen in the first-line treatment of metastatic colorectal cancer (mCRC) patients.. Patients were evaluated in two groups. Group A did not receive any treatment before, and group B had metastasectomy or metastasectomy plus primary tumor resection.. In total, 132 mCRC patients had received FOLFOX7 regimen. The A group consisted of 117 (88.6%) patients, and group B consisted of 15 (11.4%) patients. In the A group, 52.1% had an objective response, 9.4% complete response, 42.7% partial response, 24.8% stable response, and 23.1% progression, and there was a 54.5% rate of primary tumor resection, 22.2% rate of metastasectomy, 80.7% rate of R0 metastasectomy, 19.1% rate of R1 metastasectomy, 15 (10-19) months median progression-free survival, and 32 (22-41) months median overall survival. In the B group, 40 (4-70) months median disease-free survival and 58 (21-94) months median overall survival were found. When toxicities were evaluated, grade 3/4 toxicity was observed in 35.6%. Grade 3/4 hematologic toxicity was the most frequently observed toxicity (29.5%).. FOLFOX7 regimen was found to be an efficient and safe regimen for the first-line treatment of mCRC patients.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Metastasectomy; Middle Aged; Organoplatinum Compounds; Survival Rate; Treatment Outcome; Young Adult

Fluoropyrimidines, oxaliplatin, irinotecan and targeted therapies represent the standard treatment of metastatic colorectal cancer. After failure of all these treatments, few options are available. In such chemorefractory patients the effect of triplet chemotherapy with bevacizumab (FOLFIRINOX bevacizumab) has never been investigated.. 49 consecutive patients bearing unresectable metastatic colorectal cancer and who experienced failure to oxaliplatin- and irinotecan-based chemotherapy were treated with oxaliplatin (85 mg/m(2)), irinotecan (180 mg/m(2)), leucovorin (400 mg/m(2)), and fluorouracil (400 mg/m(2) bolus then 2,400 mg/m(2)) repeated every 2 weeks.. Median age was 63 (range 36-82) years. After a median follow-up of 12 months, the median progression-free survival was 5.8 months (95% CI 3.4-6.8) and the median overall survival was 11.9 months (95% CI 8-18). The response rate after the cycle was evaluable for 36 patients, whereby we observed 18% (95% CI 8-35) partial or complete response, 45% (95% CI 28-68) stable disease of more than 2 months, and 37% (95% CI 21-58) progression.. This study suggests that bevacizumab + FOLFIRINOX may be active in mCRC patients after failure of classical lines of chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Salvage Therapy; Survival Rate

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiologic entity characterized by headaches, altered mental status, seizures, and visual disturbances. It can occur in many different clinical entities such as severe hypertension and pre-eclampsia, or due to cytotoxic or immunosuppressive therapies. The pathogenesis of PRES is unclear, with dysregulated cerebral auto-regulation and endothelial dysfunction as important mechanisms proposed. Endothelial dysfunction is important especially in cases associated with cytotoxic therapies. Herein, we describe a patient with PRES with fatal outcome, who presented 5 days after the infusion of cycle 1 of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) regimen chemotherapy, without prior hypertension and other comorbidity, suggesting a link between PRES and FOLFIRI regimen. To our knowledge, this case report is the first describing PRES after FOLFIRI regimen, although others have described PRES after FOLFIRI with bevacizumab in colonic cancer patients.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Staging; Posterior Leukoencephalopathy Syndrome

Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biomarkers, Tumor; Camptothecin; Carboxylesterase; Colorectal Neoplasms; DNA Topoisomerases, Type I; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Proteins; Thymidylate Synthase; Treatment Outcome

Colorectal cancer (CRC) is among the most common cancers worldwide, but marked epidemiological differences exist between Asian and non-Asian populations. Hence, a consensus meeting was held in Hong Kong in December 2012 to develop Asia-specific guidelines for the management of metastatic CRC (mCRC). A multidisciplinary expert panel, consisting of 23 participants from 10 Asian and 2 European countries, discussed current guidelines for colon or rectal cancer and developed recommendations for adapting these guidelines to Asian clinical practice. Participants agreed that mCRC management in Asia largely follows international guidelines, but they proposed a number of recommendations based on regional 'real-world' experience. In general, participants agreed that 5-fluorouracil (5-FU) infusion regimens in doublets can be substituted with UFT (capecitabine, tegafur-uracil) and S1 (tegafur, 5-chloro-2,4-dihydroxypyridine and oxonic acid), and that the monoclonal antibodies cetuximab and panitumumab are recommended for KRAS wild type tumors. For KRAS mutant tumors, bevacizumab is the preferred biological therapy. FOLFOX (folinic acid, 5-FU, and oxaliplatin) is preferred for initial therapy in Asian patients. The management of mCRC is evolving, and it must be emphasized that the recommendations presented here reflect current treatment practices and thus might change as more data become available.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Asia; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Drug Combinations; ErbB Receptors; Fluorouracil; Guideline Adherence; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Metastasectomy; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Oxonic Acid; Panitumumab; Practice Guidelines as Topic; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Rectal Neoplasms; Tegafur; Tomography, X-Ray Computed

We evaluated the relationship between carcinoembryonic antigen half-life (CEA-HL) in the early period of induction chemotherapy for patients with liver metastases from colorectal cancer (CRLM) and their clinicopathological response.. Seventy-four patients with initially unresectable CRLM received FOLFOX with or without bevacizumab and 30 patients underwent hepatic resection. The CEA-HL in the early postoperative period was investigated, and the pathological response was classified according to tumor regression grade (TRG).. The CEA-HL after the third chemotherapeutic course (CEA-HL3) was significantly shorter in responders compared to non-responders. In the 30 patients who underwent hepatectomy, the CEA-HL3 was significantly shorter in the major or complete-pathological-response group for the TRGs than in the the partial-pathological-response group. If the patients were divided into two groups according to the median value of 20 days, progression-free survival and overall survival were significantly better in those with CEA-HL3 below the cut-off.. The CEA-HL is an early predictor of the pathological response and prognosis after induction chemotherapy for CRLM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Treatment Outcome

The Kyushu Study group of Clinical Cancer (KSCC) conducted phase II trials (KSCC0802-UMIN000001308) concerning liver resectability after first-line treatment of advanced liver-limited colorectal metastases (CRLM) by a prospective, multi-center study.. Patients received 6 cycles of mFOLFOX6 with bevacizumab followed by evaluating liver resectability. The primary end-point was liver resection rate.. The 40 patients enrolled from September 2008 to August 2010. The median number of administration cycles was 6 (range=1-7). The liver resectability cases were 16/40 (40.0 %) and the number of R0 cases was 10 patients (25.0%). An overall response rate was 30.0% (95% CI=15.2%-44.8%). Median progression-free and overall survival of all patients was 9.7 months and 33.0 months), respectively.. mFOLFOX6 with bevacizumab regimen is safe and effective for advanced liver-limited CRLM and might lead to high liver resectability.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Prospective Studies; Survival Rate

A vast majority of patients with metastatic colorectal cancer (mCRC) are not candidates for surgical resection. Radiofrequency ablation (RFA) is a safe and effective technique for treatment of isolated liver metastasis. After radiofrequency ablation, residual tumor can have aggressive growth, part of which is driven by the up-regulation of vascular endothelial growth factor (VEGF). Angiogenesis inhibitor bevacuzimab has been used in the management of mCRC with RFA. We present a patient with recurrent colorectal cancer and four hepatic metastases who was treated with RFA combined with aflibercept, another VEGF inhibitor and systemic chemotherapy. We believe that this is the first report of using aflibercept with RFA.. A 35-year-old female with stage IV rectal cancer with metastasis to a lymph node and multiple hepatic metastases was treated with chemo-radiation, surgical resection of the tumor and surgical resection of two segments of the liver. She underwent RFA of the hepatic lesions that could not be resected. She received adjuvant chemotherapy consisting of 5-fluorouracil (5-FU) and oxaliplatin for a total of 6 months. However, a positron emission tomography (PET) scan showed progression of disease with new and growing lymph nodes. She was treated with 6 cycles of capecitabine monotherapy. A follow-up PET scan showed four new liver lesions. She has RFA of her four liver lesions and was started on a combination of aflibercept and FOLFIRI. She received 10 cycles and a repeat magnetic resonance imaging (MRI) and PET scan showed stable disease.. This is the first reported case of a patient managed with RFA with aflibercept, an anti-VEGF agent, and FOLFIRI. This case showed both efficacy, as well as safety for the combined modalities in the management of mCRC.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Safety

XELOX plus bevacizumab (XELOX-Bev) and FOLFIRI plus Bevacizumab (FOLFIRI - Bev) treatments are an effective strategies patients with metastatic colorectal cancer (mCRC).The aim of this study was to compare efficacy of first-line XELOX-Bev treatment vs FOLFIRI-Bev treatment for mCRC.. A total of 409 patients with mCRC who received chemotherapy were included and divided into 2 groups. Group 1 (n=298) received XELOX-Bev and Group 2 (n=111) FOLFIRI-Bev. Comparisons were made in terms of overall (OS) and progression-free (PFS) survival, response rate (RR), and grade 3-4 toxicity.. Median follow-up was 11 months in Group 1 and 15 months for Group 2. Complete remission was observed in 29 (9.7%) and 2 (1.8%) patients, partial remission in 139 (46.6%) and 27 (24.5%) , stable disease in 88 (29.5%) and 49 (44.1%) and progressive disease in 42 (14.1%) and 33 (30.0%) patients in Group 1 and 2, respectively. Median OS was 25 months (range 2-57 months, 95%CI; 22.2-27.7) for Group 1 and 20 months (range 1-67 months, 95%CI; 16.8-23.1) for Group 2 (p=0.036). Median PFS was 9.6 months (range 2-36 months, 95%CI; 8.8-10.4) for Group 1 and 9 months (range 1-44 months, 95%CI; 7.4-10.5) for Group 2 (p=0.019). Objective RR was 56.4% in Group 1 and 26.1% in Group 2 (p<0.001).. First-line XELOX-Bev is more effective with a better response rate, prolongation of median PFS/OS, and a superior safety profile compared with FOLFIRI-Bev.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Neoplasms; Camptothecin; Capecitabine; Carcinoma; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Oxaloacetates; Retrospective Studies; Treatment Outcome

A 6 6-year-old woman with hematochezia was admitted to our hospital. A colonoscopy detected KRAS wild-type rectal cancer. An abdominal computed tomography (CT) scan revealed a liver metastasis, and invasion to the uterus was suspected. The patient underwent a laparotomy, and intraoperative cytology and peritoneal dissemination proved positive. The tumor had invaded the uterus. We administered chemotherapy consisting of 5-fluorouracil, Leucovorin, and oxaliplatin(mFOL FOX6)plus panitumumab. A CT scan and colonoscopy performed after 10 courses of chemotherapy indicated remarkable tumor regression. An abdominal CT scan did not detect any liver metastases, and we performed a laparoscopic low anterior resection. In the second operation, peritoneal dissemination and washing cytology were negative. The pathological diagnosis of the surgically resected specimen was ypStageII. The patient is recurrence-free 7 months after surgery.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Panitumumab; Peritoneal Neoplasms; Rectal Neoplasms; Tomography, X-Ray Computed

A case of successful chemotherapy for a metachronous liver metastasis following resection for sigmoid colon cancer is presented. A 51-year-old man underwent sigmoidectomy, ileocecal resection, and descending colon colostomy for sigmoid colon cancer with ileum invasion. Six courses of FOLFOX4 were performed as adjuvant chemotherapy. One year after sigmoidectomy, a liver metastasis was detected on computed tomography (CT) examination. Chemotherapy with FOLFOX+bevacizumab was restarted. Three courses were administered, but hepatic dysfunction occurred after the second and third courses, and FOLFOX was discontinued. Subsequent chemotherapy was reinitiated with FOLFIRI+bevacizumab. After 9 courses, the carcinoembryonic antigen level was normalized and appeared to be decreased by imaging studies. Upon the patient's request, only oral S-1 was administered. After 2 courses, CT revealed that the diameter of the tumor had increased by 2 cm. Therefore, right lobectomy of the liver, colostomy closure, and anastomosis were performed. During these procedures, a nodule was found in the omentum and was removed. Rapid intra-operative diagnosis revealed peritoneal dissemination. The pathological diagnosis was liver metastasis of sigmoid colon cancer, with necrosis and fibrosis seen in approximately one-half of specimens. The surgical margins were negative. Neither metastatic cancer nor dissemination were found in the resected greater omentum.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Sigmoid Neoplasms; Tomography, X-Ray Computed; Treatment Outcome

We report a rare case of long -term survival after laparoscopic resection of sigmoid colon cancer with multiple liver metastases, followed by 5-fluorouracil Leucovorin irinotecan with bevacizumab (FOLFIRI+Bev) chemotherapy. A 61-year-old woman was referred to our hospital with a principal complaint of bloody stools. She was diagnosed with sigmoid colon cancer by colonoscopy and multiple liver metastases by ultrasonography. In October 2008, we performed laparoscopic resection of the sigmoid colon cancer with multiple liver metastases, followed by 4 courses of modified 5-fluorouracil Leucovorin oxaliplatin ( mFOLFOX6) chemotherapy. In February 2009, abdominal ultrasonography showed progressive disease, and as a result the patient was administered 73 courses of FOLFIRI +Bev chemotherapy. As of March 2014, the patient has survived for more than 5 years following treatment, but still has liver metastases. The possibility of resecting multiple liver metastases from colorectal cancer should be considered, and in some cases, chemotherapy may enhance survival.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Combined Modality Therapy; Female; Fluorouracil; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Middle Aged; Sigmoid Neoplasms; Time Factors

We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients.. All unresectable metastatic colorectal cancer patients who began receiving bevacizumab at participating facilities from 2006 to 2011 were retrospectively analyze to determine the safety and efficacy. The primary end points were Progression Free Survival (PFS) and Overall Survival (OS). The secondary end points were adverse events.. A total of 101 patients were enrolled in the study. The primary tumor site was the colon in 53 patients and the rectum in 48 patients. The most common metastatic sites were the liver (63.4%), lung (31%), and peritoneum (10%). In first-line therapy, 76 (75.2%) patients received the FOLFOX regimen. Among these patients, 33 (43.4%) patients received FOLFOX alone, and 43 (56.6%) received FOLFOX plus bevacizumab. The addition of bevacizumab to first-line chemotherapy was associated with increases in median PFS (12.5 vs. 6.0 months; P = .00001) and median OS (24.0 vs. 16.0 months; P = 0.0221). The risks of adverse events were not significantly increased with the addition of bevacizumab.. The addition of bevacizumab to first-line therapy in CRC patients provided clinically significant patient benefit, including statistically significant improvement in OS and a favorable tolerability profile.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Retrospective Studies; Time Factors; Treatment Outcome

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of Th1 cells promotes such immunity. The aim of this study was to assess changes of host immunity in relation to efficacy in patients with liver cirrhosis (LC) and advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy (CIAC).. Forty-three adult Japanese LC patients who had aHCC received CIAC. Blood samples were collected before and after CIAC.. Eleven of the 43 patients showed a partial response (group PR) and 21 patients had stable disease (group SD), but 11 patients showed no response (group PD). There were no significant differences of Th1 or Th2 cells between before and after CIAC in each group. However, groups SD and PD had higher levels of Th2 cells than in group PR before and after CIAC. The percentage of regulatory T (Treg) cells in group PD was significantly increased after CIAC compared with before CIAC, whereas groups PR and SD showed significant decrease after CIAC.. The percentage of Th2 cells is useful for predicting the response to CIAC and the percentage of Treg cells is useful for assessment of efficacy in LC patients with aHCC receiving CIAC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Lymphocyte Count; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Predictive Value of Tests; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Treatment Outcome

In this case report, the authors aim to demonstrate the success of recent methods in the radical treatment of a patient with primary inoperable liver and subsequent colorectal cancer pulmonary metastases.. A 75 year old patient with inoperable bulky metastasis in the right hepatic lobe and insufficient future remnant liver volume was indicated for a stage procedure in the liver parenchyma. Embolization of the right branch of the portal vein was first performed with subsequent administration of stem cells into the contralateral liver lobe. Following compensatory growth of the left liver lobe, right-sided hepatectomy was performed with subsequent adjuvant oncological treatment. Six months after the surgery, a metastasis developed in the right pulmonary lobe which was solved by metastasectomy.. The patient, one year after the diagnosis of inoperable liver metastasis, is completely healthy and free of signs of disease recurrence.. A comprehensive oncosurgical approach using up-to-date diagnostic and treatment options may offer patients with metastatic colorectal cancer, radical treatment with the hope of long-term quality survival.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Embolization, Therapeutic; Fluorouracil; Hematopoietic Stem Cell Transplantation; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Liver Regeneration; Lung Neoplasms; Male; Organoplatinum Compounds; Pneumonectomy

A 61-year-old man had undergone five courses of modified FOLFOX6(mFOLFOX6)chemotherapy with calcium-magnesium(Ca/Mg)infusion for a rectal cancer with multiple liver metastases from October 2008. After this treatment, the primary rectal tumor and metastatic tumors were considered as a partial response(PR), and lower anterior resection was carried out in February 2009. After the operation, mFOLFOX6 chemotherapy with bevacizumab was started in March 2009. After 15 courses of chemotherapy, the patient received 7. 5 g of gosha-jinki-gan(TJ-107)daily from August 2009, and the drug compliance was 69%. From the 18th course of chemotherapy in October 2009, glutathione(GSH)was given at a dose of 200 mg before each oxaliplatin administration. From the 35th course of chemotherapy in November 2010, the patient received 1. 5 g of powdered processed aconite root(TJ-3027)daily. TJ-3027 administration was escalated to 4. 5 g daily, and drug compliance was 73%. Grade 4 neutropenia was observed in December 2010, and we reduced oxaliplatin to 65 mg/m(2) from the 37th course. Fifty chemotherapy courses were administered until October 2011. The patient received a total 3, 970 mg/m(2) of oxaliplatin, however, the neurotoxicity level of the patient remained at grade 2. Ca/Mg infusion and TJ-107 administration have been reported not to reduce the activity of FOLFOX individually, and severe side effects are rare. So one must consider the combination treatment of Ca/Mg and TJ-107 for prevention of oxaliplatin-related neurotoxicity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Peripheral Nervous System Diseases; Rectal Neoplasms; Time Factors

Patients with metastatic colorectal cancer receive chemotherapy prior liver resection more and more frequently. This preoperative treatment has many effects which have to be analysed, like the safety of liver resection, toxicity, tissue regeneration, radiological and pathological response and survival data. The aim of the study was to evaluate the safety of bevacizumab containing preoperative chemotherapy and functional recovery of the liver after resection for colorectal liver metastases (CLM) and to analyse radiological and pathological data. Data of three groups of 120 consecutive patients-(1) CTX + BV: cytotoxic chemotherapy + bevacizumab, (2) CTX: cytotoxic chemotherapy, (3) NC: no treatment before liver resection-were analysed. Postoperative liver function and complications were compared, clinical, radiological and pathological data were evaluated. Between 01.12.2006 and 31.12.2010 41 resections was performed after chemotherapy + bevacizumab (CTX + BV) and 27 resections was performed after preoperative chemotherapy without bevacizumab (CTX). There were 60 hepatic resections in this period without neoadjuvant treatment (NC). 8 patients had repeated resections. The postoperative complication rate was 40 % but there was no statistical difference between the groups (P = 0.72). Only the type of resection was associated with a significantly higher complication rate (p = 0.03). The subgroup of patients, who received irinotecan had a higher complication rate in the CTX group than in the BV + CTX group (55 % vs 41 %). Preoperative administration of bevacizumab was associated with higher peak postoperative AST, ALT levels but did not affect functional recovery of the liver. The RECIST system was not able to predict the outcome after chemotherapy in every patient and in many cases this system overestimated the effect of chemotherapy. On histopathological examination the presence of necrosis was not associated with chemotherapy or pathological response. Use of chemotherapy before hepatic resection of CLM was not associated with a significant increase in complication rates. The functional recovery of the liver was not affected by the preoperative administration of chemotherapy. The use of combined neoadjuvant chemotherapy is safe before hepatic resection.

Topics: Adult; Aged; Aged, 80 and over; Alanine Transaminase; Analysis of Variance; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Histocytochemistry; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

Oxaliplatin-based chemotherapy has been linked to the development of sinusoidal obstruction syndrome (SOS), which is detrimental to outcome after liver resection for colorectal liver metastases (CLM). The aim of this study was to determine how the expression of genes involved in the transport and metabolism of FOLFOX chemotherapy impacts on tissue injury in a murine model of CLM.. Experimental CLM was established in C57/B16 mice and treated with FOLFOX chemotherapy. After 3 weeks, the animals were killed and RNA extracted from liver, spleen and tumour tissue. DNA damage was assessed by immunohistochemistry for γH2AX. Gene expression was determined by reverse transcriptase polymerase chain reaction.. FOLFOX treatment was associated with an increase in the number of γH2AX-positive cells in both the spleen (P < 0.01) and tumour tissue (P < 0.01), but not the liver. Tissue resistance to injury following FOLFOX was associated with high expression of the copper transporter ATP7B. Differences in the expression of genes related to 5-fluorouracil metabolism or DNA repair did not correlate with the severity of tissue injury.. High levels of expression of ATP7B are associated with resistance to tissue injury following FOLFOX chemotherapy. Polymorphisms in the ATP7B gene may explain varying susceptibility to SOS among patients following oxaliplatin-based chemotherapy.

Topics: Adenosine Triphosphatases; Animals; Antineoplastic Combined Chemotherapy Protocols; Cation Transport Proteins; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Copper-Transporting ATPases; Fluorouracil; Gene Expression Regulation; Genetic Predisposition to Disease; Histones; Leucovorin; Liver; Liver Neoplasms; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Oxaliplatin; Pharmacogenetics; Phenotype

A new method for liver hypertrophy was recently introduced, the so-called associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) procedure. We present a video of an ALPPS procedure with the use of pneumoperitoneum.. A 29-year-old woman with colon cancer and synchronous liver metastasis underwent a two-stage liver resection by the ALPPS technique because of an extremely small future liver remnant.. The first operation began with 30 min pneumoperitoneum. Anatomical resection of segment 2 was performed, followed by multiple enucleations on the left liver. The right portal vein was ligated and the liver partitioned. The abdominal cavity was partially closed, and a 10 mm trocar was left to create a pneumoperitoneum for additional 30 min. The patient had an adequate future liver remnant volume after 7 days, but she was not clinically fit for the second stage of therapy, so it was postponed. She was discharged on day 7 after surgery. The second stage took place 3 weeks later and consisted of an en-bloc right trisectionectomy extended to segment 1. The patient recovered and was discharged 9 days after second-stage surgery. Postoperative CT scan revealed an enlarged remnant liver.. The ALPPS procedure is a new revolutionary technique that permits R0 resection even in patients with massive liver metastasis. The use of pneumoperitoneum during the first stage is an easy tool that may prevent hard adhesions, allowing an easier second stage. This video may help oncological surgeons to perform and standardize this challenging procedure.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Ligation; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Pneumoperitoneum, Artificial; Portal Vein

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; ErbB Receptors; Eyelashes; Female; Fluorouracil; Hair Diseases; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Neoadjuvant Therapy; Neoplasm Proteins; Panitumumab

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Cold Ischemia; Extracorporeal Circulation; Female; Fluorouracil; Hepatectomy; Hepatic Veins; Humans; Jugular Veins; Leucovorin; Liver Circulation; Liver Neoplasms; Neoadjuvant Therapy; Neoplasms, Multiple Primary; Organoplatinum Compounds; Sigmoid Neoplasms; Treatment Outcome; Vena Cava, Inferior

We retrospectively analyzed ABCG2 expression levels in patients with metastatic colorectal cancer (CRC) to investigate the interaction between ABCG2 expression and the tumor response to oxaliplatin and 5-fluorouracil (FOLFOX).. Forty-three patients with CRC with liver metastasis who received first-line FOLFOX treatment at our institution between 2008 and 2010 were enrolled. ABCG2 expression was assessed by immunohistochemistry. Tumor response was determined using the modified Response Evaluation Criteria in Solid Tumors criteria.. At least 50% tumor shrinkage was observed in 16/43 patients (37.2%), including a complete response in 1 patient. According to the intensity of ABCG2 expression and the percentage of tumor cells expressing ABCG2, 21 tumors displayed high ABCG2 expression. Among these tumors, only 2 (9.5%) exhibited partial responses to FOLFOX; conversely, 63.6% of tumors with low ABCG2 expression (14/22) responded to FOLFOX. Primary and corresponding metastatic samples were available for 15 patients, and 13 of the metastatic tumors had higher ABCG2 expression than the corresponding primary tumors, but only 1 of these tumors responded to FOLFOX (7.7%).. ABCG2 expression is associated with the tumor response to FOLFOX in patients with metastatic CRC. ABCG2 may be a selective marker for the efficacy of FOLFOX in treating CRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biomarkers, Pharmacological; Biomarkers, Tumor; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Organoplatinum Compounds; Paraffin Embedding; Prognosis

To evaluate a strategy combining high-dose 5FU-irinotecan-leucovorin (HD-FOLFIRI) chemotherapy, radiofrequency ablation and surgery in patients with unresectable liver metastases from colorectal cancer.. Patients, all presenting UDP glucuronosyl transferase-1A1 (UGT1A1) 6/6 or 6/7 genotype, received HD-FOLFIRI (with high-dose irinotecan: 260 mg/m(2)), one cycle every two weeks. The feasibility of local therapy (surgery and/or radiofrequency) was assessed every four cycles. The objective of therapy was the complete clearance rate of metastases.. The trial was terminated after inclusion of 18 out of the 40 planned patients due to insufficient recruitment. The median number of metastases was seven (range=2-30). On intention-to-treat analysis, six patients (33.3%) received local treatment of metastases with complete clearance of metastases in each case. Median progression-free and overall survivals were 15.3 months and 33.7 months, respectively.. The assessed strategy is feasible and allows for a complete clearance of metastases in one third of patients, with prolonged survival.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Feasibility Studies; Female; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Polymerase Chain Reaction; Survival Rate; Treatment Outcome; Young Adult

Sinusoidal obstruction syndrome (SOS) following oxaliplatin based chemotherapy can have a significant impact on post-operative outcome following resection of colorectal liver metastases. To date no relevant experimental models of oxaliplatin induced SOS have been described. The aim of this project was to establish a rodent model which could be utilised to investigate mechanisms underlying SOS to aid the development of therapeutic strategies.. C57Bl/6 mice, maintained on a purified diet, were treated with intra-peritoneal FOLFOX (n=10), or vehicle (n=10), weekly for five weeks and culled one week following final treatment. Sections of the liver and spleen were fixed in formalin and paraffin embedded for histological analysis. The role of oxidative stress on experimental-induced SOS was determined by dietary supplementation with butylated hydroxyanisole and N-acetylcysteine.. FOLFOX treatment was associated with the development of sinusoidal dilatation and hepatocyte atrophy on H&E stained sections of the liver in keeping with SOS. Immunohistochemistry for p21 demonstrated the presence of replicative senescence within the sinusoidal endothelium. FOLFOX induced endothelial damage leads to a pro-thrombotic state within the liver associated with upregulation of PAI-1 (p<0.001), vWF (p<0.01) and Factor X (p<0.001), which may contribute to the propagation of liver injury. Dietary supplementation with the antioxidant BHA prevented the development of significant SOS.. We have developed the first reproducible model of chemotherapy induced SOS that reflects the pathogenesis of this disease in patients. It appears that the use of antioxidants alongside oxaliplatin based chemotherapy may be of value in preventing the development of SOS in patients with colorectal liver metastases.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Cell Cycle; Colorectal Neoplasms; Cyclin-Dependent Kinase Inhibitor p21; Cytokines; Disease Models, Animal; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Inflammation Mediators; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Organoplatinum Compounds; Oxaliplatin; Oxidative Stress; Serpin E2; Thrombosis

Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC).. (18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (∆SUVmax) and SAM (∆SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS).. A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ∆SUVmax of 25.3% and ∆SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ∆SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ∆SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS).. (18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ∆SAM were found to be significant prognostic factors for PFS and OS.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multimodal Imaging; Organoplatinum Compounds; Positron-Emission Tomography; Radiopharmaceuticals; Tomography, X-Ray Computed; Treatment Outcome

The imaging factor predicting the response to bevacizumab (BV) as concomitant chemotherapy has yet to be determined. This study examined correlation between response to chemotherapy with concomitant BV for hepatic metastasis of colorectal cancer and degree of contrast enhancement (CE) using contrast-enhanced computed tomography (CT).. Data were analyzed retrospectively for 35 patients treated with oxaliplatin-based chemotherapy as the first-line chemotherapy. Patient data were divided according to treatment with concomitant BV (BV group: n = 20, non-BV group: n = 15). Using an image control system, the degree of CE was evaluated by the ratio of the contrast-enhanced CT value of hepatic metastatic lesions to plain CT value, whereby patients were classified into the high-CE and low-CE group.. After completion of chemotherapy treatment, the degree of enhancement of hepatic metastasis in the BV group was significantly lower than that in the non-BV group (p = 0.03). In the BV group, a significant correlation between higher contrast enhancement and higher tumor shrinkage rate was observed (R² = 0.25, p = 0.03), whereas no such correlation was noted in the non-BV group. In the high-CE group (n = 18), the tumor shrinkage rate increased to 29.6 % in the BV group compared with -1.46 % in the non-BV group (p = 0.03), whereas in the low-CE group, no significant difference was noted between patients in the two groups.. Pretreatment evaluation of the degree of CE correlated with the response to concomitant chemotherapy with BV.

Topics: Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Contrast Media; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Tomography, X-Ray Computed; Tumor Burden

The FOLFOXIRI regimen produces a high rate of radiological and histopathological responses. Bevacizumab added to chemotherapy showed an improvement in pathological response and necrosis of colorectal liver metastases (CLMs). FOLFOXIRI plus bevacizumab produced promising early clinical results and is under investigation in several randomised trials, although no data are currently available on its effects on response of CLMs and on liver toxicities.. Starting from 499 patients enrolled in first-line phase II/III trials, we selected on the basis of tissue sample availability 18 patients treated with FOLFOXIRI/XELOXIRI and 24 patients treated with FOLFOXIRI plus bevacizumab who underwent secondary resection of CLMs. The 28 untreated patients who underwent primary resection of CLMs were included as control group. Responses of CLMs and chemotherapy-induced toxicities were assessed.. Among the patients, 63% of those treated with FOLFOXIRI plus bevacizumab, as compared with 28% of those treated with only FOLFOXIRI/XELOXIRI, showed a histopathological response (P=0.033). In the two groups, 52% and 12.5%, respectively, showed necrosis ≥50% (P=0.017). The incidence of liver toxicities was not significantly increased in patients treated with FOLFOXIRI plus bevacizumab.. The addition of bevacizumab to FOLFOXIRI produces high rates of pathologic responses and necrosis of CLM without increasing liver toxicity.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Case-Control Studies; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multicenter Studies as Topic; Neoadjuvant Therapy; Organoplatinum Compounds; Retrospective Studies

We examined the whole genome expression profile in advanced colorectal cancer (ACC) patients who had received FOLFOX4 chemotherapy to establish a genetic biomarker model predicting chemotherapy sensitivity.. Eligible ACC patients were divided into two groups, based on postchemotherapy evaluation results: specifically, the sensitive group (experimental group) and the resistant group (control group). The genome expression profiles of colorectal cancer tissues were examined using DNA microarray analysis, and differential gene expression was identified using a significance analysis of the microarray. The probe signal log ratios were used to produce the area-under-the-curve, sensitivity, and specificity for candidate genes. Genes exhibiting differential expression and significant predictive power were used to simulate a genetic model for estimating chemotherapy sensitivity.. Totally, 30 ACC patients were eligible for the study, 13 assigned to the experimental group and 17 to the control group. In total, 30 genes showing significant differential expression were identified. Seven candidate genes (NKX2-3, FXYD6, TGFB1I1, ACTG2, ANPEP, HOXB8, and KLK11), which exhibited positive or negative correlations, were incorporated into a genetic model, with an overall accurate predication rate of 93.3%.. The predictive model involving the seven genes listed had high accuracy in estimating chemotherapy sensitivity to the FOLFOX4 regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Liver Neoplasms; Male; Microarray Analysis; Middle Aged; Models, Genetic; Neoplasm Metastasis; Organoplatinum Compounds

Efficacy of chemotherapy plus bevacizumab has been shown in patients with metastatic colorectal cancer (mCRC) compared with chemotherapy alone. The aim of the present study was to evaluate the efficacy and safety of FOLFIRI or XELIRI regimens in combination with bevacizumab for mCRC patients in a first-line setting.. A total of 132 patients with previously untreated and histologically confirmed mCRC were included. They were treated with either FOLFIRI-Bevacizumab (Bev) or XELIRI-Bev according to physician preference. The efficacy and safety of the two regimens were compared.. Between 2006 and 2010, 68 patients were treated with the XELIRI-Bev regimen, while the remaining 64 patients received the FOLFIRI-Bev regimen. The median age was 58.5 years (53.6 years in the FOLFIRI-Bev and 59.7 years in the XELIRI-Bev arm, p=0.01). Objective response rate was 51.6% for FOLFIRI-Bev versus 41.2% for XELIRI-Bev (p=0.38). At the median follow-up of 24.5 months, the median progression-free survival (PFS) was not different between two groups (14.2 months in FOLFIRI-Bev vs. not reached in the XELIRI-Bev, p=0.30). However, median overall survival time for the FOLFIRI-Bev arm was better than that for patients treated with XELIRI- Bev, but these differences was not statistically significant (37.8 months vs. 28.7 months, respectively, p=0.58). Most commonly reported grade 3-4 toxicities (FOLFIRI-Bev vs XELIRI-Bev) were nausea/vomiting (7.8% vs. 14.7%, p=0.27), diarrhea (10.9% vs 22.1%, p=0.10), hand-foot syndrome (0% vs 8.8%, p=0.02) and neutropenia (18.7% vs 27.9%, p=0.22).. Our results showed that FOLFIRI-Bev and XELIRI-Bev regimens were similarly effective treatments in a first-line setting for patients with untreated mCRC, with manageable adverse event profiles.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Young Adult

We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC.. Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers.. Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group.. These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Drug Combinations; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Paclitaxel; Retrospective Studies; Survival Rate; Treatment Outcome

Here we bioengineered a metastatic pancreatic tumor model with homogenous human CD133(+)CXCR4(+) cancer stem cells (CSC) and a polyglyconate/gelatin electrospun scaffold. The scaffold sported a highly porous microstructure with the majority of fibers possessing a diameter between 500μm and 1500μm. The scaffold supported the growth of tumor cells without provoking apoptosis. The homogeneous CD133(+)CXCR4(+) CSC was transplanted with the scaffold into the pancreas of nude mice to establish a metastatic pancreatic tumor. After 8 weeks, the tumor volume and weight in the scaffold model were 40.52% and 51.49% greater than the traditional model, respectively. The scaffold also increased the incidence of tumor formation and readily induced a hepatic metastasis. In this model we found that FOLFIRINOX possessed a superior capability of preventing the hepatic metastasis of pancreatic tumor cells than gemcitabine. A mechanistic study attributed this superiority to the fact that FOLFIRINOX could induce a greater apoptosis of CD133(+)CXCR4(+) CSC, thus depriving the driving force of hepatic metastasis. This metastatic tumor model showed an increased incidence of tumor formation, an accelerated tumorigenesis and a significant hepatic metastasis, therefore offering scientists a proven platform to study chemotherapeutic drugs.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bioengineering; Camptothecin; Cell Line, Tumor; Deoxycytidine; Disease Models, Animal; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Organoplatinum Compounds; Pancreatic Neoplasms; Tissue Scaffolds; Xenograft Model Antitumor Assays

Marginal statistical evidence of efficacy of adjuvant and/or perioperative chemotherapy after resection of colorectal metastases exists, but formal recommendations are still lacking. The present study evaluated the adjuvant systemic chemotherapy after the first resection of liver and lung colorectal cancer metastases.. We retrospectively reviewed data of 181 consecutive unselected patients with R0 resection of colorectal metastases treated simultaneously at 2 institutions from 1997 to 2004. Patients > 75 years old, with an Eastern Cooperative Oncology Group Performance Status Score ≥ 2 or unfit for adjuvant chemotherapy were excluded from the analysis. The decision on chemotherapy after surgery was left to the patient in the absence of conclusive data on the efficacy of adjuvant chemotherapy in this setting. A total of 151 patients (131 with liver metastases, 20 with lung metastases), 78 of whom underwent adjuvant chemotherapy, were evaluable for disease-free survival (DFS) and overall survival. The main prognostic factors for DFS after resection of colorectal cancer metastases were investigated in univariate and multivariate analyses.. At the univariate analysis, the number of resected lesions, lesion volume, disease-free interval and adjuvant systemic chemotherapy were the only significant prognostic factors. At multivariate analysis, only adjuvant chemotherapy and disease-free interval were independent prognostic factors (hazard ratios 1.66 and 1.62, respectively). The median DFS of patients who underwent systemic adjuvant chemotherapy was 16 months compared with 9.7 months for patients with observation alone (hazard ratio 1.56). Estimated 5-year DFS was 17.4% and 10.5% for treated and untreated patients, respectively.. Adjuvant chemotherapy after metastasectomy in patients with colorectal cancer showed a significant benefit for DFS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Metastasectomy; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Organoplatinum Compounds

We present the clinical observation of combined treatment of a patient with metastatic gastric cancer. The patient underwent combined chemotherapy for initially inoperable gastric cancer with metastases to the liver, paragastric lymph nodes, and peritoneal carcinomatosis with complete regression of distant metastases, which allowed radical surgery. The patient is currently under regular team observation without signs of disease. His present survival is 44 months.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Fluorouracil; Gastrectomy; Humans; Induction Chemotherapy; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Peritoneal Neoplasms; Stomach Neoplasms; Taxoids; Treatment Outcome

Hepatoid adenocarcinoma (HAC) is a rare type of extrahepatic carcinoma whose morphology is similar to that of hepatocellular carcinoma (HCC). Metachronous HCC and HAC in the same patient is extremely rare. The case of a 68-year-old man with chronic hepatitis B infection who had both HCC and HAC of the stomach is reported herein. Nine years previously this patient had been diagnosed with HCC and received a right lobectomy. HCC that recurred at the caudate lobe at 6 months after the operation was successfully treated with transarterial chemoembolization. The patient was followed up regularly thereafter without evidence of tumor recurrence for 9 years. In July 2010 his serum alpha-fetoprotein (AFP) level elevated from 6.5 ng/mL to 625.4 ng/mL, and he developed a probable single metastatic lymph node around the hepatic artery without intrahepatic lesions. Subsequent evaluation with upper endoscopy revealed a 4-cm ulcerative lesion on the antrum of the stomach. Subtotal gastrectomy was performed with lymph-node dissection. Histologic examination revealed a special type of extrahepatic AFP-producing adenocarcinoma-HAC with lymph-node metastasis-which indicates that HAC can be a cause of elevated AFP even in patients with HCC. HAC should be considered if a patient with stable HCC exhibits unusual elevation of AFP.

Topics: Adenocarcinoma; Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Fluorouracil; Gastroscopy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Recurrence; Silicates; Stomach Neoplasms; Titanium; Tomography, X-Ray Computed

We report our experience with a case of colorectal cancer treated with chemotherapy for a liver metastasis patient on hemodialysis. The patient was a 67-year-old man with a history of chronic renal failure, who was on hemodialysis since 2005. High anterior resection was performed for sigmoid colon and rectal cancer in January, 2010. After starting chemotherapy while planning to use FOLFOX6+bevacizumab(BV)as a postoperative standard chemotherapy, in combination with hemodialysis three times a week while performing dose escalation, administration postponement was continued for myelosuppression that was considered to be the effect of oxaliplatin. Oxaliplatin was administered for only 2 courses, and was then changed to BV+sLV5FU2 therapy. We continued treating the metastases approximately on schedule. Imaging revealed, the liver metastases were CR because they had disappeared. The BV use case of the dialysis case had few reports, but was thought to be able to use it by careful administration safely.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Organoplatinum Compounds; Renal Dialysis; Sigmoid Neoplasms

There is no consensus for laparoscopy first in patients with rectal cancer and synchronous liver metastases, whose metastases are confined to the liver. This study aimed to evaluate its indications for one-stage surgery in laparoscopy.. Eighteen patients with rectal cancer and synchronous liver metastases, who had undergone laparoscopic colorectal resection and simultaneous treatment for liver metastases, were retrospectively reviewed.. Concomitant with laparoscopic colorectal resection, eight patients received liver resection simultaneously; 10 patients underwent a variety of down-staging management including local ablation, right hepatic portal vein ligation, and implantation of chemotherapy pumps into the hepatic artery. The colo-anal/rectal anastomoses were performed with a stapler or "pull-though" mode though the anus. Three patients underwent two-stage liver resection following tumor down-staging. Median survival time was 22.3 months.. Laparoscopy approach for rectal cancer and synchronous liver metastases is feasible in selected patients. Colon pull-through anastomosis was a potential method to avoid abdominal incision and decrease the risk of anastomotic leakage. It is worth further investigation regarding its advantages over traditional modalities with a prospective randomized controlled study.

Topics: Adenocarcinoma; Adult; Aged; Anal Canal; Anastomosis, Surgical; Antineoplastic Combined Chemotherapy Protocols; Colon; Female; Fluorouracil; Hepatectomy; Hepatic Veins; Humans; Infusion Pumps, Implantable; Laparoscopy; Leucovorin; Ligation; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Retrospective Studies; Time Factors; Young Adult

We report here a case of partial response to hepatic arterial infusion chemotherapy in a patient who developed serious hepatic failure due to unresectable colorectal cancer and hepatic metastasis and showed resistance to systemic chemotherapy with molecular targeted drugs, mFOLFOX6, and FOLFIRI. The patient was a 60-year-old woman who underwent sigmoidectomy for sigmoid colon cancer, lateral posterior hepatic segmentectomy for metastatic liver cancer, and postoperative radiation therapy for metastatic lung cancer. As first-line systemic chemotherapy, mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin), bevacizumab + FOLFIRI (irinotecan, 5-fluorouracil, leucovorin), and anti-epidermal growth factor receptor antibody  + irinotecan were administered, in that order. However, recurrent hepatic metastasis was exacerbated, which induced serious hepatic failure manifested by general malaise, jaundice, abnormal hepatic function, difficulty in walking due to bilateral lower extremity edema, and decreased appetite. The patient was admitted in a serious condition. After hospitalization, the patient received hepatic arterial infusion chemotherapy with 5-fluorouracil and l-leucovorin. After two complete courses, the symptoms improved. The patient's performance status also improved, and she was discharged from the hospital. Four months after discharge, the patient had continued outpatient chemotherapy and maintained excellent performance status. Although HAIC is not presently considered an alternative to systemic chemotherapy, it is sometimes effective in patients who show resistance to molecular targeted drug therapy, FOLFOX, and FOLFIRI, and in whom hepatic metastasis is a key factor in determining prognosis and serious hepatic failure. Further studies should be performed in the future to verify these findings.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Failure; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Remission Induction; Tomography, X-Ray Computed

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Mitomycin; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy, Intensity-Modulated; Rectal Neoplasms; Tomography, X-Ray Computed

Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Diagnosis, Differential; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Tomography, X-Ray Computed

A 77-year-old man with colon cancer and multiple metastases to the liver and lungs underwent resection of the primary tumor and D3 lymph node dissection. He presented with chronic atrial fibrillation; therefore, warfarin was used initially as an anticoagulant. Because of the need to administer a fluoropyrimidine-based antineoplastic agent[5-fluorouracil(5-FU)] during chemotherapy, we changed the anticoagulant from warfarin to dabigatran etexilate(dabigatran)before initiating chemotherapy. No complications or excessive decrease in coagulability was observed after changing the anticoagulant; chemotherapy was safely continued. Unlike warfarin, dabigatran undergoes renal excretion, and thus, can be safely used in anticoagulant therapy without any drug interaction with 5-FU. Thus, we believe that dabigatran may be the anticoagulant of choice in the future for cancer patients who are scheduled to undergo chemotherapy using fluoropyrimidine-based antineoplastic agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Atrial Fibrillation; Benzimidazoles; Colonic Neoplasms; Dabigatran; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Pyridines

A 57-year-old Caucasian man with a history of Child's class A hepatitis C, cirrhosis and progressive multifocal hepatocellular carcinoma was treated with sorafenib but progressed after 7 months of stable disease. At progression he was given salvage chemotherapy consisting of 5-fluorouracil and leucovorin and went into complete radiographic remission after 12 cycles of treatment. He did develop a portal vein thrombosis but nevertheless his hepatic lesions continued to resolve. Throughout his therapy α-fetoprotein (AFP) levels decreased only minimally. He did not seek retreatment after 14 cycles of chemotherapy and presented 3 months later with relapsed disease on CT scans with markedly elevated AFP levels. He received one more chemotherapy cycle but was unable to tolerate further treatment, succumbing to his disease 3 months thereafter, and a total of 29 months after he was deemed a sorafenib failure.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Hepatocellular; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary; Niacinamide; Phenylurea Compounds; Sorafenib; Tomography, X-Ray Computed; Treatment Outcome; Vitamin B Complex

Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury.. We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI.. In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury.. It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chemical and Drug Induced Liver Injury; Collagen Type I; Colorectal Neoplasms; Fluorouracil; Hepatic Veno-Occlusive Disease; Inflammation; Leucovorin; Liver; Liver Neoplasms; Matrix Metalloproteinase 2; Megakaryocytes; Mice; Mice, Inbred C57BL; Organoplatinum Compounds; Plasminogen Activator Inhibitor 1; Spleen; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta

The patient was a 72-year-old man with cancer of the descending colon accompanied by multiple unresectable hepatic metastases. As first-line systemic chemotherapy, mFOLFOX6, anti-vascular endothelial growth factor (VEGF) antibody+FOLFIRI, and anti-epidermal growth factor receptor (EGFR) antibody+CPT-11 were administered in order mentioned. However, recurrent hepatic metastasis was exacerbated. As fourth-line chemotherapy, the patient received hepatic arterial infusion chemotherapy (HAIC) with 5-FU and LV. The chemotherapy regimen consisted of 5-FU 600 mg/m2 and LV 250 mg/m2 given once a week. After 6 weeks, CT revealed that the multiple liver metastases had not increased, and the level of the tumor marker CA19-9 significantly decreased from 1,980 (normal range, 0-37 U/mL)to 942.9 U/mL. HAIC was continued, and the patient maintained an excellent PS for 3.5 months. We report a case of stable disease in response to HAIC in a patient who exhibited resistance to systemic chemotherapy with an anti-EGFR antibody, an anti-EGFR antibody, mFOLFOX6, and FOLFIRI.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male

A 58-year-old man was referred to our hospital for a huge tumor occupying the entire right lobe of the liver. An imaging method revealed a 15 cm-sized hepatocellular carcinoma in the right lobe which extended to the internal segment across the middle hepatic vein. The serum AFP level was 15.3 ng/mL, and the level of protein induced by vitamin K absence or antagonist II was 4,340 mAU/mL. We judged it unresectable, then arterial infusion chemotherapy using 5-fluorouracil, cisplatin, and Leucovorin was performed. After 4 courses, the tumor was markedly reduced to 56 mm. We performed an extended right lobectomy. In the operative finding, although the tumor partially reached the internal segment, the middle hepatic vein was preserved. Nine months after operation, no sign of recurrence was found. It is suggested that hepatic arterial infusion therapy is useful for pre-operative therapy of far-advanced hepatocellular carcinoma as a part of combined modality therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cisplatin; Combined Modality Therapy; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged

Converting chemotherapy followed by surgery is known to be associated with improved clinical outcomes in colorectal cancer (CRC) patients with hepatic metastasis. This study is to investigate the clinicopathological prognostic factors for disease-free survival (DFS) after curative resection of primary and metastatic lesions.. We retrospectively analyzed the medical records of 76 CRC patients who had initially had unresectable hepatic metastasis, which was considered resectable after systemic chemotherapy, and had undergone curative surgery in the period from January 2006 to December 2011. DFS was compared by assessing clinical data including age, sex, staging, number of hepatic lesion(s), size of the largest hepatic lesion and serum carcinoembryonic antigen (CEA) levels.. The median age was 57 years and 47 patients were male. The median DFS was 10.4 months. Multivariate Cox regression analysis revealed that age <50 years (HR 2.70, 95% CI 1.43-5.10, p = 0.002) and CEA elevation after curative surgery (HR 2.20, 95% CI 1.11-4.36, p = 0.023) were associated with a shorter DFS.. Given that patients <50 years old or with elevated CEA levels after curative surgery demonstrated a short DFS, additional postoperative systemic treatment or active surveillance, at least, should strongly be considered for this group.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Carcinoembryonic Antigen; Cetuximab; Colectomy; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Assessment; Risk Factors; Treatment Outcome

To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC).. Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed.. The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen.. BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Hemorrhage; Humans; Hypertension; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Proteinuria; Rectal Neoplasms; Remission Induction; Young Adult

Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and α-smooth muscle actin (α-SMA) were conducted with control group. The immunohistochemical stains for CD31 and α-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.

Topics: Actins; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Hypertension, Portal; Immunohistochemistry; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Platelet Endothelial Cell Adhesion Molecule-1; Splenomegaly; Thrombocytopenia; Tomography, X-Ray Computed

Advanced and recurrent diseases are the major causes of death in colon cancer. No standard preclinical model addresses advanced disease and spontaneous metastasis after orthotopic tumour growth. In this study, the authors report the establishment of such standardised orthotopic mouse models of colon cancer and their use in evaluating metronomic topotecan alone or in combination with standard chemotherapy.. Human colon cancer cell lines, transfected with human chorionic gonadotropin and luciferase, were injected orthotopically into the caecal wall of severe combined immunodeficient mice, intrasplenically or subcutaneously. For adjuvant therapy, caecal resections were performed 3-5 weeks after tumour cell injection. Chemotherapy drugs tested included uracil/tegafur, folinic acid, oxaliplatin, topotecan, pazopanib and various combinations.. Subcutaneous tumours showed exaggerated sensitivity to treatment by delayed tumour growth (p=0.002) and increased survival (p=0.0064), but no metastatic spread. Intrasplenic cell injection resulted in rapid and extensive but artefactual metastasis without treatment effect. Intracaecal cell injection with tumour take rates of 87.5-100% showed spontaneous metastases at clinically relevant rates. Metronomic topotecan significantly polonged survival and reduced metastasis. In the adjuvant setting, metronomic maintenance therapy (after FOLFOX-like induction) prolonged survival compared with vehicle controls (p=0.0003), control followed by topotecan (p=0.0161) or FOLFOX-like therapy (p=0.0003).. The refined orthotopic implantation technique proved to be a clinically relevant model for metastasis and therapy studies. Furthermore, metronomic therapy with oral topotecan may be promising to consider for clinical trials of metastatic colon cancer and long-term adjuvant maintenance therapy of colon cancer.

Topics: Administration, Metronomic; Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease Models, Animal; Female; Fluorouracil; HT29 Cells; Humans; Immunohistochemistry; Injections; Leucovorin; Liver Neoplasms; Mice; Mice, SCID; Organoplatinum Compounds; Survival Rate; Topotecan

Topics: Acute Kidney Injury; Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Oxaliplatin

The role of adjuvant chemotherapy for stage IV colorectal cancer has so far been under-investigated. The aim of this study was to assess the feasibility and short-term outcome of adjuvant chemotherapy with the FOLFOX regimen following liver resection for patients with colorectal liver metastasis (CRLM).. From May 2005 to September 2010, 86 patients with CRLM underwent hepatic resection in the Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University. Of these patients, 24 received FOLFOX4 or modified FOLFOX6 as postoperative adjuvant chemotherapy.. Nineteen male and 5 female patients received adjuvant chemotherapy following liver resection. Twenty-one (87.5 %) of these patients completed 6 cycles of adjuvant chemotherapy. Five patients required a dose reduction due to neutropenia, and the dose intensities of oxaliplatin and 5-FU were 93.6 and 94.1 %, respectively. There were no severe adverse events from the treatments. The median follow-up period was 48.4 months. Recurrences developed in 12 patients, and 3 patients died during the follow-up period. The 3- and 5-year disease-free survival and overall survival were 51.6 and 45.1 % and 95.5 and 76.0 %, respectively.. Adjuvant FOLFOX is feasible and might provide a good prognosis for CRLM patients who undergo liver resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Feasibility Studies; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Prospective Studies; Survival Rate; Treatment Outcome

The liver is the most common metastatic site in colorectal cancer (CRC). In this study, we evaluated if there is any difference between first-line irinotecan-based and oxaliplatin-based chemotherapies in the duration of time to disease progression (TTP) in CRC patients with only liver metastasis.. We retrospectively reviewed the medical records of patients with metastatic CRC referred to the Medical Oncology Department at the Faculty of Medicine of Ege University, between January 2002 and December 2010. Seventy-seven patients had only liver metastasis and completed their first-line chemotherapy. Forty-two patients had oxaliplatin-based treatments while 12 also had bevacizumab therapy, and 35 patients had irinotecan-based treatments while 16 also had bevacizumab therapy.. Median TTP was 6.70 ± 0.29 months for patients treated with oxaliplatin+5-fluorouracil (5-FU) and 8.33 ± 1.15 months for patients treated with oxaliplatin+5-FU+bevacizumab. TTP was significantly improved for patients who received irinotecan+5-FU+bevacizumab (median TTP, 13.73 ± 2.10 mo) when compared with irinotecan+5-FU (median TTP, 5.13 ± 0.70 mo).. Although previous studies showed no survival difference between these 2 chemotherapeutic agents in metastatic CRC, there might be differences in the benefit of delaying the disease progression in subgroup populations. Irinotecan+5-FU with bevacizumab combination chemotherapy may be superior in the first-line treatment of CRC with hepatic only metastasis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cohort Studies; Colorectal Neoplasms; Databases, Factual; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Risk Assessment; Survival Analysis; Time Factors; Treatment Outcome

To assess the effect of chemotherapy plus bevacizumab on tumor vessels, as well as the reversibility of this effect, using contrast-enhanced ultrasonography (CEUS) and histology in patients with metastatic liver tumors derived from colorectal cancer.. The study included 12 patients who received chemotherapy plus bevacizumab, experienced a reduction in tumor vascularity as demonstrated by CEUS and consequently underwent liver resection. CEUS was performed before and after four courses of chemotherapy and before surgery. The numbers of microvessels highlighted by anti-CD34 antibodies in the viable tumor tissue were counted to quantify the microvessel density (MVD). As a control, 12 surgical specimens from 12 patients who had not received chemotherapy were examined.. A reversal of tumor vascularity was observed in 10 of 12 patients. In two patients, the vascularity remained reduced. The MVD in the treatment group was significantly lower than that observed in the group without treatment.. The data suggest that the tumor vessels regenerated substantially, although the effect of chemotherapy plus bevacizumab remained weak for approximately 6 weeks after the cessation of treatment. Therefore, future research must determine whether bevacizumab should be used prior to surgery.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Contrast Media; Drug Administration Schedule; Ferric Compounds; Fluorouracil; Hepatectomy; Humans; Iron; Leucovorin; Liver Neoplasms; Microvessels; Neoadjuvant Therapy; Organoplatinum Compounds; Oxides; Retrospective Studies; Treatment Outcome; Ultrasonography

Chemotherapy can lead to tumor down-staging in patients with initially unresectable colorectal liver metastases (CRLM); however, more than half of such cases are still considered to be unresectable because of disease progression, including multiple or bilobar CRLM, and an insufficient predicted remnant liver volume. In addition, there is little evidence supporting the use of radiofrequency ablation (RFA) for patients with CRLM. This study compared the safety and efficacy of hepatic resection (HR) combined with RFA versus HR alone after effective chemotherapy in patients with initially unresectable CRLM.. Data were prospectively collected on 118 consecutive patients with initially unresectable CRLM who received FOLFOX ± bevacizumab as the first-line chemotherapy. 48 of these patients (41%) underwent HR or HR + RFA after the chemotherapy. HR was performed in 35 patients (HR group), and HR + RFA in 13 (HR + RFA group).. There was no mortality in either group. Postoperative morbidity rates in the HR group and the HR + RFA group were 17 and 23%, respectively (P = 0.640). Local recurrence at the RFA site occurred in only one tumor (1.6% per lesion, 7.7% per patients). The 3-year progression-free survival was 45.3% in the HR group and 12.8% in the HR + RFA group (P = 0.472). The 3-year overall survival rate was 70.4% in the HR group and 77.1% in the HR + RFA group (P = 0.627).. These results suggest that HR + RFA after effective chemotherapy is a safe procedure with low local recurrence at the RFA site and is a potentially effective treatment option for patients with initially unresectable CRLM.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Drug Therapy; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Treatment Outcome

Combined resection of colorectal cancer with surgery for synchronous liver metastases (LM) still remains controversial because of the possible higher morbidity rate, the necessity of an adequate abdominal approach for both resections and the impact on oncological results. However, laparoscopy may be beneficial in terms of operative results and could facilitate this combined procedure. The aim was to assess the benefit of the laparoscopic approach for colorectal cancer resection in patients undergoing simultaneous liver resection for synchronous LM.. From 2006 to 2011, all patients with colorectal cancer and resectable synchronous LM, for which the total length of the procedure was suspected to be less than 8 h, underwent colorectal laparoscopic resection combined with open and/or laparoscopic liver surgery. In order to identify selection criteria, a comparative analysis was performed between patients with and without major postoperative morbidity.. Fifty-one patients underwent combined surgery with laparoscopic colectomy (n = 31) and proctectomy (n = 20). The conversion rate was 8%. Liver resections included major surgery (n = 10) and minor surgery (n = 41). Extraction of the colorectal specimen was performed through an incision used for open liver resection, except in seven patients who underwent a total laparoscopic procedure. Overall and major morbidity rates were 55% and 25%, respectively. Median (range) hospital stay was 16 (6-40) days. Regarding patient and tumour characteristics, no independent criteria of major morbidity risk were identified.. This study showed that laparoscopic colorectal resection combined with liver resection for synchronous LM was feasible and safe. Moreover, laparoscopy facilitates the surgical abdominal approach for combined colorectal and liver resection.

Topics: Adult; Aged; Anastomotic Leak; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Chi-Square Distribution; Colectomy; Colorectal Neoplasms; Dose Fractionation, Radiation; Female; Fluorouracil; Hepatectomy; Humans; Laparoscopy; Length of Stay; Leucovorin; Liver Abscess; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Operative Time; Organoplatinum Compounds; Patient Selection; Peritonitis; Pyridines; Statistics, Nonparametric; Time Factors

Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults > 75 years of age enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. In this comparative effectiveness study, we note that older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens comparable to that of younger adults.. Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults ≥ 75 years of age who are enrolled in clinical trials, safety and effectiveness outside the trial setting are less established.. We retrospectively collected cases of patients ≥ 75 years of age who were diagnosed with stage III and metastatic CRC and initiated treatment between January 2000 and January 2007 at 2 academic hospitals in Boston, MA. Cases were matched in a 1:2 ratio to controls who were < 75 years of age by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (first- or second-line or beyond). The primary study endpoints were grade ≥ 3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival.. We identified 84 patients ≥ 75 years of age (25% ≥ 80 years) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade ≥ 3 treatment-associated toxicities between the patients and the controls (71.4% vs. 68.5%, respectively; P = .63). Further there was no statistically significant difference between patients and controls for combined endpoints of any grade ≥ 3 toxicity or hospital/facility admission (P = .92). With a median follow-up of 52 months, 2-year overall survival was similar between patients and controls (43% vs. 52%, respectively; P = .87).. Older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens that was comparable to that of younger adults.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Case-Control Studies; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Safety; Survival Rate

After curatively intended surgery for colorectal liver metastases, liver recurrences occur in more than 60% of patients, despite the administration of adjuvant systemic chemotherapy. The aim of this study was to assess the benefit of combined adjuvant hepatic arterial infusion (HAI) and intravenous (IV) 5-FU compared with standard modern adjuvant IV chemotherapy in patients at high risk of hepatic recurrence.. From January 2000 to December 2009, 98 patients, who had undergone curative resection of at least 4 colorectal liver metastases, were selected from a prospective database. Among them, 44 (45%) had received postoperative HAI combined with systemic 5-FU (HAI group) and 54 (55%) had received "modern" systemic chemotherapy (IV group).. The 2 groups were similar in terms of age, sex, the stage of the primary, and the administration of preoperative chemotherapy. The median number of HAI cycles received per patient was 7 [range, 1-12]. Twenty-nine patients (66%) had received at least 6 cycles of HAI oxaliplatin, and 22 patients (50%) had received the full planned treatment. For the remaining 22 patients (50%), HAI chemotherapy had been discontinued because of toxicity (n = 8), HAI catheter dysfunction (n = 6), an early recurrence (n = 6), and patient's refusal (n = 2). After a median follow-up of 60 months (51-81 months), 3-year overall survival was slightly higher in the HAI group (75% vs 62%, P = 0.17). Three-year disease-free survival was significantly longer in patients in the HAI group than those in the IV group (33% vs 5%, P < 0.0001). In the multivariate analysis, adjuvant HAI chemotherapy and an R0 resection margin status were the only independent predictive factors for prolonged disease-free survival.. Postoperative HAI oxaliplatin combined with systemic chemotherapy after curatively intended surgery of colorectal liver metastases is feasible and may significantly improve disease-free survival of patients at high risk of hepatic recurrence compared with adjuvant modern systemic chemotherapy alone. These results should be confirmed in a randomized study.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Analysis; Treatment Outcome

Five prognostic factors had been previously identified in patients with metastatic colorectal cancer (MCRC) who received irinotecan-based second-line chemotherapy. Patients were classified into three prognostic groups based on significant differences in median overall survival (OS). This study is conducted to validate this classification in an external validation cohort.. This retrospective study included 193 patients of an external validation cohort who received irinotecan-based second-line chemotherapy after first-line oxaliplatin-based chemotherapy, with or without bevacizumab at three institutions.. Three of the five predefined factors (poorly differentiated adenocarcinoma, LDH ≥400 IU/L, progression-free survival of first-line therapy <6 months) remained highly significant in the validation cohort, although two (performance status 2 and peritoneal metastasis) were associated with borderline significance. The distribution of the three prognostic groups (low risk = no factors, intermediate risk = 1 factor, high risk = 2 or more factors) was low risk (n = 68; 35 %), intermediate risk (n = 80; 41 %), and high risk (n = 45; 23 %). The median OS of each group were 19.8, 11.0, and 7.9 months, respectively, with significant differences between groups, as found in the previous cohort.. The previous prognostic classification of patients with MCRC who received irinotecan-based second-line chemotherapy was validated in another independent cohort. Validation in prospective studies is warranted.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Survival Rate

Monoclonal antibodies such as bevacizumab are widely used in medical oncology, either alone or in combination with chemotherapy. No specific recommendations on the management of monoclonal antibodies extravasation exist. Incidence rates vary considerably. Estimates of 0.5-6% have been reported in the literature. Also, patient-associated and procedure-associated risk factors of extravasation are multiple, such as bolus injections or poorly implanted central venous access. We report on an 86-year-old woman with colon cancer with liver metastasis who was treated with 5-fluorouracil, folinic acid, and bevacizumab. Extravasation occurred during chemotherapy infusion because of a catheter migration of the port outside of the superior vena cava, causing cervical pain without skin modifications. Diagnosis was confirmed with the appearance of clinical right cervical tumefaction and cervicothoracic computed tomography scan indicated a perijugular hypodense collection, corresponding to the extravasation. Conservative management was proposed. The patient recovered within 3 weeks from all symptoms. Physicians should be aware that in cases of bevacizumab extravasation, a nonsurgical approach might be effective.

Topics: Adenocarcinoma; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Central Venous Catheters; Colonic Neoplasms; Extravasation of Diagnostic and Therapeutic Materials; Female; Fluorouracil; Foreign-Body Migration; Humans; Leucovorin; Liver Neoplasms; Neck Pain; Organoplatinum Compounds; Radiography; Subclavian Vein; Vascular Access Devices; Vena Cava, Superior

Bevacizumab has been shown to increase progression free and overall survival in patients with metastatic colorectal cancer. Neoadjuvant bevacizumab is commonly used in patients undergoing liver resection. Our purpose was to evaluate whether bevacizumab is associated with increased rate of perioperative complications in patients undergoing hepatic resection for colorectal liver metastases (CRLM).. Retrospective analysis of patients undergoing hepatic resection for CRLM who received chemotherapy and bevacizumab (group 1, n = 134), or chemotherapy alone (group 2, n = 57). We compared demographics, surgical characteristics, and perioperative course.. Perioperative complications developed in 35 % of patients in group 1, and 47 % in group 2 (p = 0.11). Of those complications, 15 (11.2 %) in group 1, and 5 (8.8 %) in group 2 were considered major (p = 0.617). Four patients, all of whom received preoperative bevacizumab, developed enteric leaks following combined liver and bowel resection. The rate of anastomotic leak in group 1 was 10 %, compared with 0 in group 2, p = 0.56.. Neoadjuvant chemotherapy along with bevacizumab was not associated with an increased risk of postoperative complications after hepatic resection. Possible association of increased morbidity with simultaneous bowel and liver resections following bevacizumab administration was found and we recommend avoiding such treatment combination.

Topics: Adult; Aged; Aged, 80 and over; Anastomotic Leak; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Retrospective Studies

According to the 7th edition of the TNM staging system, stage IV metastatic colorectal cancer (CRC) at the time of initial diagnosis is sub-classified into stage IVA or IVB disease. Peritoneal carcinomatosis (PC), considered to have a dismal prognosis, is exclusively sub-classified into stage IVB, even though other metastases to a sole organ are sub-classified into stage IVA, which is considered to be associated with better survival. This retrospective study was undertaken to investigate the overall survival in metastatic CRC patients, focusing on PC patients.. We reviewed data on patients with metastatic CRC at initial diagnosis surgically treated between January 2006 and June 2011. A survival analysis was performed paying special attention to PC and sub-classifying patients with PC into three categories according to metastatic sites.. There were 69 stage IVA patients (IVA group) and 83 stage IVB. Among stage IVB patients, 20 had isolated PC (PC-I group), 28 had PC with one or more other sites of metastasis (PC-II group), and 35 had at least 2 metastatic without peritoneal involvement (NPC group). Of 152 stage IV patients, 132 (87 %) underwent resection of the primary tumor and 19 (12 %) underwent radical resection of metastatic disease with microscopic free margins (R0 resection) including 5/20 (25 %) patients in the PC1 group. A total of 139 patients received oxaliplatin-based chemotherapy in a palliative (n = 125), neoadjuvant (n = 3), or adjuvant setting after R0 resection (n = 11). Compared with 36.6 months in the PC-I group, median survival was 32.5 months (P = 0.48) in the IVA group, 14.7 months (P = 0.07) in the PC-II group, and 12.9 months (P < 0.01) in the NPC group.. The sub-classification of isolated PC into stage IVA instead of IVB might be more appropriate in the era of modern chemotherapy. Further investigation is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Palliative Care; Peritoneal Neoplasms; Prognosis; Retrospective Studies

The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib.. Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m(2) as a 2-hour infusion on day one, and leucovorin 200 mg/m(2) as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m(2) and a 48-hours infusion of 5-fluorouracil 2400 mg/m(2). Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred.. Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response.. In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Organoplatinum Compounds; Paris; Retrospective Studies; Survival Analysis; Time Factors; Treatment Outcome

We now describe the first example of a patient who developed perirenal hematoma during the course of bevacizumab-containing chemotherapy. A 59-years-old woman with metastatic rectal cancer treated with bevacizumab, who developed low back pain after 11 cycles of chemotherapy. CT-scan was consistent with perirenal hematoma and discontinuation of bevacizumab resulted in symptomatic improvement. Nontraumatic perirenal hematoma is a rare condition that can cause shock in severe cases. Given that several types of bleeding complication are known to be associated with bevacizumab treatment, we concluded that bevacizumab likely contributed to the perirenal hematoma in this case. Although the appropriate modification of bevacizumab treatment in the setting of perirenal hematoma is still unclear, physicians should be aware of this potential bevacizumab-associated bleeding complication.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Fluorouracil; Hematoma; Hemorrhage; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Time Factors; Tomography, X-Ray Computed

FOLFOXIRI demonstrated higher efficacy compared to 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) as first-line treatment of metastatic colorectal cancer. We evaluated the outcome of second-line treatments among 196 patients treated with first-line FOLFOXIRI in three consecutive trials conducted by the Gruppo Oncologico Nord Ovest group.. One hundred seventy-two of 196 patients so far progressed and 136 (79%) received second-line therapies: 32 (24%) were rechallenged with FOLFOXIRI, 52 (38%) were treated with irinotecan- or oxaliplatin-based doublets, and 52 (38%) received fluoropyrimidine plus mytomicin C or single-agent chemotherapy. Only 10 patients received bevacizumab (3) or cetuximab (7) with chemotherapy. Activity and efficacy data were collected and subgroup analyses were performed according to the regimen administered.. Overall response rate (RR) was 23%; median progression-free survival (PFS) and overall survival (OS) were 5.9 and 13.2 months, respectively. At an exploratory subgroup analysis, retreatment with FOLFOXIRI was associated with longer PFS (8.2 versus 6.3 months; P = .003, hazard ratio [HR] = 0.61) and OS (19.3 versus 14.0 months; P = .02, HR = 0.57) compared with doublets; single-agent chemotherapy or fluoropyrimidine plus mytomicin C was significantly lower in terms of RR (8%), PFS (3.0 months), and OS (8.7 months) compared with FOLFOXIRI or doublets.. First-line FOLFOXIRI does not impair the efficacy of second-line treatments. In some patients rechallenge with FOLFOXIRI may represent a valid option, although potential imbalances in prognostic factors due to better patient selection should be considered.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Salvage Therapy; Survival Rate; Treatment Outcome

The prognosis for hepatocellular carcinoma (HCC) along with portal vein tumor thrombi (PVTT) is poor, and surgery has not been considered an option.. To compare the outcomes and the quality of life (QoL) of patients with HCC and PVTT who underwent hepatic resection and thrombectomy for tumor thrombi in the inferior vena cava and hepatic vein with total hepatic vascular exclusion to the patients who received only chemotherapy.. We retrospectively reviewed the medical records of patients who received hepatectomy and thrombectomy (n=65), and those who received only chemotherapy (n=50). The surgical outcomes, survival, and QoL that was determined using the Functional Assessment of Cancer Therapy-Hepatobiliary instrument were analyzed and compared.. Patients who underwent surgery had a median overall survival of 17 months, compared with patients who underwent chemotherapy for 8 months (P<0.0001). Patients who underwent surgery had a median recurrence-free survival of 14 months, as compared with patients who underwent chemotherapy for 7 months (P<0.0001). The probabilities of 1-year recurrence in the surgery and chemotherapy groups were 27.7 and 70%, respectively (P<0.0001). The QoL total score of the surgery group was significantly higher than that of the control group (P<0.0001). Surgery was slightly, though significantly more cost-effective than chemotherapy based on the quality-adjusted life years.. Hepatectomy and thrombectomy using the total hepatic vascular exclusion, is a viable surgical management for patients with HCC and PVTT, and is associated with longer overall survival and recurrence-free survival and better QoL than chemotherapy alone.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Cost-Benefit Analysis; Female; Fluorouracil; Hepatectomy; Hepatic Veins; Hospital Costs; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplastic Cells, Circulating; Organoplatinum Compounds; Quality of Life; Retrospective Studies; Thrombectomy; Treatment Outcome; Vena Cava, Inferior; Venous Thrombosis

To determine the ability of dynamic contrast enhanced (DCE-MRI) to predict pathological complete response (pCR) after preoperative chemotherapy for rectal cancer.. In a prospective clinical trial, 23/34 enrolled patients underwent pre- and post-treatment DCE-MRI performed at 1.5T. Gadolinium 0.1 mmol/kg was injected at a rate of 2 mL/s. Using a two-compartmental model of vascular space and extravascular extracellular space, K(trans), k(ep), v(e), AUC90, and AUC180 were calculated. Surgical specimens were the gold standard. Baseline, post-treatment and changes in these quantities were compared with clinico-pathological outcomes. For quantitative variable comparison, Spearman's Rank correlation was used. For categorical variable comparison, the Kruskal-Wallis test was used. P ≤ 0.05 was considered significant.. Percentage of histological tumour response ranged from 10 to 100%. Six patients showed pCR. Post chemotherapy K(trans) (mean 0.5 min(-1) vs. 0.2 min(-1), P = 0.04) differed significantly between non-pCR and pCR outcomes, respectively and also correlated with percent tumour response and pathological size. Post-treatment residual abnormal soft tissue noted in some cases of pCR prevented an MR impression of complete response based on morphology alone.. After neoadjuvant chemotherapy in rectal cancer, MR perfusional characteristics have been identified that can aid in the distinction between incomplete response and pCR.. Dynamic contrast enhanced (DCE) MRI provides perfusion characteristics of tumours. These objective quantitative measures may be more helpful than subjective imaging alone Some parameters differed markedly between completely responding and incompletely responding rectal cancers. Thus DCE-MRI can potentially offer treatment-altering imaging biomarkers.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Contrast Media; Female; Fluorouracil; Gadolinium DTPA; Humans; Image Enhancement; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Prognosis; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome

The association between body composition parameters and toxicity from hepatic arterial infusion (HAI) chemotherapy regimens has not been analyzed. We assessed data from patients with advanced cancer and liver metastases treated on a clinical trial of a regimen of HAI oxaliplatin combined with systemic 5-fluorouracil/leucovorin and bevacizumab. Correlations between patient characteristics, response, and toxicity and body composition data taken from CT images were analyzed. Forty-eight of 57 patients (mean age 56 yr; 60% women) had available CT scans. The most common diagnosis was colorectal cancer (22/48, 46%); 30/48 patients (63%) had body mass index (BMI) ≥25 kg/m(2). Twenty (42%) of 48 patients were sarcopenic. Grade 3-4 adverse events did not differ among patients with and without sarcopenia or according to BMI. The median survival (95% C]) was 167 (128-206) days for sarcopenic and 280 (214-346) days for nonsarcopenic patients (P = 0.271). Among patients treated at the maximum tolerated dose, the median survival was 103 days for sarcopenic and 312 days for nonsarcopenic patients (P = 0.173). Sarcopenia was present in 30% (6/20) of patients with reduction in tumor size posttreatment, and in 52% (14/27) of patients with increased tumor size (P = 0.171). In conclusion, body composition was not significantly associated with toxicities or survival in our small sample.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Body Composition; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Sarcopenia; Treatment Outcome

The aim of this study was to evaluate the intraoperative detection rate of residual liver metastases after chemotherapy and to assess the correlation between disappeared liver metastases (DLMs) upon preoperative imaging and complete pathological response.. Between February 2004 and December 2008 clinicopathological data of 292 consecutive patients who underwent liver resection for colorectal liver metastases were prospectively collected and analyzed in a "per lesion" study. Thirty-three patients with 67 DLMs were included.. During laparotomy, we identified 45 out of 67 DLMs (67%). Six DLMs were detected by macroscopic liver examination (9%) and 39 (58%) by intraoperative ultrasound (IOUS). Overall, persistent microscopic residual disease at pathological examination of the resected specimen or recurrence in situ identified during the follow-up were observed in 41 (61.2%) of 67 LMs that had shown a complete response by imaging. At multivariate analysis moderate or severe hepatic steatosis (p = 0.016), subglissonian localization of nodules (p = 0.019) and residual microscopic disease (p = 0.0006) were associated with IOUS detection of residual metastases. Preoperative chemotherapy with more than six cycles (p = 0.022) and intraoperative detection of nodules by IOUS (p = 0.001) were independent predictors of residual disease.. Systematic US exploration of the liver leads to increase the intraoperative detection rate of DLMs. Furthermore, the majority of DLMs identified by IOUS presents residual disease at pathological examination and should be treated.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chi-Square Distribution; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Proportional Hazards Models; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography

To investigate the outcomes of adjuvant chemotherapy (CT) or chemoradiotherapy (CRT) after simultaneous surgical resection in rectal cancer patients with liver metastases (LM).. One hundred and eight patients receiving total mesorectal excision for rectal cancer and surgical resection for LM were reviewed. Forty-eight patients received adjuvant CRT, and 60 were administered CT alone. Recurrence patterns and prognosis were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were compared between the CRT and CT groups. The inverse probability of the treatment-weighted (IPTW) method based on the propensity score was used to adjust for selection bias between the two groups.. At a median follow-up period of 47.7 months, 77 (71.3%) patients had developed recurrences. The majority of recurrences (68.8%) occurred in distant organs. By contrast, the local recurrence rate was only 4.7%. Median DFS and OS were not significantly different between the CRT and CT groups. After applying the IPTW method, we observed no significant differences in terms of DFS (hazard ratio [HR], 1.347; 95% confidence interval [CI], 0.759-2.392; p = 0.309) and OS (HR, 1.413; CI, 0.752-2.653; p = 0.282). Multivariate analyses showed that unilobar distribution of LM and normal preoperative carcinoembryonic antigen level (<6 mg/mL) were significantly associated with longer DFS and OS.. The local recurrence rate after simultaneous resection of rectal cancer with LM was relatively low. DFS and OS rates were not different between the adjuvant CRT and CT groups. Adjuvant CRT may have a limited role in this setting. Further prospective randomized studies are required to evaluate optimal adjuvant treatment in these patients.

Topics: Adult; Aged; Analysis of Variance; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Pelvis; Postoperative Care; Probability; Prognosis; Rectal Neoplasms; Retrospective Studies; Selection Bias

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fatal Outcome; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin

We report a patient with a huge multiple hepatic metastases of rectal cancer treated by combination of infusional 5-FU, Leucovorin, irinotecan(FOLFIRI), and bevacizumab(BV). The patient was a 60-year-old man with cancer of the rectum, with huge multiple hepatic metastases. The serum carcinoembryonic antigen(CEA)level was 3,979.6 ng/mL, and the carbohy- drate antigen(CA)19-9 level was 66,562.6 U/mL. The patient received combined chemotherapy with FOLFIRI and BV. After completion of 8 courses, abdominal CT scans revealed that those low-density areas of the liver had reduced. The patient was judged to have achieved PR. He received combined therapy for 42 courses, and his response is SD at this point. No grade 2 adverse event occurred throughout chemotherapy. This case suggests that combined therapy with FOLFIRI+BV may be an effective regimen for advanced rectal cancer with huge multiple hepatic metastases.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Quality of Life; Rectal Neoplasms; Tomography, X-Ray Computed

Patients with chemotherapy-refractory liver metastases who are not candidates for surgery may be treated with focal ablation techniques with established survival benefits. Irreversible electroporation is the newest of these and has the putative advantages of a nonthermal action, preventing damage to adjacent biliary structures and bowel. This report describes the use of irreversible electroporation in a 61-year-old man with a solitary chemoresistant liver metastasis unsuitable for radiofrequency ablation as a result of its proximity to the porta hepatis. At 3 months, tumor size was decreased on computed tomography from 28 × 19 to 20 × 17 mm, representing stable disease according to the response evaluation criteria in solid tumors. This corresponded to a decrease in tumor volume size from 5.25 to 3.16 cm(3). There were no early or late complications. Chemoresistant liver metastases in the proximity of the porta hepatis that are considered to be too high a risk for conventional surgery or thermal ablation may be considered for treatment by the novel ablation technique of irreversible electroporation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Contrast Media; Electroporation; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Phospholipids; Sulfur Hexafluoride; Tomography, X-Ray Computed; Ultrasonography, Interventional

A83 -year-old man was admitted to our hospital for the treatment of advanced ascending colon cancer with liver metastases. He had initially undergone an ileocecal resection for ascending colon cancer. Subsequently, we started oral administration of UFT/LV(UFT 400mg/day, LV 75 mg/day, and 4 weeks of therapy followed by a week suspension of treatment). After 3 courses, his tumors responded well to treatment, and CT showed marked regression of liver metastases. After 10 courses, liver metastases had almost disappeared. Two years passed without any adverse events since UFT/LV therapy was started. These findings suggest that UFT/LV therapy is very safe and effective for elderly patients with unresectable colorectal cancer.

Topics: Administration, Oral; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Humans; Leucovorin; Liver Neoplasms; Male; Tegafur; Tomography, X-Ray Computed; Uracil

A 55-year-old male had complained of melena.Colonoscopy revealed a type 2 tumor at the rectum.CT demonstrated hepatic lymph nodes and multiple liver metastases(stage IV).Low anterior resection was performed(tub2, RsRa, circ, type 2, pSS, pN1, sH3, cHN1, sP0, cM0: fstage IV).The patient was treated with mFOLFOX6 and sLV5FU2 after operation.CT revealed a partial response after 14 courses of systemic chemotherapy.sLV5 FU2 therapy was converted to capecitabine because he experienced bone marrow suppression.CT showed that the liver metastases had enlarged but the hepatic lymph nodes disappeared.Right portal vein embolization was performed.After 4 weeks, right hepatectomy and hepatic lymph node dissection were performed.Preoperative chemotherapy with mFOLFOX6 seems beneficial as a neoadjuvant chemotherapy for hepatic lymph node-positive advanced colorectal cancer.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Rectal Neoplasms; Tomography, X-Ray Computed

We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cholangiocarcinoma; Fluorouracil; Guillain-Barre Syndrome; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

This study was designed to evaluate the long-time outcome of patients with colorectal liver metastasis (CRLM) undergoing different types of therapy and identify prognosis factors.. From 2000 to 2010, 1,613 consecutive patients with CRLM were identified. Clinicopathological and outcome data were collected and analyzed by univariate and multivariate analyses.. Synchronous liver metastasis (SLM), female, grade III-IV, T4 and N positive of primary tumor, bilobar disease, number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, serum CEA level ≥ 5 ng/ml, and CA19-9 level ≥ 37 u/ml were the predictors of adverse outcome using univariate analysis. The median survival and 5-year survival rate for patients after resection of liver metastases was 49.8 months and 47%, better than that for those after other therapy. In addition, patients without treatment had the poorest survival. Sixty-four initially unresectable patients underwent surgery after conversion therapy with a median survival of 36.9 months and a 5-year survival of 30%. By multivariate analysis, SLM, poorly differentiated primary tumor, number of liver metastases ≥ 4, size of largest liver metastases ≥ 5 cm, and no surgical treatment of liver metastases were found to be independent predictors of poor survival.. Patients with CRLM could get long-term survival benefit from different types of therapy, and resection of liver metastases was the optimal strategy. A predictive model using these above five factors may be of use in stratifying patients who may benefit from intensive surveillance and adjuvant therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Capecitabine; Carcinoembryonic Antigen; Catheter Ablation; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Chi-Square Distribution; Colorectal Neoplasms; Cryosurgery; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Proportional Hazards Models; Retrospective Studies; Tumor Burden; Young Adult

Along with advances in the chemotherapy for colorectal cancer, the strategy for hepatic metastasis has been changed. One of the most striking issues is that initially unresectable hepatic metastases can be resectable after chemotherapy with considerably high frequency. In addition, advanced chemotherapy leads to the downsizing of the metastatic foci in the liver, which is sometimes difficult to detect with conventional intraoperative ultrasonography (IOUS). To discover the undetectable hepatic lesions with IOUS, we have introduced contrast-enhanced intraoperative ultrasonography (CEIOUS). In the present study, we present evidence that viable cancer cells exist in even the shrunken tumors with high frequency and that CEIOUS contributes to detecting the minute foci.. This study was composed of eight patients; four of them had initially unresectable metastasis, and the remaining four had either H2 or H3 status of hepatic metastases. All of them underwent hepatic resection after chemotherapy.. A total of 57 metastatic lesions were detected before chemotherapy. Thirty lesions were demonstrated by CEIOUS with perflubutane and resected. In the pathological examination, tumor cells were not found in 12 of the 30 resected lesions. The degree of pathological liver damage was grade 1 or less in all patients, and no serious complication occurred after surgery in any of the patients.. The present study showed that viable cancer cells remained with high frequency, even in the minute hepatic metastasis which was reduced in size after chemotherapy, and CEIOUS was a useful examination for detecting the minute hepatic foci.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Contrast Media; Fluorocarbons; Fluorouracil; Hepatectomy; Humans; Intraoperative Period; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Ultrasonography

The significance of complete calcification of liver metastases on imaging is unknown. This study was conducted to determine whether complete calcification of liver metastases after chemotherapy, as assessed by imaging, was synonymous with sterilization of disease.. Imaging by triphasic contrast-enhanced helical CT scan and abdominal ultrasound showed complete calcification of eight liver metastases in four patients after systemic chemotherapy. All eight completely calcified liver metastases were resected within four weeks of imaging. Histological and surgical findings were analyzed to see whether there was any correlation between radiological and pathological status for completely calcified liver metastases.. The pretreatment median diameter at initial imaging of the eight liver metastases that became completely calcified after chemotherapy was 24 mm. In all eight resected calcified liver metastases, pathological examination showed the presence of residual viable tumor cells. Most of the tumor volume was occupied by calcification, necrosis and fibrosis; but small discrete islands of viable tumor cells were detected at the periphery of lesions.. This preliminary study shows that although imaging evidence of complete calcification of liver metastases may be a good indicator of chemotherapy response, it does not imply sterilization of the malignancy.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Calcinosis; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Tomography, Spiral Computed; Treatment Outcome; Ultrasonography

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Colitis; Colonic Neoplasms; Diverticulosis, Colonic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

A 64-year-old woman was introduced to our hospital with liver tumors. Our examination revealed that she had advanced colon carcinoma with multiple liver metastasis. Without symptoms from the primary cancer, she underwent chemotherapy of avastin FOLFOX. After 2 courses of chemotherapy, she suffered ileus and underwent operation. The resected specimen showed marked tumor necrosis and fibrosis, but few tumor cells remained in the primary lesion. We think this was a rare case of suffered ileus because of marked response of chemotherapy in primary colon carcinoma.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Cicatrix; Colorectal Neoplasms; Female; Fluorouracil; Humans; Ileus; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Middle Aged; Organoplatinum Compounds

A 64-year-old man who underwent rectal amputation for rectal cancer was diagnosed with multiple liver metastases and tumor embolus in the portal vein 6 months after operation. Though the patient underwent chemotherapy, mFOLFOX6, and bevacizumab+FOLFIRI, liver metastases were diagnosed as progressive disease (PD). After panitumumab+FOLFIRI was administered for three months as third-line chemotherapy, the tumor embolus completely disappeared, and liver metastases became cytoreductive on CT. The patient was judged to have achieved a partial response (PR). This case indicated that panitumumab was effective as third-line chemotherapy for unresectable recurrent rectal cancer.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Embolism; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Panitumumab; Portal Vein; Rectal Neoplasms; Salvage Therapy

A 61-year-old complaining of anorexia and general fatigue was admitted to our hospital for further examination. She was diagnosed as advanced sigmoid colon cancer with multiple metastases of lung, liver, and left hydronephrosis. Since curative surgery was not deemed possible, we started chemotherapy with bevacizumab/FOLFOX6 (bi-weekly drip infusion). After the 6th course, colonoscopy revealed a significant tumor reduction and changes to the scar tissues. CT did not reveal a complete disappearance, but found some reductions in metastases of lung and liver. Sigmoidectomy and lymph node resection (D1) were performed. We did not disappeared any dissemination and the histological diagnosis revealed a complete disappearance of cancer cells in the main tumor. She was discharged 13 days after surgery, following chemotherapy which included bevacizumab and XELOX. The chemotherapy using bevacizumab/FOLFOX6 is a candidate for the standard treatment strategy for inoperable advanced colon cancer. Herein we report this rare case with a review of the literature.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Fluorouracil; Humans; Hydronephrosis; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Sigmoid Neoplasms; Tomography, X-Ray Computed

A 31-year-old man with sigmoid colon cancer with concomitant simultaneous multiple liver metastases had received FOLFIRI (leucovorin, fluorouracil and irinotecan) and FOLFOX6 (leucovorin, fluorouracil and oxaliplatin) after an ordinary sigmoidectomy. However, his serum carcinoembryonic antigen (CEA) level increased rapidly during the fifteen months after the operation while he was on FOLFOX6. Abdominal computed tomography revealed expanding multiple liver tumors. As the third line chemotherapy, a combination therapy of cetuximab with irinotecan was given, which markedly reduced his levels of serum CEA, and the size and number of liver tumors. He underwent lateral segmentectomy of the liver and microwave coagulation of the liver metastases in the remnant liver. Thereafter, a good quality of life with tumor dormancy was obtained for 6 months. However, his serum CEA started to rise again in the absence of liver tumors. Therefore, FOLFOX6 with bevacizumab was chosen as the fourth line chemotherapy, and the serum CEA was reduced with tumor dormancy. A good quality of life was obtained again at 3 years after the first surgery. This report indicates the effectiveness of sandwiched liver surgery with the molecular targeting drugs cetuximab and bevacizumab on multiple liver metastases of colon cancer, and suggests the possibility of a regimen consisting of bevacizumab following cetuximab.

Topics: Adenocarcinoma; Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoembryonic Antigen; Cetuximab; Electrocoagulation; ErbB Receptors; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Microwaves; Molecular Targeted Therapy; Neoadjuvant Therapy; Organoplatinum Compounds; Quality of Life; Sigmoid Neoplasms; Tomography, X-Ray Computed

Bevacizumab, a monoclonal antibody to vascular endothelial growth factor-A, is approved for the treatment of various malignancies, and its hematological toxicities are considered infrequent.. A colorectal cancer patient receiving chemotherapy (5-fluorouracil and oxaliplatin) plus bevacizumab developed acute, severe thrombocytopenia. We postulated that this thrombocytopenia could be directly triggered by bevacizumab.. A man with stage IV colorectal cancer and synchronous liver metastasis had received 10 cycles of FOLFOX plus bevacizumab (5 mg/kg) without significant hematological toxicity. Due to thrombocytopenia, oxaliplatin was withdrawn after cycle 11. On cycle 12, shortly after bevacizumab infusion and before 5-fluorouracil infusion, the patient developed fever, lower limbs purpura, grade 1 proctorrhagia, and epistaxis. Platelets had decreased from 105,000/mm(3) to 3000/mm(3) within 1 hour after bevacizumab infusion. Flow cytometry identified platelet-associated immunoglobulins. Despite 2 apheresis-derived platelet transfusions, oral corticotherapy, and gamma globulin infusions, thrombocytopenia persisted, but was finally successfully treated with a peptibody thrombopoietin mimetic, which was introduced 28 days after the last bevacizumab infusion.. Clinicians should keep in mind that bevacizumab can induce acute and potentially severe immune-mediated thrombocytopenia.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Purpura, Thrombocytopenic, Idiopathic; Rare Diseases; Receptors, Fc; Recombinant Fusion Proteins; Thrombopoietin

We report on a 65-year-old female patient with a recent diagnosis of adenocarcinoma of the sigmoid colon and massive hematochezia in the context of a general bleeding disorder.. Disseminated malignant disease with hepatic metastases as well as bone marrow involvement was demonstrated. Moreover, circulating tumor cells were demonstrated by flow cytometry. The patient had right lower quadrant abdominal pain due to a spontaneous psoas intramuscular hematoma.. At the time of admission to our hospital, the patient displayed microangiopathic hemolytic anemia and secondary hyperfibrinolysis with a pronounced bleeding tendency. Moreover, there was an acute renal failure which improved with fluid resuscitation. With immediate chemotherapy consisting of 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX regimen) and cetuximab initiated with the second course, plasmatic coagulation could be stabilized. Consequently, treatment with tranexamic acid, fibrinogen, fresh frozen plasma as well as red blood cell and platelet infusions could be stopped. Continuation of chemotherapy was possible on an outpatient basis and the further course was associated with a good quality of life until her near end. The patient died at home 7 months after initial diagnosis of her colon cancer due to progressive disease with CNS metastases.. Disseminated intravascular coagulation with microangiopathic hemolysis and secondary hyperfibrinolysis is a rare albeit possible event in disseminated colorectal cancer, especially when the bone marrow is involved. Treatment of the underlying cause is the most important therapeutic measure.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Bone Marrow Neoplasms; Brain Neoplasms; Cetuximab; Disease Progression; Disseminated Intravascular Coagulation; Fatal Outcome; Female; Fluorouracil; Gastrointestinal Hemorrhage; Hematoma; Hemorrhagic Disorders; Humans; Leucovorin; Liver Neoplasms; Neoplastic Cells, Circulating; Organoplatinum Compounds; Palliative Care; Purpura, Thrombotic Thrombocytopenic; Retroperitoneal Space; Sigmoid Neoplasms; Tomography, X-Ray Computed

The patient was a 77-year-old woman with multiple liver metastases of sigmoid colon cancer. She underwent low anterior resection for sigmoid colon cancer. After surgery, she selected oral administration of UFT and LV for liver metastases and multiple lymph node metastases. After two courses, the liver metastases had markedly diminished. Thirty-two months later, liver metastases had disappeared on computer tomography. This therapy was continued for five years, and recurrences are no longer shown. Severe adverse effects were not observed. Oral anti-cancer drugs can serve as effective therapy for advanced colorectal cancer of old patients.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leucovorin; Liver Neoplasms; Sigmoid Neoplasms; Tegafur; Tomography, X-Ray Computed; Uracil

We report here a case of reversible posterior leukoencephalopathy syndrome(RPLS)induced by modified FOLFOX6(mFOLFOX6). The patient was a 43-year-old woman who had sigmoid colon cancer with multiple liver metastases. Treatment with mFOLFOX6 was started. Early in the morning of day 11, the patient was transported by ambulance to the hospital due to nausea with headache, disturbed consciousness, and visual disturbance. The patient experienced sudden, severe nausea and subsequently presented generalized tonic-chronic seizures. The seizures subsided after treatment. On the evening of day 11, another episode of generalized tonic-chronic seizures occurred. Status epilepticus developed and tracheal intubation was performed for airway protection. Cranial MRI showed increased signal intensity in both occipital lobes, centered on the boundary between the gray and white matter on FLAIR images. Her condition stabilized with no seizure recurrence following intubation. Although hypertension was present on admission to the emergency room, blood pressure gradually fell to within the normal range without antihypertensive treatment. She was extubated on day 18. There were no neurologic sequelae. Cranial MRI on day 40 showed that the increased intensity in both occipital lobes had almost disappeared. Because the patient's condition was characterized by a reversible central nervous system disorder, RPLS was diagnosed.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Organoplatinum Compounds; Posterior Leukoencephalopathy Syndrome; Sigmoid Neoplasms

In vivo real-time visualization of chemotherapy response at the cellular level provides us with direct evidence of what happens on the tumor microenvironment of metastatic organs. We imaged the response of metastatic tumor cells and host stromal cells to chemotherapeutics on liver metastatic xenografts in living mice using intravital two-photon laser scanning microscopy (TPLSM). Red fluorescent protein-expressing human colorectal cancer cells (HT29) was inoculated to the spleen of green fluorescent protein-expressing nude mice. 5-Fluorouracil or irinotecan was intraperitoneally administered after the formation of macroscopic liver metastases. Intravital TPLSM was performed at multiple time-points for time-series imaging of liver metastatic xenografts in the same mice. Under the 1st TPLSM, HT29 cells were visualized in hepatic sinusoids at the single cell level. Liver metastatic nodules consisting of viable cancer cells and surrounding stroma with tumor vessels were visualized under the 2nd TPLSM. After chemotherapy, tumor cell fragmentation, condensation, swelling and intracellular vacuoles were observed under the 3rd TPLSM. There was no obvious morphological difference in tumor response between these chemotherapeutics. Time-series intravital TPLSM imaging on the metastatic tumor xenografts may be useful for screening and evaluating new chemotherapeutics with less interindividual variability.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Colorectal Neoplasms; Fluorouracil; Green Fluorescent Proteins; HT29 Cells; Humans; Leucovorin; Liver; Liver Neoplasms; Luminescent Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Microscopy, Confocal; Neoplasm Transplantation; Organoplatinum Compounds; Red Fluorescent Protein; Transplantation, Heterologous; Tumor Microenvironment

Patients with neuroendocrine carcinomas (NECs) grade 3 have a poor prognosis. Etoposide-platinum combination is the standard chemotherapy but the role of a second-line therapy remains unknown. Irinotecan alone or in combination has shown some efficacy in patients treated for small cell lung cancer which had pathological similarities with neuroendocine tumors. The aim of this study is to determine safety and efficacy of the FOLFIRI regimen in patients with NECs grade 3 after failure of etoposide-platinum combination. This study was retrospective, including patients with NECs grade 3 and treated with the FOLFIRI regimen after progression or toxicity of etoposide-platinum combination in first-line. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≥3 and/or serum alkaline phosphatase ≥5×upper limit of normal value (ULN) and/or bilirubin ≥1.5×ULN were excluded. Among 39 patients who failed etoposide-platinum combination, 19 (49%; 12 women, median age 53 (29-78) years) received the FOLFIRI regimen with a median number of 6 (1-16) courses. Six patients (31%) had at least one episode of grades 3-4 toxicity (neutropenia, n=3; diarrhea, n=3) without toxic death. Six patients (31%) had objective response, 6 (31%) stable disease, and 7 (38%) tumor progression. Median progression-free survival under FOLFIRI was 4 months. Overall survival was 18 vs 6.8 months in noneligible patients. FOLFIRI regimen is a safe and potentially efficient chemotherapy given as second-line in patients with NECs grade 3 who remain in good condition and with correct liver tests after failure of etoposide-platinum combination. These results should be confirmed in a future prospective study.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Camptothecin; Carcinoma, Neuroendocrine; Disease-Free Survival; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Grading; Pancreatic Neoplasms; Pelvic Neoplasms; Platinum; Treatment Outcome

We hypothesized that metachronous colorectal liver metastases (CLM) have different biology after failure of oxaliplatin (FOLFOX) compared to 5-fluorouracil (5-FU) or no chemotherapy for adjuvant treatment of colorectal cancer (CRC).. It is unclear whether patients treated with liver resection for metachronous CLM after adjuvant FOLFOX for CRC have worse outcomes than those who received 5-FU or no chemotherapy.. We identified 341 patients who underwent hepatectomy for metachronous CLM (disease-free interval ≥12 months, 1993-2010). Mass-spectroscopy genotyping for somatic gene mutations in CLM was performed in a subset of 129 patients.. Adjuvant treatment for primary CRC was FOLFOX in 77 patients, 5-FU in 169 patients, and no chemotherapy in 95 patients. Node-positive primary was comparable between FOLFOX and 5-FU but lower in the no-chemotherapy group (P < 0.0001). Median metastasis size was smaller in the FOLFOX group (2.5 cm) than in the 5-FU (3.0 cm) or no-chemotherapy (3.5 cm) groups, (P = 0.008) although prehepatectomy chemotherapy utilization, metastases number, and carcinoembryonic antigen levels were similar. Disease-free survival (DFS) and overall survival (OS) rates after hepatectomy were worse in patients treated with adjuvant FOLFOX [DFS at 3 years: 14% vs 38% (5-FU) vs 45% (no-chemo), OS at 3 years: 58% vs 70% (5-FU) vs 84% (no-chemo)]. On multivariate analysis, adjuvant FOLFOX was associated with worse DFS (P < 0.0001) and OS (P < 0.0001). Mutation analysis revealed ≥1 mutations in 57% of patients (27/47) after FOLFOX, 29% (12/41) after 5-FU, and 32% (13/41) after no chemotherapy (P = 0.011).. Adjuvant FOLFOX for primary CRC is associated with a high rate of somatic mutations in liver metastases and inferior outcomes after hepatectomy for metachronous CLM.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Mass Spectrometry; Middle Aged; Multivariate Analysis; Mutation; Organoplatinum Compounds; Postoperative Complications; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Adenocarcinoma; Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Disease Progression; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Organoplatinum Compounds; Tomography, X-Ray Computed; Uterine Perforation

The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response.. This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR.. Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed.. Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Survival Analysis; Treatment Outcome

Mucinous adenocarcinoma (MA) of colorectal cancer seems associated with reduced responsiveness to chemotherapy. The overexpression of markers of resistance to fluorouracil and oxaliplatin has recently been demonstrated. We revised the outcomes of metastatic MA of the colon treated with FOLFOX. From January 2002 to December 2009, we treated 198 patients with metastatic colon cancer, of which 21 (10.6%) had diagnosis of MA and were compared with 42 control patients with non-mucinous adenocarcinoma (NMA). In MA group, three patients [14%; inhibitory concentration 95: ± 7.5%] reached partial response, and in NMA group, two patients obtained complete response and 16 obtained partial response with an overall response rate of 43% (inhibitory concentration 95: ± 7.6%) with a significant statistical difference (P = 0.027). Median progression-free survival for MA group was 4 months with respect to 8 months for NMA (P = 0.0001); regarding overall survival, we registered a median of 8 months with respect to 18 months for MA and NMA (P = 0.001). In multivariate analysis, MA histology, Eastern Cooperative Oncology Group performance status 2, more than two metastatic sites, and peritoneal metastatic involvement resulted in negative independent prognostic factors. Also in our study, MA is connected to poor prognosis and reduced activity of chemotherapy. In the absence of randomised studies, it may be convenient to analyse this subgroup of patients within the large trials carried out on colorectal cancer.

Topics: Activities of Daily Living; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Remission Induction; Retrospective Studies; Survival Analysis

We experienced a rare case of intussusception due to sigmoid colon cancer during chemotherapy. A-62-year-old female was started on mFOLFOX6 due to sigmoid colon cancer and hepatic metastases(stage IV). After 2 courses, she had abdominal pain and bloody stool. Abdominal ultrasonography showed a target sign, and abdominal CT showed edema of the mucosa of the sigmoid colon and invagination. She was diagnosed with intussusception due to sigmoid colon cancer, and underwent a bloodless reduction. However, because it was unavailable, we performed an emergency operation. The sigmoid colon invaginated 10 cm to the anal side. We then performed sigmoidectomy and lymphadenectomy(D2). The histopathological diagnosis was mucinous carcinoma, stage I. There was no report of intussusception with the chemotherapy. It is important to consider the intussusception of colon cancer even during chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Intussusception; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Sigmoid Diseases; Sigmoid Neoplasms

A 68-year-old man had undergone right hemicolectomy of ascending colon cancer with multiple liver metastases. This case of k-ras status on the cancer tissue also showed wild type. Chemotherapy with panitumumab and 5-FU/LV/irinotecan (FOLFIRI)regimen was performed after the resection of the ascending colon cancer. After seven curses of treatment, metastatic liver tumors were reduced considerably(PR). Liver resection(left hepatic lobectomy and partial resection of S4 and S5)and radiofrequency ablation therapy were performed. Recently, chemotherapy has improved overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. Combination chemotherapy using panitumumab, and FOLFIRI plus operation is a candidate as a standard treatment strategy for multiple liver metastases of colon cancer.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Panitumumab; Tomography, X-Ray Computed

Hepatic arterial infusion chemotherapy for liver metastases is under evaluation because of the high target dose and low general toxicity. To investigate the efficacy and safety of a Folfox4 regimen administered through a combined hepatic arterial and systemic infusion for the first-line treatment of colorectal cancer (CRC) with unresectable liver metastases.. Twenty-seven CRC patients with unresectable hepatic metastases and no prior chemotherapy were enrolled into the study. They received a Folfox4 regimen; 1st day: HAI of oxaliplatin 85 mg/m(2) and L-folinic acid 200 mg/m(2), followed by a bolus hepatic arterial injection of 5-fluorouracil 400 mg/m(2), then continuous HAI of 5-FU 600 mg/m(2); 2nd day: infusion of L-folinic acid 200 mg/m(2) i.v. followed by an intravenous bolus injection of 5-Fluorouracil 400 mg/m(2), then continuous infusion of 5-fluorouracil 600 mg/m(2) i.v. The patients received HAI during the odd cycles, and the intravenous administration of the same Folfox4 regimen during the even cycles.. A total of 236 treatment cycles were given with a median of 10 cycles. The therapy generated the following results after six treatment cycles: complete response (CR) 1/27 (3.7%), partial response (PR) 17/27 (63.0%), stable disease (SD) 6/27 (22.2%), and progress disease (PD) 3/27 (11.1%). Five patients had hepatectomy. The serum levels of both carcinoembryonic antigen (CEA) and CA19-9 were significantly reduced (P < 0.05). A median time to progression of 11 months and a median overall survival of 24 months were documented. The major adverse events included grade 1/2 nausea/vomiting, upper abdominal pain, peripheral neuropathy, and neutropenia/thrombocytopenia.. The Folfox4 regimen administered through combined hepatic arterial and systemic infusions is efficacious and safe for the treatment of CRC with unresectable liver metastases, and it facilitates the control of local lesions.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

The coexistence of liver cirrhosis with hepatocellular carcinoma (HCC) and colon cancer (Ca), which is a rare clinical condition, was treated in a liver transplant recipient.. A 46-year-old man, diagnosed incidentally during an ultrasound (US) examination with a 3.5-cm HCC in segment VII related to chronic hepatitis C virus (HCV), was referred for liver resection. He underwent a laparoscopic protocol evaluation for liver cirrhosis. Liver appearance and biopsy of the left lobe showed Child B/C liver cirrhosis. Because he fulfilled the Milan criteria, we suggested an orthotopic liver transplantation (OLT). During protocol colonoscopy, we discovered an ulcerative sigmoid colon Ca. Three weeks after completing the pre-OLT assessment he underwent an OLT and was discharged home on day 9 on an immunosuppressive regimen of Everolimus, Myfortic, and Prezolone. Two months after transplantation, the patient underwent a sigmoidectomy and for nearly 1 month thereafter received chemotherapy for colon Ca (6 cycles of FOLFOX:Folinic Acid+Fluorouracil+Oxaliplatin). One and a half years after OLT, patient was in good condition but presented with an increased alpha fetoprotein (a-FP) without other findings. A couple of months later we discovered a colon Ca recurrence and 3 small liver metastases. Patient underwent a bowel resection with Hartmann's procedure. Almost immediately after the last operation, he was found to suffer multiple myeloma. He underwent chemotherapy for both malignancies with good responses, but a few months later died of severe sepsis.. The relevant literature regarding treatment of liver cirrhosis complicated with HCC and synchronous colon Ca reveals poor and controversial outcomes. Our patient underwent chemotherapy immediately after colon resection in the presence of with a good functioning liver. Although his condition was satisfactory after OLT, the optimal treatment of such complicated patients is as yet uncertain.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Colonoscopy; Fatal Outcome; Fluorouracil; Hepatitis C, Chronic; Humans; Incidental Findings; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Multiple Myeloma; Neoplasm Recurrence, Local; Neoplasms, Multiple Primary; Organoplatinum Compounds; Sepsis; Time Factors; Treatment Outcome

The aim of the present study was to evaluate single center experience with hepatic arterial infusion (HAI) of irinotecan, 5-fluorouracil and leucovorin in patients with liver metastases from colorectal carcinoma (CRC).. A retrospective analysis of 68 patients treated between 1998 and 2007 was performed.. Among 60 patients who had no simultaneous liver-directed procedure (LDP), the best results obtained were complete response in two patients (3%), partial response in 18 patients (30%), and stable disease in 23 patients (38%), for an overall disease control rate of 72%. Median progression-free survival was 11 months, and median survival was 24 months. Overall survival was significantly better in patients with simultaneous LDP or secondary resection. Steatosis was present in all secondary resection specimens.. Our data demonstrate the efficacy of HAI of irinotecan combined with 5-fluorouracil and leucovorin for liver metastases from CRC, specifically in patients also treated with LDP.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Survival Rate

Protein-bound polysaccharide K (PSK) has been used as a chemoimmunotherapy agent for the treatment of colorectal cancer. Recently, PSK was reported to be able to decrease some adverse effects of FOLFOX therapy, including neutropenia and peripheral neurotoxicity. Here, we report 2 patients with metastatic colorectal cancer, who unexpectedly were able to receive many courses of PSK+mFOLFOX6 therapy for a prolonged period. We speculate that FOLFOX therapy may achieve long-term tumor control with the aid of PSK without serious side effects for metastatic colorectal cancer patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Polysaccharides; Time Factors

The prognosis for patients with unresectable intrahepatic cholangiocarcinoma(ICC) is extremely poor. Case 1 was a 65- year-old woman who had an ICC of 9 cm in diameter (mass-forming type) in the right lobe with portal trunk invasion. She was treated with hepatic arterial infusion chemotherapy[cisplatin(CDDP)/5-fluorouracil(5-FU)/l-leucovorin(l-LV)] and radiation therapy (total dose, 50 Gy). After 6 months, abdominal computed tomography (CT) revealed that the tumor had regressed. She survived for 7 years without recurrence of the ICC; subsequently, she died of peritoneal cancer. Case 2 was a 59-year-old woman who had an ICC of 8 cm in diameter (mass-forming type) in the left lobe with lymph node metastasis in the hepatoduodenal ligament; the right hepatic artery was involved by the metastatic lymph nodes. She was treated with hepatic arterial infusion chemotherapy(CDDP/5-FU/l-LV) and radiation therapy(total dose, 30 Gy). After 10 months, abdominal CT revealed that the tumor had disappeared, but paraaortic and mediastinal lymph node metastases were detected. She was therefore treated with systemic chemotherapy. Treatment with systematic chemotherapy enabled her to survive for over 5 years with a good performance status.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Chemoradiotherapy; Cholangiocarcinoma; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Staging; Time Factors

The aim of this retrospective study was to analyze the predictive value of Köhne's index on the efficacy of FOLFIRI regimen in the treatment of unresectable liver metastasis of colorectal cancer. The subjects were 44 patients with unresectable liver metastasis from colorectal cancer treated with FOLFIRI regimen as second-line, for all of whom oxaliplatin-based regimen had previously failed. Bevacizumab was concomitantly used in 23 patients. Classification of the Köhne's index revealed high risk in 22 patients, intermediate risk in 7 patients, and low risk in 15 patients. The response rate was 13.6% in the patients with high risk(H group) and 27.3% in the patients with intermediate or low risk(non-H group)(p=0.45). The disease control rate was 50% in the H group and 68.2% in the non-H group (p=0.36). In the H group, the median progression -free survival time was 4.1 months and in the non-H group it was 7.1 months (p=0.33). Compared with the H group, the non-H group showed significantly better overall survival (10.8 months vs 23.9 months, p=0.03). None of the patients has received hepatectomy (conversion therapy). These results suggest that the predictive value of Köhne's index is limited in terms of the effect of shrinkage of liver metastases, including conversion therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Retrospective Studies

Case 1: A 69-year-old man was diagnosed with rectal cancer and liver metastasis. After low anterior resection, mFOLFOX6 plus cetuximab therapy was started for resection of the liver metastasis. However, he had to forgo liver resection because he developed acute exacerbation of interstitial pneumonitis (IP) after 6 courses of chemotherapy. Despite beginning the second-line treatment with mFOLFOX6 plus bevacizumab, he died in June 2012. Case 2: A 71-year-old man had undergone sigmoidectomy for sigmoid colon cancer in 2005, and right lower lobe partial resection for metastatic lung cancer in 2006. Although radiofrequency ablation or transcatheter arterial chemoembolization had been performed for multiple liver metastases several times since 2007, his multiple liver metastases were uncontrollable. Therefore, FOLFOX4 therapy was started in 2010, and mFOLFOX6 plus cetuximab therapy was substituted for FOLFOX4 therapy in 2011. The patient died in March 2012 due to the rapid development of IP, and thus, it appears that IP was the cause of death in both patients. The general condition, including pulmonary function, of patients at risk of IP must be checked before starting cetuximab therapy for metastatic colorectal cancer.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Neoplasm Staging; Organoplatinum Compounds; Rectal Neoplasms

The FOLFOX regimen is approved as an adjuvant therapy for colon cancer in Japan. We report a case of pathological damage in the resected non-cancerous liver after 12 courses of mFOLFOX6 therapy as an adjuvant therapy for stage IIIb colon cancer. A 45-year-old man underwent laparoscopic right hemicolectomy for ascending colon cancer. After completing 12 courses of adjuvant mFOLFOX6 therapy, this patient exhibited liver metastasis. Lateral segment resection was performed, and pathological examination of the resected specimen revealed irregular sinusoidal dilatation and cell apoptosis in the non-tumorous part of the liver. This was probably due to the effects of mFOLFOX6. We stress that when resectable liver metastasis is found after 12 courses of FOLFOX as an adjuvant therapy for colon cancer, careful attention should be paid during surgery and during postsurgical management because there may be damage in the remnant liver.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Chemical and Drug Induced Liver Injury; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds

In 2006, a 70-year-old man who underwent low anterior resection for rectal cancer (SS, N0, H1, Stage IV)at a nearby hospital was referred to our hospital. He was noted to have multiple liver metastases of approximately 1 cm in diameter in S2, S3, S6, and S7, and was subsequently treated with chemotherapy for 5 courses of mFOLFOX6 regimen. He achieved a complete response radiographically. Thereafter, he underwent lateral segmentectomy of the liver and was noted to have residual tumor cells by histopathological examination of the resected tissue. Seven months after the hepatectomy, recurrence occurred in S6 and S7 and a new lesion in S8 was noted. He then underwent 12 courses of mFOLFOX6. As of June 2012, the patient is alive without recurrence. A prolonged survival may be possible if downstaging is achieved with successful chemotherapy. However, similar to the present case, the detection of residual cancer cells during histopathological examination of the resected tissues has been reported in the literature. Thus, further investigation is needed to determine the optimal treatment of cases achieving a radiographic complete response.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Organoplatinum Compounds; Radiography; Rectal Neoplasms

The patient was a 68-year-old man. Because sigmoid colon cancer and metastatic liver cancer was diagnosed in August 2009, an indwelling central venous port and sigmoid colon resection were implemented. The metastatic liver cancer was a huge tumor occupying the right hepatic lobe and caudate lobe. In consideration of the risk associated with the resection and the possibility of early recurrence, the postoperative chemotherapy was selected. He underwent 9 courses of bevacizumab (Bev)+FOLFOX. The tumor was observed to reduce but continued to occupy the right lobe and caudate lobe. At this point, the surgical treatment was selected because the tumor has been shrunk and there is no appearance of new metastases. In order to preserve residual liver function, he underwent percutaneous transhepatic portal embolization and then resection of the right lobe of the liver in February 2010. Although the Bev+FOLFOX treatment was started again after surgery as adjuvant chemotherapy, the metastatic liver cancer recurred in the remnant liver in August 2010. Because it was about 6 months from the first recurrence of liver resection, we decided to continue chemotherapy immediately without resection. However, the chemotherapy was insufficient to shrink the tumor, which increased because it was present at 3 locations in the liver. Therefore, partial hepatectomy at the 3 locations with positron-emission tomography was performed in February 2011. Since then, chemotherapy has not been performed in patients, and there is no recurrence as of March 2012. In the guideline for the treatment of liver metastasis of colorectal cancer, even though chemotherapy is currently developed, the surgical procedure is recommended for patients who are responsive to local therapy. If the cancer recur immediately after resection, it is difficult to decide whether to re-resect. We report the case in which the tumor-free status can be observed as a result of a combination of systemic chemotherapy and local therapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Sigmoid Neoplasms; Time Factors

Even in the era of new anticancer drugs, an optimal treatment strategy for colorectal cancer associated with liver metastasis and peritoneal carcinomatosis has yet to be established. Here we report the case of a long-term survivor with very advanced colon cancer who underwent repeated resective surgery and chemotherapy. This 69-year-old man underwent a Hartmann's procedure and the resection of peritoneal metastases of cancer of the rectosigmoid, which had infiltrated the retroperitoneum giving rise to multiple liver metastases and peritoneal carcinomatosis. The resection margin was positive for cancer. After 14 courses of a modified FOLFOX6 (mFOLFOX6) regimen, a partial response with no development of new lesions was obtained. Multiple partial hepatectomies were subsequently performed. After the completion of an additional 6 courses of mFOLFOX6, a positron-emission tomography (PET)/computed tomography (CT) examination demonstrated a hot spot in segment 4. This hot deposit disappeared after a further 8 courses of mFOLFOX6. The patient then underwent a left lateral segmentectomy for a newly developed lesion in segment 3, which was detected 2 years and 7 months after the first operation. The patient has remained free from recurrence for 2 years since his last operation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Peritoneal Neoplasms; Sigmoid Neoplasms; Time Factors

Colon cancer during pregnancy is a relatively rare occurrence. To date there has been sparse clinical evidence about the safety of chemotherapy in this setting because the available data derive only from single-institution case reports.. Irinotecan and fluorouracil, as part of the FOLFIRI regimen, were administered to a 33-year-old pregnant woman at an estimated gestational age of 23+ weeks. She had been diagnosed with adenocarcinoma of the transverse colon with liver and lymph node metastases.. Chemotherapy was administered from the 23+th to the 28+th week of gestational age. Chemotherapy was stopped because of disease progression. At 30 weeks' gestational age, the patient underwent an emergency cesarean section and colon resection. She gave birth to a healthy male infant with no particular problems in neurological, respiratory, cardiovascular, digestive and nutritional function. At follow-up, the 13-month-old child had achieved all appropriate growth and developmental milestones.. Our report demonstrates the safety of exposure to FOLFIRI for both mother and fetus. The absence of any abnormalities in the infant makes irinotecan and fluorouracil a valid therapeutic option for colon cancer during pregnancy.

Topics: Adenocarcinoma; Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cesarean Section; Colectomy; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Gestational Age; Humans; Infant, Newborn; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Outcome; Treatment Failure

Laparoscopic left lateral sectionectomy (LLS) has gained popularity in its use for benign and malignant tumors. This report describes the evolution of the authors' experience using laparoscopic LLS for different indications including living liver donation.. Between January 2004 and January 2009, 37 consecutive patients underwent laparoscopic LLS for benign, primary, and metastatic liver diseases, and for one case of living liver donation. Resection of malignant tumors was indicated for 19 (51%) of the 37 patients.. All but three patients (deceased due to metastatic cancer disease) are alive and well after a median follow-up period of 20 months (range, 8-46 months). Liver cell adenomas (72%) were the main indication among benign tumors, and colorectal liver metastases (84%) were the first indication of malignancy. One case of live liver donation was performed. Whereas 16 patients (43%) had undergone a previous abdominal surgery, 3 patients (8%) had LLS combined with bowel resection. The median operation time was of 195 min (range, 115-300 min), and the median blood loss was of 50 ml (range, 0-500 ml). Mild to severe steatosis was noted in 7 patients (19%) and aspecific portal inflammation in 11 patients (30%). A median free margin of 5 mm (range, 5-27 mm) was achieved for all cancer patients. The overall recurrence rate for colorectal liver metastases was of 44% (7 patients), but none recurred at the surgical margin. No conversion to laparotomy was recorded, and the overall morbidity rate was 8.1% (1 grade 1 and 2 grade 2 complications). The median hospital stay was 6 days (range, 2-10 days).. Laparoscopic LLS without portal clamping can be performed safely for cases of benign and malignant liver disease with minimal blood loss and overall morbidity, free resection margins, and a favorable outcome. As the ultimate step of the learning curve, laparoscopic LLS could be routinely proposed, potentially increasing the donor pool for living-related liver transplantation.

Topics: Adenocarcinoma; Adenoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Camptothecin; Carcinoma, Hepatocellular; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Stromal Tumors; Hepatectomy; Humans; Laparoscopy; Length of Stay; Leucovorin; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Melanoma; Middle Aged; Organoplatinum Compounds; Postoperative Complications; Retrospective Studies; Tissue and Organ Harvesting

Gastric cancer is the third most common cancer worldwide and the second leading cause of cancer deaths. Appropriate staging and treatment options relate to the stage of disease and performance status of the patient.. Here we present the case of a 72 year old male, with an initial presentation of apparently locally advanced gastric cancer. On discovery of metastatic disease, the utility of palliative gastrectomy, and first and second line chemotherapy are discussed.. This case demonstrates the potential value of sequential lines of chemotherapy in good performance status patients with advanced gastric cancer. Further research will be necessary in order to assess the utility of newer targeted agents in this setting.

Topics: Adenocarcinoma; Adenoma, Villous; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Fluorouracil; Gastrectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Neoplasms, Second Primary; Organoplatinum Compounds; Oxaliplatin; Stomach Neoplasms; Treatment Outcome

The liver is the most frequent site of metastases from colorectal cancer (CRC), and extensive liver metastases often cause severe secondary liver dysfunction. However, whether chemotherapy for metastatic CRC with severe liver dysfunction offers any clinical benefit is unclear since patients in this setting are typically excluded from clinical trials.. We report herein a case of metastatic sigmoid colon cancer with severe liver dysfunction that was successfully treated using infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX). FOLFOX was effective and well tolerated in the present case, and subsequent addition of bevacizumab to FOLFOX after disease progression was similarly feasible.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Remission Induction; Treatment Outcome

The benefit of preoperative chemotherapy in patients with initially resectable liver metastases from colorectal cancer is still a matter of debate.. We aim to evaluate the role of neoadjuvant chemotherapy on the outcome of patients with colorectal cancer metachronous liver metastases undergoing potentially curative liver resection.. One-hundred four patients were available for analysis. Tested variables included age, sex, primary tumour TNM stage, location and grading, the number of liver metastases, monolobar or bilobar location, interval time between liver metastases diagnosis and liver resection, Fong Clinical Risk Score (CRS). Neoadjuvant chemotherapy was administered according to the FOLFOX4 regimen.. Forty-four patients underwent liver resection without receiving neoadjuvant chemotherapy (group A); 60 patients received neoadjuvant chemotherapy (group B). At univariate analysis, only the time of liver resection seemed to affect overall survival: patients in group A showed a median survival time significantly superior to that of patients in group B (48 vs. 31 months; p=0.0358).. Our findings suggest that, when feasible, resection of liver metastases should be considered as an initial approach in this setting. Further studies are needed to better delineate innovative therapeutic strategies that may lead to an improved outcome for colorectal cancer patients with surgically resectable liver metastases.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Retrospective Studies; Risk Assessment; Survival Analysis; Time Factors; Treatment Outcome; Young Adult

5-Fluorouracil remains widely used in colorectal cancer treatment more than 40 years after its development. 19F magnetic resonance spectroscopy can be used in vivo to measure 5FU's half-life and metabolism to cytotoxic fluoronucleotides. Previous studies have shown better survival associated with longer 5FU tumour half-life. This work investigated 5FU pharmacokinetics in liver metastases of colorectal cancer.. A total of 32 subjects with colorectal cancer undergoing 5FU treatment, 15 of whom had liver metastases, were examined in a 1.5T MRI scanner, using a large coil positioned over the liver. Non-localised spectra were acquired in 1-min blocks for 32 min after injection of a 5FU bolus. The 5FU half-life was measured in each subject, and averaged spectra were examined for the presence of fluoronucleotides. Associations with progression-free survival were assessed.. No association was observed between 5FU half-life, tumour burden and survival. Half-lives were all shorter than those associated with improved survival in the literature. Remarkably, in the group with liver metastases, high levels of fluoronucleotides were associated with poorer survival; this counterintuitive result may be due to the higher levels of fluoronucleotides (whose level is higher in tumour tissue than in normal liver) in patients with higher tumour burdens.. It is recommended that future studies use chemical shift imaging at higher field strengths to better resolve tumour from normal liver. Non-localised spectroscopy retains prognostic potential by enabling straightforward detection of fluoronucleotides, which are present at very low concentrations distributed throughout the tissue.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carbon Dioxide; Colon; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Oxygen; Rectum; Tumor Burden

Chemotherapy-induced liver injury is a considerable problem in patients undergoing surgery for colorectal liver metastases, since an increase in postoperative morbidity and mortality has been observed. We investigated whether liver damage had further implications on long-term outcome in these patients.. Liver specimens from 196 patients resected for colorectal liver metastases were evaluated for chemotherapy-associated hepatic damage in the nontumorous liver. Injury patterns were correlated with recurrence free (RFS) and overall survival (OS). Factors leading to sinusoidal injury were identified.. Patients who developed grade 2 or 3 sinusoidal dilatation had a significantly shorter RFS (hazard ratio [HR] 2.05; 95% confidence interval [95% CI] 1.23-3.39, P = .005) and OS (HR 2.90; 95% CI 1.61-6.19, P < .001), compared to patients without this alteration. Those patients also had significantly more intrahepatic recurrences (66.7% vs 30.5%, P = .003). Other patterns of chemotherapy-associated liver damage (nonalcoholic steatohepatitis, fibrosis) were not associated with impaired survival. Factors indicating sinusoidal injury were oxaliplatin-based chemotherapy, tumor size >5 cm, and elevated alkaline phosphatase or gamma glutamyltransferase.. Sinusoidal obstruction syndrome due to oxaliplatin-based chemotherapy may not only compromise perioperative outcome, but can lead to early recurrence and decreased survival in the long term. Strategies to prevent this condition are clearly needed.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Survival Rate; Time Factors; Treatment Outcome

Resection + radiofrequency ablation (RFA) + hepatic artery infusion (HAI) + systemic chemotherapy for patients with unresectable synchronous liver-only metastases from colorectal cancer was rarely used previously.. We compared the outcomes of 42 patients underwent resection + RFA + HAI + systemic chemotherapy (RRHS) with that of 43 patients underwent resection + RFA + systemic chemotherapy (RRS).. The overall survival, the survival free of hepatic recurrence and the median survival in the RRHS group were all significantly higher than those in RRS group at 4 years. While the rates of adverse effects were similar in the two groups.. For patients with unresectable synchronous liver-only metastases from colorectal cancer, RRHS not only decreases but also postpones hepatic recurrence and therefore improves overall survival at 4 years, as compared with RRS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Proportional Hazards Models; Recurrence; Survival Rate; Treatment Outcome

Regenerative nodular hyperplasia (RNH) represents the end-stage of vascular lesions of the liver induced by chemotherapy. The goal was to evaluate its incidence and impact on the outcome of patients resected for colorectal liver metastases (CLM).. Patients who underwent hepatectomy for CLM after six cycles or more of first-line chemotherapy, between January 1990 and November 2006, were included. Detailed histopathologic analysis of the nontumoral liver was performed according to a standard format.. From a cohort of 856 resected patients at our institution, 771 (90%) received preoperative chemotherapy. Of these, 146 fulfilled the selection criteria and were included: 24 (16%) received 5-fluorouracil (5-FU) and leucovorin (LV) alone, 92 (63%) had 5-FU/LV and oxaliplatin, 18 (12%) had 5-FU/LV and irinotecan, and 12 (8%) were treated by 5-FU/LV, oxaliplatin, and irinotecan. RNH occurred in 22 of 146 patients (15%). Twenty of these patients (91%) received oxaliplatin, of whom six (30%) had chronomodulated therapy. Patients treated by oxaliplatin more often had RNH compared with oxaliplatin-naïve patients (22 vs. 4%). Although operative mortality was nil, the presence of RNH was associated with increased postoperative hepatic morbidity (50 vs. 29%). Elevated preoperative gamma-glutamyltransferase (GGT) (>80 U/L; >1N) and total bilirubin levels (>15 μmol/L; >1N) were independent predictors of RNH.. Patients with CLM who receive preoperative oxaliplatin have an increased risk of RNH and associated postoperative morbidity. Increased serum GGT and bilirubin are useful markers to predict the presence of RNH.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Focal Nodular Hyperplasia; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Treatment Outcome

In breast cancer patients, Mailliez and others described that 5 of 70 patients (7%) developed a bevacizumab-induced nasal septal perforation. However, to date, no studies have reported such rates in colorectal cancer patients, who derive a survival advantage with this drug.. This study examined the incidence of bevacizumab-induced, clinically symptomatic, otolaryngology specialist-confirmed nasal septal perforation among 100 patients who had been consecutively-treated for metastatic colorectal cancer.. The incidence of nasal septal perforation was 1% (95% confidence intervals: -0.95% to 2.95%). This single adverse event was successfully managed conservatively. Within the whole group, 94 had been treated with bevacizumab at 5 mg/kg every two weeks, except for four patients treated at higher doses. The median number of bevacizumab doses (range) was seven (1-96). Concomitant chemotherapy had been prescribed to all patients, consisting of oxaliplatin, 5-fluorouracil, leucovorin, as per one of the FOLFOX regimens (44 patients); irinotecan, 5-fluorouracil, leucovorin, as per the FOLFIRI regimen (13 patients); both these regimens and no other (five patients); or a different regimen (38 patients).. Nasal septal perforation from bevacizumab occurs infrequently among colorectal cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Incidence; Leucovorin; Liver Neoplasms; Male; Middle Aged; Nasal Septum; Nose Diseases; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Treatment Outcome; Young Adult

An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI).. Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors.. Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95% confidence interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures.. FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Female; Floxuridine; Fluorouracil; Follow-Up Studies; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Retrospective Studies; Survival Rate; Treatment Outcome

Systemic chemotherapy may render initially unresectable colorectal cancer liver metastases resectable. Histopathologic examinations of resected nontumoral liver tissue revealed chemotherapy-associated liver injuries, which was recognized to impair the function of the remnant liver. We therefore evaluated whether indocyanine green (ICG) plasma clearance helps to assess chemotherapy-induced liver damage.. Data of 101 liver resections performed between 2006 and 2008 for colorectal liver metastases were analyzed for this study. Eighteen patients had liver resection without preoperative treatment, whereas 83 patients underwent neoadjuvant chemotherapy before surgery. ICG clearance was assessed by pulse densitometry before surgery.. Comparison of ICG retention clearances demonstrated that patients pretreated with systemic chemotherapy had a significantly lower plasma disappearance rate (ICG-PDR; 19.3 ± 5.9 vs. 23.1 ± 3.8%/min; P = 0.002) and a significantly elevated ICG retention rate at 15 min (7.9 ± 6.6 vs. 3.8 ± 1.9%; P < 0.001). The percentage of subjects with an abnormal ICG-PDR (≤18%/min) was significantly higher in the pretreated group (48.2% vs. 5.6%; P = 0.001). Patients with an ICG-PDR of ≤18 had a prolonged postoperative hospital stay and experienced four times more complications in their postoperative course.. ICG clearance helps to identify patients with impaired liver function after neoadjuvant chemotherapy and aids in the estimation of the postoperative risk of morbidity after liver resection for colorectal liver metastases.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Humans; Indocyanine Green; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Preoperative Care; Survival Rate; Treatment Outcome

Tolerability to irinotecan may be explained by pharmacogenomic polymorphisms. The purpose of this pharmacogenetic trial was to study the relevance of thymidylate synthase (TS) genotyping and of the isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT1A1) in order to tailor a combination chemotherapy regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) in metastatic colorectal cancer.. Patients with favourable TS and UGT1A1 profiles received high-dose (HD) FOLFIRI. Patients with TS-3R/3R could not receive HD-FOLFIRI, and those with UGT1A1-7/7 received standard FOLFIRI. The endpoints were overall response rate and safety.. Sixty-nine patients were enrolled in the study. Sixty-five patients received chemotherapy. Twenty patients (30.8%) achieved a partial response. The haematological toxicity was less in the HD-FOLFIRI subgroup. Patients having received HD-FOLFIRI did not experience increased levels of nausea-vomiting, asthenia or alopecia. Diarrhoea was more frequent with HD-FOLFIRI.. The genotypic assessment allowed a safer use of HD-FOLFIRI. Further investigations may target patients who benefit from intensification.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; DNA, Neoplasm; Female; Fluorouracil; Follow-Up Studies; Genotype; Glucuronosyltransferase; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mutation; Neoplasm Staging; Pharmacogenetics; Pilot Projects; Polymerase Chain Reaction; Survival Rate; Thymidylate Synthase; Treatment Outcome; Young Adult

Here we reassess anticipated inability to obtain a microscopically clear surgical margin as an absolute contraindication to surgery for colorectal liver metastases in view of improvements in treatment modalities adjunctive to surgery.. We retrospectively analysed 310 patients treated at our institution to estimate the survival benefit from R1 hepatectomy performed to remove liver metastases from colorectal cancer.. Considering all 310 patients evaluated, the R1 resection group (positive margin; n = 55) showed a lower disease-free rate (P < 0.01) and worse overall survival (P < 0.01) than the R0 resection group (negative margin; n = 255). When patients were divided according to initial resectability, similar differences in disease-free rate and overall survival (P = 0.03) between R1 (n = 19) and R0 (n = 182) were observed in patients whose metastases were resectable. However, superior impact of R0 resection (n = 73) compared to R1 resection (n = 36) on disease-free rate (P = 0.44) and overall survival (P = 0.50) was not confirmed in patients with initially unresectable or marginally resectable metastases, especially those with a favourable response to prehepatectomy chemotherapy.. A predicted positive surgical margin after resection no longer should be an absolute contraindication to surgery for aggressive or advanced liver metastases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Cisplatin; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Analysis; Treatment Outcome

Expression of IL-23, a heterodimeric cytokine involved in the induction of Th17 cells, is increased in human tumors. Although the endogenous IL-23 expression has been reported to promote tumor development and growth, the studies using local and systemic administration of IL-23 have shown that its application at the excessive amount induces antitumor immune responses. IL-23 is, today, considered the key driver of intestinal inflammation and its role in inflammatory responses is tissue-specific. The aim of this study was to investigate the role of circulating levels of IL-23 in patients with resected colorectal cancer (CRC) before and after chemotherapy, respect to healthy controls. Twenty-five patients were enrolled between June 2007 and January 2009, and followed through 2010. All patients underwent chemotherapy, mostly FOLFOX4. Twenty-sex and age-matched healthy donors were recruited as controls. IL-23 serum concentrations, measured by a quantitative enzyme immunoassay technique, were significantly higher in patients with resected CRC (26.02 ± 28.63 pg/ml versus 7.1 ± 6.4 pg/ml, P < 0.001) and after chemotherapy respect to controls (21.74 ± 23.82 pg/ml versus 7.17 ± 6.43 pg/ml, P < 0.001). An increase was documented also before chemotherapy (26.02 ± 28.63 pg/ml versus 21.74 ± 23.82 pg/ml, P = 0.7) but not statistically significant. This work investigated, for the first time, the role of IL-23 in CRC resection and chemotherapy, showing no correlation with the severity of disease, tumor removal, and chemotherapeutic treatment. However, other works are needed to better clarify if IL-23 could be considered a key-molecule in human CRC and a target for tumor treatment.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Case-Control Studies; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interleukin-23; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Severity of Illness Index

After approval of bevacizumab in Japan, post-marketing surveillance studies reported on safety. However, few reports have shown the efficacy of bevacizumab as used in daily practice. We evaluated the efficacy and safety of bevacizumab for metastatic colorectal cancer patients in daily practice.. All unresectable metastatic colorectal cancer patients who began receiving bevacizumab in participating facilities from June 2007 to October 2008 were retrospectively analyzed for safety and efficacy. Adverse events were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Response Evaluation in Solid Tumors criteria, version 1.0, was used for the tumor response rate.. A total of 212 patients from 17 institutions were assessed. Grade 3 or higher adverse events related to bevacizumab included gastrointestinal perforation in 3, thrombosis in 7, hypertension in 30 and gastrointestinal bleeding in 2. Response rates were 62.5, 30.1 and 11.8% overall among patients receiving bevacizumab as first-, second- and third-line or greater therapy. Median progression-free survival was 14.4 [95% confidence interval (CI): 10.8-18.1], 7.8 (95% CI: 6.5-9.1) and 6.0 (95% CI: 4.6-7.3) months, and median overall survival was 32.5 (95% CI: 24.6-40.3), 16.4 (95% CI: 14.4-18.5) and 11.8 (95% CI: 8.6-15.0) months, respectively.. The general cohort of patients in HGCSG0801 showed a similar efficacy and safety profile of bevacizumab as seen in clinical trials. Although the sample size was small and there were several study limitations, these results suggest that colorectal cancer patients in Japan might safely receive and benefit from bevacizumab in combination with chemotherapy in daily practice, as is seen in patients in other countries.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colorectal Neoplasms; Confidence Intervals; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Epistaxis; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Hypertension; Irinotecan; Japan; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxonic Acid; Proteinuria; Retrospective Studies; Tegafur; Thrombosis; Treatment Outcome

We administered hepatic arterial infusion chemotherapy (HAIC) prior to FOLFOX to three patients with unresectable liver metastases from colorectal cancer. The patients' disease state was found to be highly advanced based on both computed tomography findings and liver function tests. The treatment strategy included an initial administration of HAIC to control liver metastases and improve liver function in order to facilitate the subsequent safe administration of FOLFOX without drug loss. As the HAIC regimen, 1,000 mg/m2 of 5-FU was administered weekly by continuous 5-h infusion after performing laboratory investigations through an implanted port-catheter system. After 3 HAIC cycles administered over 3 consecutive weeks, the mean alkaline phosphatase levels decreased from 969.3IU/l to 422IU/l due to shrinkage of the liver metastases. Thereafter, FOLFOX without drug loss could be safely initiated for all patients. Two patients succumbed 488 and 333 days after HAIC was initiated;the third patient is still alive and has been followed-up for 1215 days. The combined use of HAIC and standard systemic chemotherapy could be a feasible and efficacious treatment in highly advanced cases of liver dysfunction.

Topics: Angiography; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheterization; Colorectal Neoplasms; Combined Modality Therapy; Embolization, Therapeutic; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Cetuximab is an agent approved as epidermal growth factor receptor (EGFR)-positive for unresectable advanced or recurrent colorectal cancer. A 58-year-old man with liver metastasis had relapsed after resection of rectal cancer. We treated him with cetuximab monotherapy as third-line chemotherapy after treatment failures with infusional 5-FU, LV and oxaliplatin (FOLFOX4 regi- men); and infusional 5-FU, LV and irinotecan(FOLFIRI regimen). The patient was administered cetuximab (400 mg/m² initial dose and 250 mg/m²/ week thereafter). After sixteen weeks of treatment, a computed tomography scan revealed reduced sizes of the liver metastases. The tumor response has still been maintained after thirty courses of treatment, and the chemotherapeutic response was evaluated as a partial response according to the Response Evaluation Criteria In Solid Tumor guidelines. The main toxicity was a grade 2 rash, but was manageable by topical steroid and moisturizing agent. We have added some review of the literature, and the cetuximab therapy is reported.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Drug Resistance, Neoplasm; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Recurrence; Salvage Therapy

A 73-year-old man was referred to our hospital with sigmoid colon cancer in July 2009. CT and MRI showed synchronous multiple liver metastasis. After a sigmoid colon resection in August, he received convergent chemotherapy in combination with 5-fluorouracil(5-FU)/Leucovorin(LV)(RPMI regimen)and bevacizumab for liver metastasis. After two courses without any major adverse effects, liver metastasis remarkably reduced on CT and MRI examination. We thus performed a liver resection, and pathological examination revealed a complete response in liver. Combination chemotherapy of 5-FU/LV and bevacizumab can be expected to provide safe and effective treatment for liver metastasis of colon cancer.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Remission Induction; Sigmoid Neoplasms; Tomography, X-Ray Computed

Limited options remain for patients with metastatic colorectal cancer (CRC) after failure of standard systemic chemotherapy. Readministration of chemotherapeutic agents by hepatic arterial infusion (HAI) has the rationale of providing higher concentrations of chemotherapeutic agents to hepatic metastases. The present study was conducted to evaluate the efficacy and safety of HAI of fluorouracil with leucovorin (HAI 5-FU/LV) for patients with liver metastases from CRC.. Fourteen patients with liver metastases from CRC who received HAI 5-FU/LV after failure of systemic chemotherapy containing fluorouracil and leucovorin were identified and their medical records were reviewed.. Of 10 patients evaluable for response, one partial response, six stable disease, and three progressive disease were reported. Additionally, the overall response and disease control rates were 7% and 50%, respectively. The median time to progression was 4.3 months (range, 2.9 to 5.6), to hepatic progression was 5.8 months (range, 4.7 to 6.9), and to extrahepatic progression was 5.8 months (range, 2.3 to 9.2). No grade 3/4 hematologic toxicities occurred and one case of abdominal pain and two cases of oral mucositis were the only grade 3 nonhematologic toxicities. Catheter-related complications occurred in three patients: one thrombosis, one infection, and one displacement.. HAI 5-FU/LV was well tolerated and showed modest efficacy for patients with liver metastases from refractory CRC. Readministration of previously used chemotherapeutic agents via the hepatic artery could be an effective salvage option and warrants further investigation in a prospective trial.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Salvage Therapy

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; ErbB Receptors; Eyelashes; Female; Fluorouracil; Hair Color; Hepatectomy; Humans; Hypertrichosis; Leucovorin; Liver Neoplasms; Neoplasm Proteins; Organoplatinum Compounds; Oxaliplatin

To establish an appropriate administration schedule for oxaliplatin in FOLFOX plus bevacizumab therapy for a hemodialytic patient.. A 50-year-old man on chronic hemodialysis was treated for colon cancer and synchronous hepatic metastasis with modified FOLFOX-6 plus bevacizumab therapy every 3 weeks. The plasma concentration of free platinum was measured at eight points, before and within the first 50 h after oxaliplatin administration. A dose escalation study of oxaliplatin was performed at doses of 60, 70, and 85 mg/m(2). A 4-h dialysis session was begun at the end of the oxaliplatin treatment.. The pharmacokinetics of free platinum showed a bimodal pattern at each dose: The serum concentration decreased rapidly soon after dialysis, then increased, and remained at a high level for 24 h. The areas under the curves (AUC) for free platinum were 17.6, 23.6, and 32.6 μg h/mL after doses of 60, 70, and 85 mg/m(2) oxaliplatin, respectively. These exceeded the AUC when 90 mg/m(2) was given to a patient with normal renal function (7.9 μg h/mL). Treatment was safely continued for 6 months without severe toxicity.. FOLFOX plus bevacizumab therapy can be given safely to hemodialytic patients with no reduction in the dose of oxaliplatin if hemodialysis is performed soon after the administration of oxaliplatin and the dosing interval is extended to 3 weeks.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Renal Dialysis

To report clinical experience with radioembolization (RE) plus systemic chemotherapy as a first-line treatment for liver metastases from colorectal cancer (CRC).. Clinical outcomes were evaluated retrospectively among 19 patients with unresectable liver metastases from CRC who had a good performance status and a low burden of extrahepatic disease (EHD) and were eligible for RE. Most (74%) had disease confined to the liver. Concurrent treatment with 5-fluorourail/leucovorin (n = 7) or 5-fluorourail/leucovorin/oxaliplatin (FOLFOX; n = 12) was started 3-4 days before single treatment with RE.. Overall response rate according to the Response Evaluation Criteria in Solid Tumors was 84% (two complete responses and 14 partial responses). Median progression-free survival (PFS) time was 10.4 months and median overall survival (OS) time was 29.4 months. For patients with disease confined to the liver, PFS improved (10.7 mo vs 3.6 mo; P = .09), with significant prolongation of OS (median, 37.8 mo vs 13.4 mo; P = .03) compared with those who had EHD. Nine patients, including three long-term (> 3 y) survivors, remained alive after a median follow-up of 18.6 months. Serious treatment-related toxicities included febrile neutropenia with concurrent FOLFOX treatment, a perforated duodenal ulcer, and one death from hepatic toxicity.. The present findings confirm the effectiveness of RE plus systemic chemotherapy for metastatic CRC. Patients with liver-confined disease derived the greatest benefit, with median survival times beyond 36 months. Larger datasets from ongoing phase III trials are needed to further define the safety and efficacy of RE in the first-line setting.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Brachytherapy; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Embolization, Therapeutic; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Yttrium Radioisotopes

Disseminated intravascular coagulation (DIC) is a complication that may be experienced by patients with solid tumors. The prognosis of solid tumors with DIC is much poorer than those without DIC. Although treatment of the underlying disease is critical for improvement of DIC, the efficacy and safety of chemotherapy in patients with DIC associated with colorectal cancer are not clear. A 50-year-old man with advanced rectal cancer and multiple liver metastases experienced DIC during third-line treatment with cetuximab plus irinotecan, following 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) plus bevacizumab and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab. Combination chemotherapy consisting of FOLFOX plus bevacizumab was reintroduced. Although platelet and fresh-frozen plasma transfusions were required daily before chemotherapy, the patient's laboratory values improved after two cycles of chemotherapy, without severe toxicity. The patient was discharged, and FOLFOX plus bevacizumab has been continued on an outpatient basis without sign of recurrence of DIC as of December 2010 (4 months after initiation of chemotherapy). This case suggests that reintroduction of combination chemotherapy with FOLFOX plus bevacizumab is effective and feasible in patients with colorectal cancer with DIC and that chemotherapy may be a treatment option for such patients.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Disseminated Intravascular Coagulation; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Rectal Neoplasms

Chemotherapeutic options for patients with metastasised colorectal cancer and impaired liver function are limited. Although oxaliplatin and 5-FU are well tolerated as single therapeutic agents, data supporting their use as combination chemotherapy in the setting of severe hepatic dysfunction are insufficient.. Here, we report on 2 patients with colorectal cancer and severe liver dysfunction secondary to hepatic metastases. On admission both patients displayed a bilirubin of > 22 mg/dL and an alkaline phosphatase (AP) of > 350 U/L as signs of extensive hepatic tumor spread. We initiated a 5-FU/oxaliplatin-based combination chemotherapy in both patients.. Liver function and clinical performance improved dramatically within the first cycles of therapy in both patients. On radiologic evaluation, we observed 1 partial response and one long-term (10 months) disease stabilization. The toxicity was acceptable in both patients.. We concluded that oxaliplatin-based combination chemotherapies (eg FOLFOX4) may achieve good tumor response without significant side effects in patients with metastatic colorectal cancer and hepatic dysfunction.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bilirubin; Camptothecin; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin

The antivascular endothelial growth factor monoclonal antibody bevacizumab with infusional 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) is a standard first-line treatment option for metastatic colorectal cancer. However, clinical data for capecitabine and irinotecan (XELIRI) with bevacizumab are limited.. A retrospective study was conducted on 139 patients with metastatic colorectal cancer to assess the efficacy and safety of first-line bevacizumab in combination with XELIRI or FOLFIRI. Primary endpoints were overall response rate (ORR), disease control rate and radical resection rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS) and safety.. No significant differences in efficacy were observed between patients administered XELIRI or FOLFIRI with bevacizumab. The ORR, median OS and PFS and recorded adverse events (AEs) were comparable to those previously reported, with no new or unexpected AEs observed.. Bevacizumab is similarly efficacious and well tolerated when administered with XELIRI or FOLFIRI.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate; Treatment Outcome; Vascular Endothelial Growth Factor A

About 50% of patients with primary colorectal cancer (CRC) will develop liver metastases (CLM). Currently, carcinoembryonic antigen (CEA) is the most common tumour marker for CRC and CLM. However, the sensitivity and specificity of this marker is not optimal, as almost 50% of patients have tumours that do not produce CEA. Therefore there is a need for better markers for CRC and CLM.. The circulating levels of type IV collagen were measured in patients with CLM, primary CRC and in healthy controls. The expression pattern of type IV collagen was studied by immunofluorescence in CLM and normal liver tissue. The metastatic volume of CLM in the liver was estimated from CT.. In CLM tissue type IV collagen is highly expressed in the areas of desmoplasia. Patients with primary CRC (Dukes' A-C) did not show any increase in circulating type IV collagen compared to healthy controls. However, patients with CLM have significantly elevated levels of circulating type IV collagen when compared to patients with primary CRC and healthy controls. The levels of type IV collagen decreased during chemotherapy and increased at the time of disease progression. The circulating levels of type IV collagen seem to reflect the tumour burden in the liver.. Type IV collagen has the potential to be used as tumour associated biomarker for CLM. These results indicate the importance of interaction between cancer cells and the stroma in the tumour microenvironment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Collagen Type IV; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Tumor Burden

In patients with metastases limited to the liver (liver-limited disease [LLD]), effective therapies such as monoclonal antibodies combined with chemotherapy may facilitate metastasis resection and improve long-term survival.. This study assessed the cost-effectiveness of bevacizumab and cetuximab in the treatment of patients with colorectal cancer presenting with initially unresectable liver metastases of the Kirsten rat sarcoma viral oncogene homolog (K-ras) wild type, from the perspective of German statutory health insurance.. The health-economic modeling approach presented here made indirect comparisons between available data on bevacizumab and cetuximab treatment outcomes using evidence synthesis techniques, extrapolating from the follow-up duration of identified clinical trials to a longer time horizon of up to 10 years and inferring costs and health outcomes based on modeled patient pathways. Expert opinion and Delphi panel methods were used for some assumptions, when evidence was missing. Probabilistic sensitivity analyses and different scenario analyses were applied to test for uncertainty around input parameters and assumptions.. For the metastatic colorectal cancer LLD population with K-ras wild-type genotype, mean overall survival estimates were 37.7 months for first-line treatment with cetuximab plus FOLFIRI (irinotecan, leucovorin, fluorouracil) and 30.4 months for bevacizumab plus FOLFOX (oxaliplatin, leucovorin, fluorouracil). Corresponding discounted survival estimates were 2.88 life-years with cetuximab plus FOLFIRI versus 2.38 life-years with bevacizumab plus FOLFOX, an average gain of 0.50 discounted life-years. The incremental cost-effectiveness ratio of cetuximab plus FOLFIRI versus bevacizumab plus FOLFOX was €15,020 (year 2010 €) per life-year gained in the base case (with a 95% CI from the probabilistic sensitivity analysis of €3806-€24,660). Results were robust in different scenario analyses as well as in the probabilistic sensitivity analysis.. First-line treatment with cetuximab plus FOLFIRI offers a cost-effective treatment option versus bevacizumab plus FOLFOX for the metastatic colorectal cancer LLD population with K-ras wild-type genotype in Germany. K-ras testing should be performed on all presenting cases of metastatic colorectal cancer to ensure access to this treatment option.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Cost-Benefit Analysis; Drug Delivery Systems; Fluorouracil; Follow-Up Studies; Genes, ras; Germany; Humans; Leucovorin; Liver Neoplasms; Models, Economic; Models, Statistical; Organoplatinum Compounds; Survival Rate

There is limited evidence that imaging biomarkers can predict subsequent response to therapy. Such prognostic and/or predictive biomarkers would facilitate development of personalised medicine. We hypothesised that pre-treatment measurement of the heterogeneity of tumour vascular enhancement could predict clinical outcome following combination anti-angiogenic and cytotoxic chemotherapy in colorectal cancer (CRC) liver metastases.. Ten patients with 26 CRC liver metastases had two dynamic contrast-enhanced MRI (DCE-MRI) examinations before starting first-line bevacizumab and FOLFOX-6. Pre-treatment biomarkers of tumour microvasculature were computed and a regression analysis was performed against the post-treatment change in tumour volume after five cycles of therapy. The ability of the resulting linear model to predict tumour shrinkage was evaluated using leave-one-out validation. Robustness to inter-visit variation was investigated using data from a second baseline scan.. In all, 86% of the variance in post-treatment tumour shrinkage was explained by the median extravascular extracellular volume (v(e)), tumour enhancing fraction (E(F)), and microvascular uniformity (assessed with the fractal measure box dimension, d(0)) (R(2)=0.86, P<0.00005). Other variables, including baseline volume were not statistically significant. Median prediction error was 12%. Equivalent results were obtained from the second scan.. Traditional image analyses may over-simplify tumour biology. Measuring microvascular heterogeneity may yield important prognostic and/or predictive biomarkers.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Colorectal Neoplasms; Contrast Media; Drug Therapy, Combination; Female; Fluorouracil; Gadolinium DTPA; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Treatment Outcome

Topics: Adenocarcinoma; Age Factors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; France; Hepatectomy; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Prognosis

A patient is described who presented with an obstructive adenocarcinoma in the ascending colon and two liver metastases. She underwent right hemicolectomy with concurrent lymphadenectomy. As one of the liver metastases was considered irresectable, she received bevacizumab-containing chemotherapy. The disease responded well to treatment and after 4 months the largest lesion was subjected to radiofrequency ablation and the smaller could be removed. Eventually, systemic treatment was discontinued. At a later time-point the patient developed a new metastasis in the hilum of the liver. Bevacizumab-containing treatment was again successful; the patient experienced a complete response. Currently, she feels well. The only sign of disease is a slightly elevated carcino-embryonic antigen level at 36 months after diagnosis of metastatic colon cancer.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoembryonic Antigen; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Treatment Outcome

Metastatic colorectal cancer has a low cure rate. When resection of metastases is feasible, however, survival is increased. We present a case of a patient with metastases that responded well to bevacizumab-containing treatment. Consequently, surgical resection of metastases was possible resulting in increased survival.

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Organoplatinum Compounds; Treatment Outcome

Studies suggest that the continuous use of bevacizumab, a vascular endothelial growth factor inhibitor, may play a crucial role in improving therapy success in patients with metastatic colorectal cancer. This is a case report of a female 60-year-old patient with colon cancer metastases in the liver and lungs refractory to mFOLFOX6 and FOLFIRI given as first and second-line therapy, respectively, who demonstrated a good response to FOLFOXIRI and bevacizumab as third-line therapy. Bevacizumab may be added to first, second and third-line chemotherapy for palliative treatment of metastatic colorectal cancer, and data indicate an increase in patient survival with a good response rate and low toxicity.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Treatment Outcome

The prognosis of patients with advanced colorectal cancer with icterus is dismally poor, and adequate chemotherapy for these patients has not been established yet. A 59-year-old male with fatigue, anorexia and icterus with serum total bilirubin 9.7 mg/dL was referred to our institution. He was diagnosed with advanced sigmoid colon cancer with multiple liver metastases. A biopsy specimen of the primary tumor showed well-differentiated adenocarcinoma without KRAS mutation. Since biliary drainage was impossible due to diffuse liver metastases, we initiated combination chemotherapy with 5-fluorouracil, Leucovorin, oxaliplatin (modified FOLFOX6) and cetuximab. The doses of 5-fluorouracil and oxaliplatin were reduced, but cetuximab was administered at the standard dosage. After 3 courses of chemotherapy, total bilirubin dropped to 0.8 mg/dL. No significant toxicity other than grade-2 skin toxicity and neuropathy was observed, and the patient has continued chemotherapy on an outpatient basis. Combination chemotherapy with mFOLFOX6 plus cetuximab was effective and feasible in this case of metastatic colon cancer with icterus due to diffuse liver metastasis.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Jaundice; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Tomography, X-Ray Computed

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoembolization, Therapeutic; Chemotherapy, Adjuvant; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Pelvic Exenteration; Positron-Emission Tomography; Proctocolectomy, Restorative; Quality of Life; Tomography, X-Ray Computed; Treatment Outcome

Seven patients with rectal cancers which were difficult to ensure surgical margins for because of huge tumors(over 60mm in diameter), invasion to other organs, or severe nodal metastases, were treated with preoperative chemotherapy consisting of 2-10 courses of mFOLFOX6.The response rate was 85. 7%.Complete response was observed in one patient, and partial response was observed in 5 patients.Four to 5 weeks after chemotherapy, surgery was performed for all patients.Following surgical procedures, abdominoperineal resections were performed in 4 cases, low anterior resections in 3 cases, and removal of the liver metastases(not diagnosed preoperatively)in 2 cases.R0 resections were also performed in all patients. According to the histological regression grading of the resected specimens, one patient had a complete disappearance of tumor, 5 had grade 1a regression, and one had grade 1b regression.One of the 7 patients had recurrence at the lung. However, another patient survived without recurrence. In this study, preoperative mFOLFOX6 chemotherapy was expected to be an effective treatment for improving the curative resection rate of patients with tumors which were difficult to ensure surgical margins because of huge tumors, invasion to other organs, or severe nodal metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Pilot Projects; Rectal Neoplasms

Recently, in patients with unresectable colorectal liver metastasis, liver resection sometimes becomes possible by intensive systemic chemotherapy, i.e. conversion therapy. However, among cases that do not respond well to first-line chemotherapy, it is rare that second-line chemotherapy results in a marked response allowing liver resection. We consider that the liver resection rate may be increased by initiating second-line treatment at an earlier stage before progression subsequent to first-line chemotherapy. We are conducting a multicentre Phase II study to evaluate the efficacy and safety of sequential chemotherapy using six cycles of cetuximab plus FOLFIRI (5-fluorouracil, folinic acid and irinotecan) followed by six cycles of bevacizumab plus FOLFOX (5-fluorouracil, folinic acid and oxaliplatin) as conversion chemotherapy. The primary endpoint is the liver resection rate during the bevacizumab + FOLFOX phase. Fifty patients are required for this study.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Humans; Japan; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Patient Selection

To evaluate the influence of preoperative FOLFOX chemotherapy on CCL20/CCR6 expression in liver metastases of stage IV colorectal cancer (CRC) patients.. Using Real Time-PCR, enzyme-linked immunosorbent assay, Western Blots and immunohistochemistry, we have analyzed the expression of CCL20, CCR6 and proliferation marker Ki-67 in colorectal liver metastasis (CRLM) specimens from stage IV CRC patients who received preoperative FOLFOX chemotherapy (n = 53) and in patients who did not receive FOLFOX chemotherapy prior to liver surgery (n = 29).. Of the 53 patients who received FOLFOX, time to liver surgery was ≤ 1 mo in 14 patients, ≤ 1 year in 22 patients and > 1 year in 17 patients, respectively. In addition, we investigated the proliferation rate of CRC cells in liver metastases in the different patient groups. Both CCL20 and CCR6 mRNA and protein expression levels were significantly increased in patients who received preoperative FOLFOX chemotherapy ≤ 12 mo before liver surgery (P < 0.001) in comparison to patients who did not undergo FOLFOX treatment. Further, proliferation of CRLM cells as measured by Ki-67 was increased in patients who underwent FOLFOX treatment. CCL20 and CCR6 expression levels were significantly increased in CRLM patients who had undergone preoperative FOLFOX chemotherapy.. This chemokine/receptor up-regulation could lead to increased proliferation/migration through an autocrine mechanism which might be used by surviving metastatic cells to escape cell death caused by FOLFOX.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cell Proliferation; Chemokine CCL20; Colorectal Neoplasms; Fluorouracil; Humans; Ki-67 Antigen; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Preoperative Period; Receptors, CCR6

A 44-year-old female was referred to our hospital with a complaint of abdominal fullness. Computed tomography(CT) showed multiple liver masses and a huge ovarian tumor. Colonoscopy revealed a type 4 advanced cancer in the sigmoid colon. She was diagnosed with unresectable liver and ovarian metastases from advanced sigmoid colon cancer, for which we were obliged to select chemotherapy. As the first line, FOLFOX was applied and performed for 6 cycles, followed by FOLFOX plus bevacizumab(BV)for 5 cycles. While no deterioration of liver and ovarian metastases was observed during the course of those chemotherapy regimens, the patient developed a considerable level of acute sensorimotor neuropathic symptoms associated with oxaliplatin-induced peripheral neurotoxicity, forcing us to replace FOLFOX plus BV with FOLFIRI plus BV. Three cycles of FOLFIRI plus BV, however, turned out to be progressive disease with deterioration of liver and ovarian metastases. Since her oxaliplatin-induced neurotoxicity was improved, a regimen of FOLFOX plus BV was once again applied to her for 3 cycles, which failed to prevent her from having a progressive disease. The sequencing of K-RAS genes from the biopsy specimens of sigmoid colon cancer revealed an expression of a wild-type K-RAS. Thus, an addition of panitumumab to FOLFOX was made. Surprisingly, after 3 cycles of the chemotherapy regimen over 3 months, a significant reduction in the size of liver and ovarian metastases was observed. Her sense of abdominal fullness was apparently reduced and was even lower than what it was at admission. Panitumumab has great potential for effective treatment of patients with unresectable stage IV colorectal cancer, even after having acquired resistance to prior chemotherapy regimens.

Topics: Adult; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Ovarian Neoplasms; Panitumumab; Sigmoid Neoplasms

We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Fluorouracil; Humans; Hyperinsulinism; Hypoglycemia; Leucovorin; Liver Neoplasms; Malignant Carcinoid Syndrome; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor, has proven to be efficient in the treatment of metastatic colorectal cancer. We made a prospective study of the efficacy and toxicities of cetuximab-combination first-line (FOLFOX4) versus second/third-line (FOLFIRI) chemotherapy in 98 KRAS wild-type patients who had metastatic colorectal cancer. Wild-type KRAS had been identified by direct sequencing. Associations between clinical response/progression-free survival/overall survival/toxicities and cetuximab-combination chemotherapy timing were evaluated. The overall response rate was significantly higher for first-line treatment than for second/third-line treatment (relative risk = 1.707, 95% confidence interval = 1.121-2.598). Both progression-free survival and overall survival indicated significantly longer survival of first-line treatment than second/third-line treatment patients. This study is a validation of a molecular analysis of KRAS wild-type status for the prediction of response to cetuximab-combination chemotherapy for metastatic colorectal cancer patients; its predictive role was less prominent in the second/third-line than in the first-line treatment patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Routes; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Prospective Studies; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

We report a case of synchronous multiple liver metastases of rectal cancer successfully treated with tegafur/uracil(UFT) and oral Leucovorin (LV) chemotherapy. Lower anterior resection was carried out on the rectal cancer patient (an 80-year- old man), who had synchronous multiple liver metastases. The UFT (450 mg/day) and oral LV (75 mg/day) were orally administered for 4 weeks, followed by a 1-week interval after the surgical procedure. After completion of 16 courses, CT scan showed no liver metastases, and the patient was judged to have achieved a complete response (CR). The interval of CR was maintained for sixteen months until the age of 82. This chemotherapy is expected to have a potent therapeutic efficacy for older adult patients with advanced rectal cancer, because it is convenient and causes no severe diverse events.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Leucovorin; Liver Neoplasms; Male; Rectal Neoplasms; Tegafur; Tomography, X-Ray Computed; Uracil

This patient is a male in his 30's. He was diagnosed as hepatitis B virus-related huge primary liver cancer, 10cm in diameter, located in segment 4, accompanied with left portal thrombus and multiple lung metastases. Ten months after repeating systemic chemotherapy using gemcitabine (GEM)+carboplatin (CBDCA)+5-FU/leucovorin (LV) and hepatic arterial infusion chemotherapy with cisplatin (CDDP) 4 times, extended left lobectomy with caudate lobe could be successfully performed because of marked reducion of the huge tumor. The pathology revealed almost entirely necrotic changes of the main tumor, and the remaining, viable tumor nests showed combined hepatocellular and cholangiocarcinoma. Systemic chemotherapy was repeatedly given afterwards, which kept the pulmonary metastases stable without growth. The present case suggests that systemic chemotherapy using GEM+CBDCA+5-FU/LV may be useful in the multimodal treatment for the combined hepatocellular and cholangiocarcinoma with distant metastases.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carboplatin; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cisplatin; Combined Modality Therapy; Deoxycytidine; Fluorouracil; Gemcitabine; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male

Although surgical resection alone has been validated as a standard treatment for patients with liver metastases from colorectal cancer, a high rate of recurrence is still an issue to be overcome. We aimed to assess the efficacy of adjuvant chemotherapy using an oxaliplatin-based regimen in patients who underwent hepatic and primary colorectal cancer resection.. Sixty patients who received oxaliplatin-based postoperative chemotherapy combined with curative resection of primary colorectal cancer and synchronous liver metastases between January 2000 and February 2008 were retrospectively reviewed. The Kaplan-Meier method was used to estimate survival, and prognostic factors were evaluated with the log-rank test.. Median overall survival (OS) was 62.8 months [95% confidence interval (CI) 44.1-81.3], and median relapse-free survival (RFS) was 32.8 months (95% CI 5.8-59.6). The 1-, 3- and 5-year survival rates were 95.0, 68.8 and 55.5%, respectively. The relapse-free interval and modality of liver resection were independently associated with OS.. Oxaliplatin-based adjuvant chemotherapy after radical resection resulted in increased OS and RFS with acceptable tolerability compared to surgery alone. However, it is not yet clear whether postoperative oxaliplatin-based chemotherapy improves outcome compared to patients treated with 5-fluorouracil plus leucovorin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

A 63-year-old woman with a synchronous huge colorectal liver metastasis was referred to our institution.The lesion was technically diagnosed unresectable because the estimated future remnant liver volume was insufficient due to the invasion of the three hepatic veins and hepatic hilum.She underwent 7 courses of mFOLFOX6 and 14 administrations of cetuximab as conversion chemotherapy.Periodic abdominal CT scans revealed the tumor becoming PR, and she was free of cancer invasion to the left hepatic vein.After the remainder of chemotherapy lasting 4 weeks, right trisectionectomy and combined partial resection of the inferior vena cava and primary closure was performed.The postoperative course was uneventful and the patient was discharged at 20 days after the operation.She underwent chemotherapy postoperatively, and then underwent laparoscopic sigmoidectomy.A conversion chemotherapy using cetuximab may contribute to ward rapidly reducing tumor size and improving the resectability of initially unresectable huge colorectal liver metastases, thus leading to prolonged survival.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Organoplatinum Compounds; Sigmoid Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Diagnosis, Differential; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Nephrolithiasis; Tomography, X-Ray Computed

The patient is a 62-year-old female who underwent a right hemicolectomy for type-2 ascending colon cancer (moderately-differentiated adenocarcinoma, ss, n0, H0, P0, M0, stage II). Six months after the surgery, a solitary metastatic focus was expressed in the liver S3. Because schizophrenia was present concurrently, tegafur and uracil/folinate (UFT/Leucovorin) treatment was selected and performed for 3 months. Because the tumor shrank afterward, a partial hepatectomy was performed to obtain a curative resection. In a pathological examination of the resected focus, cicatricial/necrotic findings were observed, but no cancer cells were observed; hence, it was determined to be a pathological complete response (CR). In regard to chemotherapy for distant metastasis of colorectal cancer, many molecular-targeted agents are being introduced, thus resulting in more treatment options; however, depending on the patient's background, UFT/LV treatment can be an effective treatment option.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Female; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Remission Induction; Tegafur; Uracil

The current chemotherapy for metastatic colon cancer has improved an overall survival. In this study, we retrospectively analyzed the efficacy of mFOLFOX6 in colorectal cancer patients with synchronous unresectable liver metastases and compared the prognosis between before and after the administration of mFOLFOX6. The subject was 28 patients of colorectal cancer with synchronous unresectable liver metastasis who received mFOLFOX6 as a first-line treatment from 2005 to 2010. The median frequency of mFOLFOX6 was 10 times( range, 2-24 times), relative dose intensity of oxaliplatin was 75.0% (range, 42 .9-100), response rate was 32%, and median progression-free survival was 9 . 9 months. Surgical resection of colorectal liver metastases was performed to 4 patients (14.3%) as a conversion therapy. The overall survival of the patients with mFOLFOX6 was significantly better than that of 31 patients who received the chemotherapy via hepatic artery or the chemotherapy before the administration of oxaliplatin (31.8 months vs. 15 .1 months, p<0.01). Our results suggested that mFOLFOX6 treatment for unresectable liver metastases of colorectal cancer was made not only the conversion therapy possible, but it has improved the prognosis when compared with previous treatment without oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Some colorectal liver metastases disappear during chemotherapy. Some of those disappearing lesions recur, but there are few reports aiming this topic. We examined 6 patients with 55 disappearing liver metastases (DLMs) during mFOLFOX6 regimen. Six DLMs were resected, of which 3 (50%) had remnant cancer cells. Among the 49 DLMs not resected, 9 recurred after 23.5 (4.2-41.4) months. Cumulative risks of recurrence were 10.5% at 1 year, 10.5% at 2 years and 27. 5% at 3 years. Among these, some went through additional mFOLFOX6 or FOLFIRI regimen after they disappeared, but there was no significant difference among the number of the chemotherapy regimen and whether recurrences occur or not. The recurrence rate of the DLMs may be small, but further review with larger-scale group of DLMs is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Recurrence

Only a few reports have suggested the efficacy of adjuvant chemotherapy including oxaliplatin based regimens following surgical resection of liver metastases from colorectal cancer. Since an administration of mFOLFOX6 was approved to medical insurance for advanced colorectal cancer as adjuvant chemotherapy, we applied mFOLFOX6 treatment (6 to 12 courses) to the patients who underwent curative resection of colorectal liver metastasis. The subjects were 14 patients who underwent curative resection for synchronous or metachronous colorectal liver metastasis and received mFOLFOX6 treatment postoperatively from January 2006 to January 2011. We retrospectively analyzed the patient's characteristics, relapse free survival, overall survival, and adverse events in these patients. Synchronous liver metastasis was found in 5 patients, while metachronous liver metastasis was observed in 9 patients. There were no significant differences between these patients in terms of clinical characteristics, the relapse free survival and overall survival. All patients had some adverse events including bone-marrow suppression and diarrhea. Especially, grade 3 or higher bone-marrow suppression were recognized in 6 patients (42.8%). Neurologic toxicity (≤ grade 2) was observed in 10 patients (71.4%). Adjuvant chemotherapy with mFOLFOX6 treatment following surgical resection of synchronous or metachronous liver metastasis was safely administered. We will further examine the benefit of mFOLFOX6 treatment for the patients who undergo a surgical resection of liver metastasis in the future.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Recurrence; Survival Rate; Treatment Outcome

The aim of this study was to determine whether mRNA levels of thymidylate synthase (TS), excision repair cross-complementing -1 (ERCC-1), excision repair cross-complementing-2 (ERCC-2) and methylenetetrahydrofolate dehydrogenase( MTHFD) mRNA in the primary tumor could predict a tumor response in patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy as a first-line treatment. Eighteen patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy as a first-line treatment were enrolled in this study. There were no significant differences between the response rate and these enzymes mRNA levels. In ERCC-1 and MTHFD mRNA expression, the progression-free survival time tended to be longer in patients with low levels than in patients with high levels( ERCC-1: p=0.08, MTHFD: p=0.07). The progression-free survival time was significantly longer in patients with both ERCC-1 and MTHFD mRNA were low levels than in patients with other( p=0.03). The levels of ERCC-1 and MTHFD were low in patients who could perform a conversion therapy. There were no significant differences between an overall survival time and these enzymes mRNA levels. In this study, the ERCC-1 and MTHFD mRNA expression may be useful for the prediction of progression-free survival time in patients with unresectable liver metastasis from colorectal cancer treated with mFOLFOX6 therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Liver Neoplasms; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Middle Aged; Organoplatinum Compounds; RNA, Messenger; Thymidylate Synthase; Xeroderma Pigmentosum Group D Protein

Hepatic resection is a first choice for resectable liver metastatic tumor from colorectal carcinoma. In the case of unresectable tumor or a refusal to operation, laparoscopic radiofrequency ablation (RFA) becomes an option to treat. We report a case of laparoscopic RFA for liver metastatic tumor from colorectal carcinoma. A 74-year-old woman had a laparoscopic transverse colectomy for transverse colon cancer with multiple liver metastases in February 2009. She received UFT/LV and liver metastases were reduced. After the second course, the patient desired to stop chemotherapy. But the liver metastases had grown again. We recommended a hepatic resection. Since she didn't want to have the operation, we performed RFA. After the RFA, a liver metastasis was detected twice. After tumors were located near other organs, we performed a laparoscopic RFA. At 9 months after undergoing last RFA, she had no recurrence in the liver. We thought laparoscopic RFA was safe and effective for the lesion, which was difficult to treat with percutaneous approach RFA.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Catheter Ablation; Colonic Neoplasms; Female; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Tegafur; Tomography, X-Ray Computed; Uracil

We describe the case of a 74-year-old man with liver resection for originally unresectable liver metastasis from colorectal cancer after multiagent chemotherapy. Eleven bilobar liver metastases appeared four months after curative resection for double cancer of sigmoid colon and upper rectum. After 6 courses of multiagent chemotherapy (mFOLFOX 6 with bevacizumab), the number of liver metastasis decreased from 11 to 5. The patient underwent curative resection for liver metastasis. A new lesion of 7 mm in the segment 6 appeared 8 months after an initial liver resection. After 3 months' observation, two more liver metastases appeared. All liver metastases were resected. Solitary lung metastasis appeared 10 months after the second liver resection. The lung metastasis was also resected. The patient was alive with no evidence of disease in 33 months after the initial liver resection. We experienced the case with repeated liver resections after multiagent chemotherapy for originally unresectable bilobar liver metastasis. The therapeutic strategy which combines surgical resection with cytotoxic chemotherapy will be important more than ever.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Rectal Neoplasms; Sigmoid Neoplasms

We report a case of encephalopathy that was suspected to be caused by chemotherapy for liver metastasis from sigmoid colon cancer. A 72-year-old male was suspected that he had drug-induced eukoencephalopathy because he was presented with physical disorders during the FOLFOX/bevacizumab therapy. Although a brain MRI revealed Alzheimer disease, leukoencephalopathy was not excluded from the diagnoses due to a fact that his findings could not be compared before and after the chemotherapy. If leukoencephalopathy was suspected, chemotherapy should have been discontinued as soon as possible. Although a partial response was achieved, chemotherapy had to be discontinued in this case. The cases whose physical and neurological disorders were at risk due to a past history need an examination for nervous system in order to make a comparison with the findings before and after chemotherapy.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Dementia; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Sigmoid Neoplasms

The outcomes and management of colorectal cancer (CRC) hepatic metastasis have undergone many evolutionary changes. In this study, we aimed to analyze the outcomes of patients with CRC hepatic metastasis in terms of the era of treatment.. We conducted a retrospective review of 279 patients who underwent liver resection (LR) for CRC hepatic metastases. The prognoses of patients treated pre-2003 (era 1) and post-2003 (era 2) were examined.. Of the patients included in the study, 210 (75.3%) had CRC recurrence after LR. There was a significant difference in the ratio of CRC recurrence between the 2 eras (82.0% in era 1 vs. 69.5% in era 2; p = 0.008). Analysis of recurrence-free and overall survival rates also showed that the patient outcome was significantly better in the post-2003 era than in the pre-2003 era. Further analysis showed that a significantly higher percentage of patients in era 2 had received modern chemotherapeutic regimens including irinotecan and oxaliplatin, while patients in era 1 were mainly administered fluorouracil and leucovorin for adjuvant chemotherapy. Among patients with CRC recurrence, a significant ratio of those in era 2 underwent surgical resection for recurrent lesions, and these patients had a better survival curve than did patients without resection (34.1% vs. 2.2% for 5-year survival; p < 0.0001).. The incidence of CRC recurrence after LR for hepatic metastasis remains very high. However, the management and outcomes of patients with CRC hepatic metastasis have greatly improved with time, suggesting that the current use of aggressive multimodality treatments including surgical resection combined with modern chemotherapeutic regimens effectively prolongs the life expectancy of these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate; Time Factors; Treatment Outcome; Young Adult

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Neoadjuvant Therapy; Organoplatinum Compounds; Patient Selection; Time Factors; Treatment Outcome

As the real clinical significance of carcinoembryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9) evolution during preoperative chemotherapy for colorectal liver metastases (CLM) is still unknown, we explored the correlation between biological and radiological response to chemotherapy, and their comparative impact on outcome after hepatectomy.. All patients resected for CLM at our hospital between 1990 and 2004 with the following eligibility criteria were included in the study: (1) preoperative chemotherapy, (2) complete resection of CLM, (3) no extrahepatic disease, and (4) elevated baseline tumor marker values. A 20% change of tumor marker levels while on chemotherapy was used to define biological response (decrease) or progression (increase). Correlation between biological and radiological response at computed tomography (CT) scan, and their impact on overall survival (OS) and progression-free survival (PFS) after hepatectomy were determined.. Among 119 of 695 consecutive patients resected for CLM who fulfilled the inclusion criteria, serial CEA and CA19.9 were available in 113 and 68 patients, respectively. Of patients with radiological response or stabilization, 94% had similar biological evolution for CEA and 91% for CA19.9. In patients with radiological progression, similar biological evolution was observed in 95% of cases for CEA and in 64% for CA19.9. On multivariate analysis, radiological response (but not biological evolution) independently predicted OS. However, progression of CA19.9, but not radiological response, was an independent predictor of PFS.. In patients with CLM and elevated tumor markers, biological response is as accurate as CT imaging to assess "clinical" response to chemotherapy. With regards to PFS, CA19.9 evolution has even better prognostic value than does radiological response. Assessment of tumor markers could be sufficient to evaluate chemotherapy response in a nonsurgical setting, limiting the need of repeat imaging.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CA-19-9 Antigen; Camptothecin; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome

A 56-year-old man with abnormal chest X-P and stool occult bleeding was admitted. Colonoscopy detected rectal cancer and sigmoid al polyps. The biopsy results suggested that the rectal lesion was well- to moderately-differentiated adenocarcinoma and the sigmoidal polyp contained well -differentiated adenocarcinoma. CT scan revealed multiple lung, liver and lymph node metastasis. We judged the case to be inoperable and decided to start systemic chemotherapy (FOLFOX4). After treatment with chemotherapy, the tumor shrank and metastatic lesions disappeared. Low anterior resection was done, and final pathological examination revealed a complete response of the main tumor by treating with FOLFOX4.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Rectal Neoplasms

A 48-year-old woman was referred to our hospital with complaints of appetite loss caused by a sigmoid colon cancer and multiple liver metastasis. To prevent bowel obstruction, a sigmoid colon resection was performed. On postoperative day 27, FOLFOX was begun for the liver metastasis. But FOLFOX6 was discontinued due to diarrheal symptoms of grade 3. The liver metastasis was pointed out again in CT after two months, and S-1 was begun. It became CR on CT again. S-1 can be expected to be an effective agent for the treatment of colon cancer with liver metastasis.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Combinations; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Sigmoid Neoplasms; Tegafur

The combination of chemotherapy and surgery holds promise for improving CRC patient prognosis. We evaluated the pathological impact of chemotherapy on primary lesions and lymph node (LN) metastases retrospectively.. Sixteen CRC patients with synchronous liver metastasis underwent a radical operation between March 2005 and August 2007. Eight of the 16 cases (surgery group) were operated on for the primary lesion without chemotherapy and another 8 cases (chemotherapy group) were operated on after chemotherapy with FOLFOX (median: 8 courses).. Five of the 8 patients in the surgery group were found to have pathological LN metastasis (62.5%; N0 37.5%, N1 37.5%, N2 25%). However, only 2 of the 8 patients in the chemotherapy group were found to have LN metastasis (25%; N0 75%, N1 25%, N2 0%). The ratio of LN metastasis (number of metastatic LNs/resected LNs in total) was 11.1% in the surgery group, but it was 4.8% in the chemotherapy group. Necrotic areas were widely detected in the LN specimens of the chemotherapy group. The percentage of lymphatic (ly) and vascular (v) invasion in the primary lesions was smaller in the chemotherapy group (ly 12.5% vs. 25.0%) than in the surgery group (ly 62.5% vs. 50.0%). The patients in the chemotherapy group had no significant adverse effects and did not show an worse survival rate overall than the surgery group.. A promising effect of chemotherapy on the status of LN metastasis and vessel invasions at the primary site was observed in the patients who responded to FOLFOX.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Treatment Outcome; Vascular Neoplasms

To clarify the therapeutic strategies and prognosis factors of primary clear cell carcinoma of the liver (PCCCL).. The clinical pathological data of 64 patients with PCCCL treated with hepatectomy in our hospital from January 2000 to January 2006 were analyzed retrospectively. The patients were divided into two groups to make treatment analysis: curative resection only (n = 40); and curative resection and postoperative chemotherapy with calcium folinate and tegafur (n = 24). Meanwhile, the PCCCL patients were subdivided into two subgroups on the basis of the proportion of clear cells in the tumor for pathological analysis. There were 36 cases in subgroup A for which the proportion of clear cells was more than 70%, and 28 cases in subgroup B for which the proportion was less or equal to 70%, comparing analysis of median survival time of the counterpart groups. Univariate and multivariate analyses were performed to examine factors that affected clinical prognosis, recurrence and metastasis.. Median survival period of the curative surgery group was 38 mo, while the counterpart was 41 mo. Median survival period for group A was 41 mo, while group B was 19 mo. The Kaplan-Meier method showed that capsule formation, preoperative liver function, hepatitis C virus infection, large vascular invasion and multiple tumor occurrences were related to disease-free survival. Cox regression analysis showed that the clear cell ratio, capsule formation, preoperative liver function and large vascular invasion were independent risk factors for overall survival.. Postoperative chemotherapy has no obvious effect on survival of patients with PCCCL. Clear cell ratio, capsule formation, preoperative liver function, and vascular invasion were independent risk factors for prognosis.

Topics: Adenocarcinoma, Clear Cell; Adult; Aged; Antimetabolites, Antineoplastic; Combined Modality Therapy; Female; Hepatectomy; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; Tegafur; Treatment Outcome

We report a resected case of ascending colon cancer with left supraclavicular and paraaortic lymph nodes and liver metastases which completely responded in terms of metastases but not the primary tumor to FOLFOX4 therapy. A 62-year-old woman with epigastric discomfort was initially diagnosed as malignant lymphoma by FDG-PET with abnormal accumulation at left supraclavicular and paraaortic lesions. Pathological examination of the supraclavicular lymph nodes showed undifferentiated adenocarcinoma, and ascending colon cancer was detected by colonoscopy which was a mixture of various types of differentiation. FOLFOX4 therapy was effective for metastatic lesions but colon tumor did not regress and was accompanied by abdominal pain. Macroscopically, a curative right hemicolectomy was performed, and microscopic examination revealed that the tumor had become a mass of undifferentiated cancer cells. Thus, the present case demonstrates the dedifferentiation of colon cancer during chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Positron-Emission Tomography; Remission Induction; Tomography, X-Ray Computed

A69-year-old man was diagnosed with sigmoid colon cancer and underwent resection of the sigmoid colon. He was later diagnosed with multiple liver metastases 11 months after resection of the sigmoid colon cancer. He was treated by intraarterial chemoembolization using degradable starch microspheres (DSM) and radiofrequency ablation therapy. As a systemic therapy, combined oral administration of tegafur/uracil (UFT) and Leucovorin(Uzel) was started (UFT 450 mg/day, Leucovorin 75 mg/day, 4 weeks of therapy followed by a 1-week treatment break). Two months after 4 courses, the liver metastases had markedly diminished and CEA was within the normal range. The metastases had almost disappeared and tumor markers decreased to within normal limits. This treatment was very safe and effective. Such a strategic multidisciplinary treatment can lead to a better prognosis for colorectal cancer with liver metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Catheter Ablation; Combined Modality Therapy; Humans; Leucovorin; Liver Neoplasms; Male; Microspheres; Remission Induction; Sigmoid Neoplasms; Starch; Tegafur; Tomography, X-Ray Computed; Uracil

The patient was a 55-year-old female who had multiple liver metastases of rectal cancer. This patient underwent hepatic arterial infusion chemotherapy after low anterior resection for rectal cancer. Hepatic arterial infusion was discontinued due to severe diarrhea, and the administration of UFT (300 mg/day) and LV(75 mg/day) was then begun. The carcinoembryonic antigen (CEA) level was normalized immediately after the start of this administration. One year later, liver metastases disappeared on computed tomography (CT) and a complete response (CR) was achieved. No adverse events were noted, and CR was maintained for 2 years. This therapy can serve as one of the chemotherapies for advanced colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Middle Aged; Neoplasm Staging; Rectal Neoplasms; Remission Induction; Tegafur; Tomography, X-Ray Computed; Uracil

Histological response of colorectal cancer liver metastases to chemotherapy may be graded based on the extent of tumor regression. The knowledge about the effect of bevacizumab, if given in addition to fluoropyrimidines and oxaliplatin, on tumor regression and its consequences on clinical outcome is limited.. Resected liver metastases from patients of 2 prospective nonrandomized trials (fluoropyrimidines and oxaliplatin +/- bevacizumab) were analyzed retrospectively. Histological response was analyzed according to an established tumor regression grading for colorectal cancer liver metastases. Tumor regression grades (TRGs) were correlated to progression-free and overall survival.. Bevacizumab improved tumor regression to chemotherapy significantly. Improvement in histological response was translated into a significant prolongation of progression-free and overall survival.. Classifying histological response based on tumor regression grades qualifies to predict the outcome of patients with colorectal cancer liver metastases. Tumor regression grading provides a standardized pathological response evaluation, against which radiologic response on chemotherapy including biologicals can be prospectively evaluated.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaloacetates; Remission Induction; Retrospective Studies; Survival Analysis; Treatment Outcome

We have previously reported that 24-h intra-arterial combination chemotherapy (IACC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, it has also been reported that 5-fluorouracil (5-FU) exacerbates liver damage in patients with liver cirrhosis (LC). The aim of this study was to clarify the hepatotoxicity of IACC in LC patients with aHCC.. Twenty-one adult Japanese patients (20 men and 1 woman) with aHCC and LC underwent IACC between 2004 and 2007 at our hospital. These patients showed multiple partial responses or stable disease, except for five patients who showed no response and three patients with tumors more than 30 mm in diameter. All patients had inoperable disease on the basis of computed tomography (CT) findings. IACC (leucovorin at 12 mg/h, cisplatin at 10 mg/h, and 5-FU at 250 mg/22 h) was delivered via the proper hepatic artery every 5 days for 4 weeks.. Twelve patients were in Child-Pugh class A (group A), and nine were in class B (group B). The Child-Pugh score was significantly increased after chemotherapy compared with before chemotherapy in both groups. Serum albumin was significantly decreased after chemotherapy, and the number of patients with ascites also increased after chemotherapy. Serum type IV collagen and N-terminal propeptide of type III procollagen were significantly increased after chemotherapy, although there was no significant change in serum aminotransferases.. IACC might cause hepatotoxicity that induces fibrosis without releasing aminotransferases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Hepatocellular; Cisplatin; Collagen Type IV; Female; Fluorouracil; Hepatic Artery; Humans; Hyaluronic Acid; Infusions, Intra-Arterial; Japan; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Peptide Fragments; Procollagen; Serum Albumin; Tomography, X-Ray Computed; Transaminases

A 73-year-old man had undergone right hemicolectomy for advanced colon cancer in May 2006, and he concurrently had multiple liver metastases. After the operation, the patient was given chemotherapy with FOLFIRI. A partial response was achieved for twelve months, and then the liver tumors enlarged. Second-line chemotherapy with FOLFOX was delivered. After several months the liver tumors further enlarged and a new pulmonary lesion appeared with an increased serum CEA level. Therefore, chemotherapy with S-1 (120 mg/day) was started, with 2 weeks' administration followed by a one-week drug-free period. Several months later, the liver tumors and tumor makers decreased. S-1 is expected to be an effective agent for the treatment of advanced colon cancer with liver metastases after FOLFIRI and FOLFOX.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Drug Combinations; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxonic Acid; Salvage Therapy; Tegafur; Tomography, X-Ray Computed

Small-bowel adenocarcinoma (SBA) is a rare tumor of poor prognosis. Data on the efficacy of chemotherapy for advanced SBA are scarce.. All patients with advanced SBA who received frontline chemotherapy from 1996 to 2008 were eligible for this retrospective multicenter study.. Ninety-three consecutive patients were included. In the entire population, the median progression-free survival (PFS) and overall survival (OS) times were 6.6 and 15.1 months, respectively. Median PFS times among patients treated with LV5FU2 (n = 10), FOLFOX (n = 48), FOLFIRI (n = 19) and LV5FU2-cisplatin (n = 16) were 7.7, 6.9, 6.0 and 4.8 months, respectively, while median OS times were 13.5, 17.8, 10.6 and 9.3 months, respectively. In multivariate analysis, World Health Organization performance status (PS) (P < 0.0001) and elevated serum levels of carcinoembryonic antigen (CEA) (P = 0.02) and carbohydrate antigen 19-9 (CA 19-9) (P = 0.03) were the only variables significantly associated with poor OS. In the subgroup of patients treated with platinum-based chemotherapy, multivariate analysis showed that LV5FU2-cisplatin was associated with poorer PFS (P < 0.0001) and OS (P = 0.02) compared with FOLFOX.. This is the largest study of chemotherapy in advanced SBA. Baseline PS and CEA and CA 19-9 levels were the main prognostic factors. FOLFOX seems to be the most effective platinum-based chemotherapy regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Duodenal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Ileal Neoplasms; Intestine, Small; Irinotecan; Jejunal Neoplasms; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Retrospective Studies; Survival Rate

The aim of this study was to analyze the impact of hepatic arterial infusion (HAI) of oxaliplatin with systemic 5-Fluorouracil and leucovorin on patients with isolated unresectable liver metastases.. A total of 87 patients treated in our hospital with HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin for isolated unresectable colorectal liver metastases from May 1999 to May 2007 were extracted from a prospective database and analyzed. The resectability rate, perioperative findings, postoperative outcomes, and long-term follow-up were evaluated.. HAI was delivered after failure of previous systemic chemotherapy in 69 patients (79%). The main criterion for unresectability was massive liver involvement (86% of patients). Most patients had synchronous (85%), bilateral metastases (89%). The median number of HAI courses was 8 (0-25). About 31 patients experienced technical catheter-related problems, which were responsible for withdrawal of HAI in only 7 patients (8%). Finally, a total of 23 patients (26%) were operated on, and resection or radiofrequency ablation was performed in 21 patients (24%). No postoperative mortality was observed and the morbidity rate was 35%. Five-year overall survival was 56% in the surgery group versus none in the nonsurgery group (P < 0.0001). After a median follow-up of 63 months, intrahepatic recurrence occurred in 10 patients among the 23 operated patients.. HAI of oxaliplatin with systemic 5-Fluorouracil and leucovorin offers a second chance to remove initially unresectable isolated colorectal liver metastases in 24% of patients, and appears to be more efficient when performed as first-line therapy. Long-term overall survival can be obtained with this approach.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Survival Rate

Topics: Aneurysm; Angiogenesis Inhibitors; Angiomyolipoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kidney Neoplasms; Leucovorin; Liver Neoplasms; Middle Aged; Neoplasms, Second Primary; Tomography, X-Ray Computed

This study was performed to clarify the influence of preoperative chemotherapy on liver function and the correlation between histological hepatic injury and the postoperative outcome in patients with colorectal liver metastases who underwent a hepatic resection.. Twenty-seven patients who underwent a hepatic resection for colorectal liver metastases were included. Fifteen patients with initially unresectable colorectal liver metastases who were able to undergo a tumor resection after FOLFOX (oxaliplatin plus fluorouracil and leucovorin, with a mean number of 7.7 cycles) were compared to 12 patients who underwent a hepatectomy with no preoperative chemotherapy. The postoperative mortality, morbidity, changes in liver function tests, and pathology of the resected liver were examined.. Preoperative FOLFOX therapy was significantly associated with the macroscopic appearance of oxaliplatin-associated blue liver (p = 0.02), and a tendency toward sinusoidal dilatation (33.3% in the FOLFOX group versus 8.3% in the no-chemotherapy group, p = 0.056). Preoperative liver function tests showed that the albumin and indocyanine green retention rate at 15 min (ICG-R15) test values were significantly worse after FOLFOX therapy; however, intraoperative events, postoperative liver function test values, and morbidity rates were similar in the two groups. There was no postoperative mortality in any of the patients.. Although preoperative FOLFOX administration in patients with colorectal liver metastases caused macroscopic blue liver, microscopic sinusoidal dilatation in the liver parenchyma, and a significant decrease in liver function, there was no increase in the morbidity and mortality rates, in comparison to findings in patients without preoperative chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chi-Square Distribution; Colorectal Neoplasms; Dilatation, Pathologic; Female; Fluorouracil; Hepatectomy; Humans; Japan; Leucovorin; Liver; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Recovery of Function; Time Factors; Treatment Outcome

To evaluate the efficacy of oxaliplatin plus fluorouracil and leucovorin (FOLFOX) on initially unresectable colorectal liver metastases (CRLM).. From May 2005 to December 2008, FOLFOX was administered to 71 patients with initially unresectable CRLM. Hepatic resection was performed promptly after CRLM became resectable.. Twenty-six patients (37%) were downstaged as being resectable. The mean interval between the first FOLFOX and hepatic resection was six months (range, 3-7 months), and 7.1 courses (range, 2-12). Operative morbidity was 12% and mortality was nil. The median progression-free survival time was 19 and 7 months, and the median survival time was over 48 and 20 months, in finally resectable and unresectable patients, respectively. Multivariate analysis revealed that additional hepatic resection was the only independent prognostic factor (hazard ratio 4.80, p<0.01).. FOLFOX is an effective chemotherapeutic regimen leading to successful hepatic resection and an excellent prognosis for patients with initially CRLM.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Preoperative Care; Prognosis

We report the histopathological results of a novel "inversed" strategy designed to manage patients with colorectal cancer (CRC) who have synchronous liver metastases by using chemotherapy first, liver surgery second, and resection of the primary tumor as a final step. This study was designed to compare the response to chemotherapy in liver metastases, primary tumors, and locoregional lymph nodes.. Twenty-nine patients with stage IV CRC received a combination of oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (OCFL) for 3-4 months. Histological response to chemotherapy was assessed by using a tumor regression grading (TRG) score based on presence of residual tumor cells and extent of fibrosis.. Median age of patients was 56 (range, 37-69) years. Primary tumor location was right colon (n = 5), left colon (n = 7), and rectum (n = 17 patients). TRG scores correlated across disease sites (Spearman correlation coefficients for TRG in the primary tumor and lymph nodes was 0.59 [P = 0.005]; for the primary tumor and metastases 0.44 [P = 0.021]; and for lymph nodes and metastases 0.58 [P = 0.006]). Complete absence or poor tumor response (TRG4/5) was significantly more frequent in primary tumors (35.7%) and locoregional lymph nodes (38%) than in liver metastases (6.9%; McNemar test, P = 0.02). Two patients had a complete pathologic response (pT0N0M0).. In patients with stage IV colorectal cancer, liver metastases exhibit a better histological response than primary tumors to OCFL neoadjuvant chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Survival Rate; Treatment Outcome

We report a case of fluoropyrimidine-resistant recurrent colon cancer with liver and paraaortic lymph node metastases successfully treated with weekly administration of irinotecan (CPT-11). The patient was a 70-year-old man who underwent rt-colectomy for advanced colon cancer in January 2008. After the operation, adjuvant chemotherapy with uracil/tegafur and oral l-leucovorin was started and continued. However, the CEA level increased after six months, so we switched to CPT-11 at a dose of 100 mg/m2/day for 3 consecutive weeks followed by a week rest. CEA decreased to within the normal range after administration of 4 courses, and CT scan revealed metastatic lesions were reduced after 6 courses. Grade 1 general fatigue, nausea, diarrhea and grade 2 anemia and alopecia were noted, but no serious adverse reaction appeared. After that, CEA slightly increased, so the interval of administration was changed to bi-weekly in consideration of the adverse effect, restarted, and is now continuing. This was then restarted as a bi-weekly treatment, and is being continued now. It is thought this treatment may be simple, easy and promising second-line chemotherapy for uracil/tegafur and oral l-leucovorin-resistant metastatic colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Drug Resistance, Neoplasm; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Recurrence; Tegafur; Tomography, X-Ray Computed; Uracil

Preoperative chemotherapy containing oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) causes histological liver injury and increases postoperative morbidity and mortality in patients with colorectal liver metastasis (CRLM). However, information on the aggravation of liver function and its reversibility is scarce.. A total of 55 patients who underwent a hepatectomy after receiving FOLFOX and/or FOLFIRI were included in the present study. Indocyanine green tests were repeatedly performed before hepatectomy for monitoring the change of hepatic functional reserve.. A significant decrement in the ICG R15 value was observed at 2-4 weeks (12.9%, P = .04), 4-8 weeks (11.4%, P = .01), and 8 or more weeks (11.1%, P = .006) after the last chemotherapy, compared with results documented within 2 weeks (16.8%). However, no significant change was observed among the values obtained at 2-4 weeks, 4-8 weeks, and 8 or more weeks. The individual ICG R15 values at the beginning and end of the cessation period also improved from 17.7% to 11.6% (P = .001). Histological liver injury was associated with larger amounts of operative blood loss but not with morbidity. Neither liver failure nor mortality occurred in the present series.. The hepatic functional reserve, represented by the ICG R15 value, improves during the period after chemotherapy cessation. The present study suggests that chemotherapy cessation for at least 2-4 weeks enables an improvement in the hepatic functional reserve, especially among patients with an abnormal ICG R15 value (> 10%) who have received 6 or more cycles of FOLFOX and/or FOLFIRI.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Indocyanine Green; Irinotecan; Leucovorin; Liver; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Preoperative Care; Prospective Studies; Recovery of Function; Survival Rate; Time Factors; Treatment Outcome

To analyse the effects of the preoperative targeted molecular therapy (cetuximab (cetu) or bevacizumab (beva)) on non-tumorous liver parenchyma, and the clinical and biological outcome after liver resection for colorectal liver metastases (CLM).. Between January 2005 and December 2007, 36 patients receiving preoperatively cetu (n = 15) or beva (n = 21) were, respectively, matched to a control group of patients who did not receive targeted molecular therapy. They were matched on the basis of age, gender, body mass index, extent of hepatectomy, and type and number of neoadjuvant chemotherapy. Liver function tests, postoperative outcome and histopathology of the resected liver were compared.. There was no mortality. Postoperative morbidity and perioperative bleeding rates were similar in both groups. In the beva group, liver function tests showed higher serum bilirubin level on postoperative day (POD) 1 (p = 0.001) and POD 3 (p = 0.01), higher serum aspartate aminotransferase on POD 1 (p = 0.004), and lower prothrombin time on POD 5 (p = 0.02). In both groups, cetu and beva, the postoperative peaks of gamma-glutamyl transpeptidase and alkaline phosphatase were statistically higher than in the control groups. Interestingly, the prevalence of sinusoidal injury and fibrosis was lower in patients receiving cetu (p = 0.04), while the prevalence of steatohepatitis was lower in patients receiving beva (p = 0.04).. The addition of beva or cetu to the neoadjuvant chemotherapy regimens does not appear to increase the morbidity rates after hepatectomy for CLM. The pathological examination did not show additional injury to the non-tumorous liver parenchyma.

Topics: Age Factors; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Body Mass Index; Case-Control Studies; Cetuximab; Chi-Square Distribution; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Function Tests; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Postoperative Complications; Sex Factors; Statistics, Nonparametric

We report a case of pathologically complete response of multiple liver metastases from rectal cancer after neoadjuvant chemotherapy. The patient was a 74-year-old woman who had advanced rectal cancer with synchronous liver metastases (T4N1M1). Following resection of the primary tumor, she received biweekly mFOLFOX6 plus bevacizumab neoadjuvant chemotherapy. After 5 courses, the liver tumors were markedly reduced in size. Three weeks after the final treatment, she underwent partial hepatectomies. Histologically, no cancer cells were detected in any resected specimens. The postoperative course was uneventful, and she has been well without recurrence for one year at the time of writing. Regimens containing bevacizumab may result in good tumor response. Surgical resection is crucial for proof of pathologically complete response.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Rectal Neoplasms

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dexamethasone; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Survival Analysis; United States

The case is a 66-year-old woman. CT showed multiple metastasis of the liver and lung after operation by colectomy for ascending colon carcinoma. A close inspection showed progressive stomach cancer with lymph node metastasis. Metastasis was considered an effect when it was of colon cancer origin, and treatment by mFOLFOX6 was started. In the results, we confirmed contraction of the liver and lung metastasis and contraction of the regional lymph node metastasis of the stomach by CT. The gastric cancer lesion became only a cicatrix with endoscopic examination. For gastric cancer, the availability of mFOLFOX6 was suggested.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Organoplatinum Compounds; Positron-Emission Tomography; Stomach Neoplasms; Tomography, X-Ray Computed

A 7 0-year-old man with multiple liver metastases from rectal cancer was admitted to our hospital. From imaging inspection, a resection was determined to be difficult, so he was treated with FOLFOX4 therapy. After ten courses of FOLFOX4, the liver metastases showed 52% reduction in size and were judged to be PR. Therefore low anterior resection of the rectum, left lobectomy of the liver and partial resection of the liver(S7, S8)were performed. He was able to undergo curative surgery after FOLFOX4 therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Rectal Neoplasms; Tomography, X-Ray Computed

The patient, a male in his 70s, was referred to this hospital by his neighborhood doctor with what was said to be impaired hepatic function. Detailed examinations revealed a circumferential ascending colon cancer, diffuse hepatic metastases scattered over both liver lobes, and lymph node metastases in the left axilla. With the primary lesion-induced symptoms of stenosis controllable, the patient began systemic chemotherapy by mFOLFOX6 without a resection of the primary lesion. After completing a 10-course treatment, the patient underwent surgery to resect the primary lesion in preparation for bevacizumab treatment. In the postoperative systemic chemotherapy, FOLFIRI and mFOLFOX6 were administered concomitantly with bevacizumab. After a total of 19 courses, the patient's systemic condition gradually deteriorated. He eventually died of cancer one year and seven months after diagnosis of the primary lesion or one year and one month subsequent to the resection of the primary lesion. No consensus has been reached on the necessity to resect the primary lesion in patients with advanced colorectal cancer who also have unresectable distal metastases. Systemic chemotherapy, nevertheless, can provide tumor control on both primary and metastatic lesions and could become a treatment option in the future.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colonoscopy; Combined Modality Therapy; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Organoplatinum Compounds; Tomography, X-Ray Computed

The optimal duration, safety, and benefit of preoperative chemotherapy in patients with colorectal liver metastases (CLM) are unclear. We evaluated the association between the duration of preoperative chemotherapy with 5-fluorouracil (5-FU), leucovorin, oxaliplatin (FOLFOX) ± bevacizumab, pathologic response, and hepatotoxicity after hepatic resection for CLM.. A total of 219 patients underwent hepatic resection following FOLFOX with or without bevacizumab and were divided into 2 groups according to the chemotherapy duration: 1-8 cycles (short duration [SD]; N = 157) and ≥9 cycles (long duration [LD]; N = 62). The frequency of complete or major pathologic response, sinusoidal injury, and major postoperative morbidity were compared.. Treatment consisting of ≥9 cycles was not associated with an increase in complete or major pathologic response (SD vs. LD, 57% vs. 55%; P = .74). The incidence of sinusoidal injury was higher in the LD group (26% vs. 42%; P = .017). The incidence of liver insufficiency was higher in the LD group (4% vs. 11%; P = .035). Sinusoidal injury did not predict postoperative liver insufficiency; multivariate analysis revealed ≥9 cycles was the only independent predictor of postoperative liver insufficiency (P = .031; odds ratio = 3.90). Chemotherapy including bevacizumab was associated with a significantly higher frequency of complete or major response in both SD and LD groups.. Extended preoperative chemotherapy increases the risk of hepatotoxicity in CLM without improving the pathologic response. The type of chemotherapy (FOLFOX with bevacizumab) has more impact on pathologic response than the duration of chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatectomy; Hepatic Insufficiency; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Preoperative Care; Remission Induction

Adjuvant systemic 5-fluorouracil (5-FU)-based chemotherapy improves survival after resection of synchronous colorectal liver metastases (CLMs), but not metachronous. We retrospectively examined if adjuvant chemotherapy with new regimen containing oxaliplatin or irinotecan improved survivals after resection of metachronous CLMs.. Between 2000 and 2007, 52 patients having undertaken resection of metachronous CLMs with curative intent were identified from Taipei Veterans General Hospital hospitalization registry. One patient with perioperative mortality and another being lost to follow-up within 3 months after metastasectomy were excluded. Thirty-one patients experienced six to 12 cycles of FOLFOX or FOLFIRI chemotherapy while 19 patients with 5-FU/leucovorin (LV)-based chemotherapy following CLM resection. The primary end point was disease-free survival (DFS) and secondary end point, overall survival (OS).. By the univariate analysis, median DFS was 34.3 months in the FOLFOX/FOLFIRI group vs 14.2 months in the 5-FU/LV group (P = 0.022). The median OS and 5-year survival rates were longer than 57.7 months (not reached, with median follow-up of 35.5 months) and 54.0%, respectively, in the FOLFOX/FOLFIRI group compared to 49 months and 34.6% in the 5-FU/LV group (P = 0.027). FOLFOX/FOLFIRI chemotherapy was shown by multivariate analyses to be an independent factor predicting a better DFS (hazard ratio [HR] = 0.37; 95% CI: 0.15-0.94; P = 0.036) and a better OS (HR = 0.27; 95% CI: 0.083-0.86, P = 0.026) than 5-FU/LV-based.. Adjuvant FOLFOX/FOLFIRI chemotherapy following resection of metachronous CLMs is demonstrated to have better DFS and OS than 5-FU/LV chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate; Treatment Outcome

We evaluated the effect of hepatic arterial infusion(HAI)chemotherapy for liver metastases from colorectal cancer. A total of 65 patients received HAI chemotherapy. The chemotherapy regimen consisted of weekly 5-FU (1, 500 mg/body) or 5-FU (400 mg/mm2) and l-LV (200mg/mm2). The survival and response rates were assessed according to RECIST. Median survival time with HAI chemotherapy was 13. 5 months, 5-year survival rate 8% and response rates 55%. There was no evidence of myelosuppression, and HAI could be continued for a long time even for poor PS patients. There were no differences in survival time between synchronous, metachronous and postoperative metachronous liver metastases. In the patients who underwent curative hepatectomy after HAI chemotherapy, the 5-year survival rate was 21%, which was better than in patients with HAI chemotherapy alone. HAI chemotherapy could thus be an option for unresectable liver metastases, which could be well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Survival Rate

Adverse events associated with bevacizumab (BV) were haemorrhage, impaired wound healing and arterial thromboembolism. We report 2 patients with colorectal cancer who underwent percutaneous coronary intervention (PCI) for unstable angina soon after administration of chemotherapy including BV. CASE 1: A 74-year-old male with rectal cancer and simultaneous liver metastases was admitted to our hospital for unstable angina. Before admission he had received 4 courses of chemotherapy including BV. He had no coronary risk factors besides old age. Since coronary angiography (CAG) revealed significant stenosis in the mid-left circumflex coronary artery, PCI with a coronary stent was performed without any complications. CASE 2: A 67-year-old male with colon cancer and liver and lung metastases was referred to our Dept. of Internal Medicine for unstable angina. Before referral, he had undergone 28 courses of chemotherapy including BV. He had a history of familial hyperlipidemia and smoking. Since CAG revealed significant stenoses in the proximal left anterior descending coronary artery, PCI with coronary stents was performed without any complications. These 2 patients had no angina after PCI. PCI with coronary stent was safely performed in this patient with unstable angina soon after administration of chemotherapy including BV.

Topics: Aged; Angina, Unstable; Angiogenesis Inhibitors; Angiography; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Electrocardiography; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms

We have experienced and report here a case of postoperative recurrence of colon cancer with metastases in the liver and the periaortic lymph nodes, where we attained CR through combination therapy with bevacizumab+mFOLFOX6. The patient was a male aged 65. He had already had cecal cancer, metastasis in the para-aortic lymph nodes, and multiple hepatic metastases. The surgery involved right colon resection+partial hepatectomy as well as dissection of the para-aortic and the superior mesenteric lymph nodes. The postoperative stage was SSN3H1P0M1 (#216)-pStage IV. S-1+CPT-11 was chosen as an adjuvant therapy. The para-aortic lymph nodes at the level of renal hilus were found enlarged after 17 courses of the therapy. Hence bevacizumab+mFOLFOX6 was chosen for the first-line treatment. After 14 courses of the therapy, CR was proved on the RECIST standard. On continued chemotherapy, CR has been maintained at present, 2 years and 11 months after the surgery or 10 months after confirmation of CR.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aorta; Bevacizumab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Organoplatinum Compounds; Recurrence; Tomography, X-Ray Computed

The use of yttrium-90 microspheres is a novel interventional radiological procedure that has delivered promising results in the treatment of liver cancer. Multiple treatments in combination with systemic chemotherapy may be realised as an effective modality for unresectable colorectal liver metastases. This case study reports the first case of a patient who had a complete response of 7 out of 10 liver metastases following multiple doses of yttrium-90 microsphere therapy, who then underwent a curative hepatic resection. This case demonstrates the feasibility and potential use of this management strategy to expand the role of successful therapies that will bridge the road towards curative liver resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Microspheres; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Radiotherapy, Adjuvant; Yttrium Radioisotopes

The patient was a sixty-five-year-old man who had an advanced rectal cancer (Ra, type 2) with liver metastases. Low anterior resection with lymphnode dissection (D3) was done, but hepatectomy was not performed because of the multiple metastases besides the five tumors detected preoperatively. The pathological finding was moderately-differentiated adenocarcinoma. He was treated with 5-FU via the hepatic artery, but the therapy failed due to catheter infection after 3 postoperative months. Then, he received general 5-FU/l-LV therapy intravenously from 3 to 8 months after the operation, and oral UFT/LV (Uzel®) from 9 to 22 months. Next, we switched to single UFT therapy at 23 months because CT findings showed remarkable calcification in the liver metastases. But only one tumor of the liver (S6) among liver metastases enlarged at 27 months. We switched the chemotherapy again to UFT/Uzel and mFOLFOX6, but decided to perform hepatectomy of S6/7 at 39 months since it proved ineffective. The pathological finding was 90% necrosis and calcification of the tumor. Metastasis of the right 10th rib was newly found and was removed at 63 months after the first operation. Now, NC in the liver is continued 67 months after the first operation, and the patient is doing well.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Neoplasm Staging; Rectal Neoplasms; Tegafur; Tomography, X-Ray Computed; Uracil

Combination of bevacizumab and FOLFIRI has currently become one of the standard therapeutic regimens. However, published information is still limited. The objective of the present retrospective observational study is to analyse the response and toxicity of first-line treatment with FOLFIRI+bevacizumab in patients with metastatic colorectal cancer (mCRC).. Data were collected from patients from nine Spanish sites diagnosed with mCRC, ECOG≤2, whose first treatment for advanced disease was at least three cycles of FOLFIRI+bevacizumab.. A total of 95 patients were enrolled into the study: 64.2% males, median age of 59 years (53.2-67.1 years), ECOG=0-1 in 96.9% of patients. The main site of primary tumour was the colon (69.7%), and most metastases occurred in the liver (71.6%). Clinical benefit was detected in 67.4% (57.0-76.6; 95% confidence interval (CI)), with 8.4% of CR and 42.1% of PR. Median TTP was 10.6 months (10.0-11.3; 95% CI), PFS was 10.6 months (9.8-11.3; 95% CI), and OS was 20.7 months (17.1-24.2; 95% CI). Main grade I-II toxicities included haematological toxicity (35.8%), diarrhea (27.3%), mucositis (25.3%), asthenia (19.0%), haemorrhages (11.6%), and emesis (10.6%). Toxicities reaching grades III-IV were haematological toxicity (9.5%), diarrhea (8.5%), mucositis (5.3%), hepatic toxicity (2.1%), asthenia (2.1%), proteinuria (1.1%), emesis (1.1%), pain (1.1%), and colics (1.1%).. Results of this study support the beneficial effect of adding bevacizumab to FOLFIRI regimen in terms of efficacy and show a favourable tolerability profile.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Drug Tolerance; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Retrospective Studies; Safety; Spain; Treatment Outcome

We assessed the effectiveness of cetuximab plus chronomodulated irinotecan, 5-fluorouracil (5-FU), leucovorin (FA) and oxaliplatin (L-OHP) (chrono-IFLO) administered as neoadjuvant chemotherapy to increase the resectability of colorectal liver metastases.. This was a phase II prospective trial with rate of liver metastases resection as primary end point. Forty-three patients with unresectable metastases were enroled: 9 with metastases >5 cm; 29 with multinodular (>4) disease; 1 with hilar location; 4 with extrahepatic lung disease. Treatment consisted of cetuximab at day 1 plus chronomodulated irinotecan 5-FU, FA and L-OHP for 2-6 days every 2 weeks. After the first 17 patients, doses were reduced for irinotecan to 110 mg m⁻², 5-FU to 550 mg m⁻² per day and L-OHP to 15 mg m⁻² per day.. Macroscopically complete resections were performed in 26 out of 43 patients (60%) after a median of 6 (range 3-15) cycles. Partial response was noticed in 34 patients (79%). Median overall survival was 37 months (95% CI: 21-53 months), with a 2-year survival of 68% in the entire population, 80.6% in resected patients and 47.1% in unresected patients (P=0.01). Grade 3/4 diarrhoea occurred in 93% and 36% of patients before and after dose reduction.. Cetuximab plus chrono-IFLO achieved 60% complete resectability of colorectal liver metastases.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colorectal Neoplasms; Diarrhea; Disease-Free Survival; ErbB Receptors; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Research Design; Survival Rate; Tomography, X-Ray Computed

Liver failure due to disseminated hepatic secondaries represents a therapeutic dilemma in patients with metastatic breast cancer (MBC). Reduced liver function and non-assessable toxicity are limiting factors in the selection of chemotherapeutic agents. Currently, there is no standard treatment after failure of anthracycline-and taxane-based first-line therapies, although there is a variety of well evaluated drugs such as capecitabine.. We report on a 45-year-old breast cancer patient with disseminated hepatic metastases. She presented in markedly poor condition, showing substantial ascites and extensive jaundice. Blood chemistry analysis showed increased serum levels of liver enzymes (aspartate aminotransferase 271 U/l, alanine transaminase 101 U/l), bilirubin (7.9 mg/dl), and CA 15-3 (1,459 U/l). We induced a palliative chemotherapy with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU). The patient improved impressively after the first cycle of systemic therapy. Liver enzymes stabilized continuously, CA 15-3 returned to normal. The patient was discharged 2 weeks after the treatment start. Chemotherapy was well tolerated under dose escalation, no grade 3/4 toxicity was observed. The progression-free interval was 5 months.. A combination therapy with Mi/Fo/FU appears to be a reasonable and tolerable alternative salvage strategy for patients with liver failure due to hepatic breast cancer metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Middle Aged; Mitomycin; Treatment Outcome

Surgical strategy of colorectal liver metastases depends on clinical and pathological response to neoadjuvant chemo- and target therapy. Recently, surgical treatment of advanced colorectal cancer appears as an everyday challenge for surgeons and oncologists. The new oncologic procedures invented last years led to significant therapeutic improvement. Combination of neoadjuvant chemotherapy with biological answer modifiers increased greatly the clinical response rate given to cytoreductive therapy. Due to these facts the complete disappearance of liver metastases can be observed more and more frequently after 2000. Literature of metastasis surgery clarified the exact difference between clinical and pathological response, at the same time exact criteria of the connections between two responses have been set. In complex treatment of colorectal liver metastases complete pathological response became the end point of treatment.. Between January, 2009 and August, 2010, 39 patients with originally non resectable liver metastases (colorectal cancer origin) have been studied. All patients were treated by neoadjuvant chemo- and targeted therapy before the resection of liver.. Complete pathological response has been observed in 3 patients, major pathological response (necrosis: >50%) in 11 patients, minor pathological answer (necrosis <50%) in 22 patients and finally no necrosis at all in 3 patients.. Complete pathological response can be regarded as the final goal of neoadjuvant targeted therapy. Pathological response seems to be the most important prognostic factor which reflects long-term survival after the R0 resection of liver metastases. Complete disappearance of liver metastases is an undesirable side effect of oncological therapy, which causes difficulties during surgical intervention. In this term the overtreatment of patients resulting in a disappearance of metastases should be avoided. Multidisciplinary team is responsible for the indication of resection of liver metastases in time before their disappearance.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Molecular Targeted Therapy; Neoadjuvant Therapy; Organoplatinum Compounds; Patient Care Team; Treatment Outcome

Most colorectal cancer patients with liver metastases are not resectable upon initial diagnosis. Recently, chemotherapy improves overall survival of initially unresectable patients by allowing tumor downstaging and complete resection. We report a FOLFOX-refractory rectal cancer patient with unresectable multiple liver metastases, whose tumors could be downstaged and completely resected after initiation of FOLFIRI with cetuximab.. A 41-year-old male demonstrated rectal cancer with unresectable multiple liver metastases. He was treated by FOLFOX4 therapy as first-line chemotherapy. After initiating 14 courses, he was treated by FOLFIRI with cetuximab because of disease progression. After initiation of chemotherapy, radiographic examination demonstrated remarkable reduction of primary rectal tumor and metastatic liver tumors. He underwent complete rectal tumor resection after 13 courses of chemotherapy, and metastatic liver tumor resection after 18 courses of chemotherapy.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Drug Resistance, Neoplasm; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms

Hypersensitivity reaction (HSR) and sensory neuropathy are major complications of oxaliplatin-based chemotherapy. Preplanned withdrawal of oxaliplatin after the first six cycles and reintroduction at the time of disease progression (stop-and-go strategy) may reduce neurotoxicity. However, the effect of an oxaliplatin-free interval on HSR occurrence remains poorly understood.. Data on patients with colorectal cancer who received FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) treatment between June 2005 and June 2009 were retrieved from the prospective cohort database of the Outpatient Oncology Unit of the Kyoto University Hospital. Factor analysis was performed.. Among patients who received six or fewer cycles of FOLFOX, the incidence of HSR was low (7/99, 7.1%). For patients who received more than six cycles, the incidence of HSR was higher among patients treated with stop-and-go FOLFOX than among patients treated with continuous FOLFOX (25/61, 41.0% vs. 13/63, 20.6%; p = 0.019). Interestingly, most cases of HSR during stop-and-go FOLFOX occurred during the second or third cycle of the reintroduction phase (21/25, 84%). Multivariate analysis identified undergoing an oxaliplatin-free interval as an independent risk factor (p = 0.016).. An oxaliplatin-free interval may increase the risk of HSR. Special vigilance is needed during the second and third cycles after reintroduction of oxaliplatin.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Drug Hypersensitivity; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Logistic Models; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Risk Factors; Time Factors

A 62-year-old man had undergone anterior resection of rectum for rectosigmoid colon cancer with liver metastases. Postoperatively, the FOLOFOX6 regimen was performed in three courses. Metastatic liver tumors showed progressive disease(PD) on CT scan. The treatment was then changed to the FOLFIRI regimen for three courses. Metastatic liver tumors showed a partial response(PR)on CT scan. After six courses of the FOLFIRI regimen, the patient was given seven courses of the FOLFIRI +BV regimen. Hepatic resection of S2, S3, S4 and S6 segment was performed. The histological effect of chemotherapy was complete response(CR).

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Rectal Neoplasms; Treatment Outcome

This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function.. Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin. Median total bilirubin was 2.8 mg/dL (range, 0.2-5.2 mg/dL). Median Child-Pugh score was 7 (range, 5-10).. Thirty treatments were delivered (2-7 per patient). Median age of patients was 57 years (range, 25-69 years). Three patients (1 with colorectal, 1 with hepatocellular, and 1 with ovarian cancer) attained partial responses. Two had failed previous oxaliplatin and cisplatin treatment. Some with elevated bilirubin at baseline had a significant drop in bilirubin with treatment (bilirubin 5.2 → 1 mg/dL, 4.8 → 1.1 mg/dL, and 5.2 → 1.8 mg/dL). The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. One patient died of enzyme-linked, immunoassay-confirmed, heparin-induced thrombocytopenia during the sixth cycle of therapy.. At doses tested, this regimen was safe and demonstrated antitumor activity in patients with advanced refractory malignancies involving the liver, including those with hepatic insufficiency. Further study is warranted.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Pilot Projects; Salvage Therapy; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome

The purpose of this study was to determine the efficacy of hepatic artery infusion (HAI) plus systemic chemotherapy (SYS) as the prehepatectomy chemotherapy for liver metastases from colorectal cancer. Clinicopathologic data were available for 117 patients who were treated with chemotherapy before liver surgery. Response rate of chemotherapy and frequency of liver resection after chemotherapy of patients treated with HAI/SYS (n=26; 65% and 96%, respectively) were higher than those treated with HAI alone (n=63; 41% and 70%) or SYS alone (n=28; 25% and 42%). Histological examination of adjacent nonneoplastic liver confirmed that severe sinusoidal dilatation was less frequent in HAI/SYS group than in SYS group, and moderate to severe steatosis was also less frequent in HAI/SYS group as compared to HAI group. The combination of regional HAI and systemic chemotherapy is an effective prehepatectomy regimen for the treatment of patients with aggressive liver metastases from colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

A-75 year-old man, diagnosed as ascending colon cancer with large bowel obstruction, multiple hepatic, lunge metastases and peritoneal dissemination, was treated with neoadjuvant chemotherapy (FOLFOX4: 2 courses) and subsequent ileocecal resection. Postoperative systemic chemotherapy with hepatic arterial infusion (HAI) of 5-FU was performed in the following fashion: FOLFOX4, FOLFIRI with or without bevacizumab or cetuximab was administered every 4 weeks and a weekly HAI twice every 4 weeks. By those treatments, the patient could maintain a 30-month long NC effect and a good performance status.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds

A man in his early seventies underwent low anterior resection and partial resection of the liver for the rectal cancer and liver metastasis. However, 4 months after the surgery, he was found to have a liver tumor at S5 and S7 by abdominal CT scan. Then, he underwent chemotherapy (mFOLFOX6), but the metastatic tumor was progressive. We selected FOLFIRI + cetuximab regimen for second-line therapy to resect the metastatic tumor. As the metastatic lesion was become smaller after 4-course of the regimen including cetuximab, we decided to perform a radical resection. We conducted a right lobectomy of the liver, and the tumor was completely resected.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male

The patient was a 59-year-old man who was hospitalized at our department for intestinal obstruction. Contrast enhanced abdominal CT showed a rectosigmoid tumor invading the left pelvic wall and multiple metastatic hepatic tumors. Colonoscopy showed a type-2 cancer in the rectosigmoid region. The patient underwent sigmoid colostomy 3 days after admission. Postoperative upper gastrointestinal endoscopy showed a type 3 cancer in the fornix. From the above findings, the patient was diagnosed with unresectable gastric and rectosigmoid cancers with multiple hepatic metastases, and systemic chemotherapy was initiated. The first line treatment was two courses of S-1, but it was discontinued due to PD. FOLFIRI was begun as the second line treatment. After 5 courses of FOLFIRI, upper gastrointestinal endoscopy showed a marked reduction in tumor size. Twelve courses of FOLFIRI chemotherapy were performed in total. Subsequently, 11 courses of mFOLFOX6 and 1 course of RPMI were performed, but the patient died from carcinomatous peritonitis. However, the gastric lesion had been controlled well after the second line treatment. The findings of the present study suggested that FOLFIRI could be an effective treatment for unresectable multiple advanced cancers of the stomach and colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary; Sigmoid Neoplasms; Stomach Neoplasms

The advancement of systemic chemotherapy for colorectal carcinoma has improved a clinical response rate and expanded a possibility of resection, which we thought we could not have been operable at the initial visit. It also improved a prognosis of patients. We report here a case with liver resection of metastasis from rectal cancer followed by bevacizumab treatment.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Reoperation

We report a case of multiple lung and liver metastases from colon cancer treated with clinical benefit by hepatic arterial infusion chemotherapy plus cetuximab mono-therapy after a standard chemotherapy was failed. A 61-year-old female who had sigmoid colon cancer with unresectable multiple lung and liver metastases underwent sigmoidectomy. Bevacizumab plus mFOLFOX6 was performed as first-line therapy. Partial response was obtained temporarily. After the first-line therapy failed, bevacizumab plus FOLFIRI as second-line, and cetuximab plus CPT-11 as third-line therapy were performed. Since these regimens did not work, her performance status got worse by cholangitis due to progressive liver metastases and anemia. Hepatic arterial infusion chemotherapy for liver metastases and cetuximab for lung metastases as fourth therapy were chosen because we thought her liver metastases should be critical for the maintenance of her QOL and diagnosis. After that, serum CEA was reduced from 14,715 to 6,940 ng/mL during the 3 month period. And her performance status got better as cholongitis and anemia were improved. Additionally, lung metastases were controlled by cetuximab.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoembryonic Antigen; Cetuximab; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Middle Aged; Organoplatinum Compounds; Sigmoid Neoplasms

A 60-year-old male underwent sigmoidectomy for sigmoid colon cancer with synchronous multiple liver and lung metastases. Six weeks after the sigmoidectomy, mFOLFOX6 + bevacizumab (Bmab) was initiated. After 7 courses, lung tumors were almost disappeared and liver tumors shrunken up to 69% in size, and metastasectomy of liver tumors was performed with R0 resection. Pathological examination disclosed that tumor response to chemotherapy was Grade 2. mFOLFOX6 + Bmab, FOLFIRI + Bmab, and cetuximab were administered after liver surgery before the patient died 25 months after the sigmoidectomy. Combination therapy of metastasectomy and intensive chemotherapy might benefit to prolong survival of the patient.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colectomy; Colon, Sigmoid; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Sigmoid Neoplasms

A 73-year-old man underwent a sigmoid colon resection and an insertion of a hepatic arterial infusion catheter for multiple liver metastases from sigmoid colon cancer. After the hepatectomy, the patient was detected a lung metastasis and was scheduled to undergo mFOLFOX6 chemotherapy. The tumor lesion was reduced once in size, but it has grown again after the chemotherapy. So, we underwent a stereotactic radiotherapy (60 Gy/10 Fr). The tumor lesion became a scar and the patient was doing well without any recurrence at 21 months after undergoing stereotactic radiotherapy. Lung resection has a better result than other treatments for a lung metastasis caused from colon cancer, but there are some cases with no indication of the operation due to a complication. Stereotactic radiotherapy can be an effective treatment for lung metastasis from colon cancer with no indication of the operation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Organoplatinum Compounds; Radiosurgery; Sigmoid Neoplasms

We report a case of 57-year-old woman suffering from advanced sigmoid colon cancer with adrenal and para-aortic lymph node recurrence. Sigmoidectomy was performed for sigmoid colon cancer in January 2002. Pathological staging was Stage II (pT3, pN0, pM0, Cur A). She received a UFT + CPT-11 regimen as preoperative chemotherapy for liver metastasis (S2, S7) from December 2002. A partial liver resection (S2, S7) was performed for liver metastasis in July 2003, and the UFT + CPT-11 was introduced as adjuvant chemotherapy. However, adrenal and para-aortic lymph node recurrence was detected in February 2007, and mFOLFOX6 was performed as preoperative chemotherapy. Right adrenalectomy and para-aortic lymph node dissection was performed in July 2007. mFOLFOX6 as postoperative chemotherapy was done, mFOLFOX6 + bevacizumab was started because of CEA increase. The chemotherapy was performed for 23 courses and temporarily stopped due to adverse reactions, such as peripheral neuropathy (grade 2), general fatigue (grade 1), and nausea (grade 1). She had no recurrence for almost 3 years after a resection of adrenal and para-aortic lymph node metastasis.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Aorta; Bevacizumab; Camptothecin; Combined Modality Therapy; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Sigmoid Neoplasms; Tegafur; Uracil

Only a partial benefit of adjuvant chemotherapy administered after curative resection of colorectal cancer (CRC) metastases has been demonstrated. We report here our experience of 7 cases that were administered FOLFOX4 regimen as adjuvant chemotherapy after a curative resection of liver metastases from CRC. Five patients received 6 cycles of FOLFOX4 after prophylactic hepatic arterial infusion of 5-FU, and 2 remaining patients simply received 8 cycles of FOLFOX4. All patients completed the planned cycles of FOLFOX4 without any dose reduction of oxaliplatin. No patients developed a severe adverse effect greater than grade 2 except for grade 3 neutropenia observed in 4 cases. Although lung metastases occurred in 2 cases 28.1 and 21.3 months after liver resection, respectively, all patients are alive after a median follow up of 23.5 months. Our experience indicates that adjuvant chemotherapy with six to eight cycles of FOLFOX4 regimen is safe with a high dose intensity of oxaliplatin and expected to provide a survival benefit.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

A 60-year-old man having metachronous multiple bilobar colorectal liver metastases was referred to our institution. The lesions were diagnosed unresectable due to a lack of the estimated future remnant liver volume. He underwent 13 courses of mFOLFOX6 + bevacizumab as down-staging chemotherapy. The periodic abdominal CT scans revealed metastatic lesions to become PR. We had decided to perform two-stage hepatectomy to preserve a hepatic functional reserve. After the rest of chemotherapy for 4 weeks, four tumors were resected and right branch of the portal vein embolization was performed at the first operation. Right hemihepatectomy was performed 5 weeks after the first operation to achieve curative resection. Postoperative course was uneventful and the patient was discharged at 17 days after the operation. He has no signs of tumor recurrence during the follow-up. The combination of two-stage hepatectomy and neoadjuvant systemic chemotherapy may contribute to improve prognoses of initially unresectable multiple bilobar colorectal liver metastases, leading to prolonged survival.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Recent advances in chemotherapy for colorectal cancer prolonged survival. Tumor necrosis may develop as a side effect of chemotherapeutic agents. Recently, radiofrequency ablation sometimes indicated to patients with colorectal liver metastasis, when hepatectomy cannot be performed due to impaired hepatic functional reserve or general condition. We experienced hepatectomy for colorectal liver metastasis containing necrotic foci which was induced by anti-cancer drugs and radiofrequency ablation. Massive liver necrosis and abscess developed in a patient with initially unresectable large liver metastasis 6 months after induction of mFOLFOX6 and bevacizumab. Chemotherapy was discontinued due to systemic inflammatory responses. Extended right hepatectomy resulted in both resection of the tumor and significant improvement of septic condition. Chemotherapy was re-started after the operation. Bevacizumab targeted to tumor-related vascular endotherial cells might be responsible for the massive tumor necrosis. Another patient with chronic renal dysfunction underwent radiofrequency ablation for colorectal liver metastasis 2 cm in diameter in the segment 7. Three months after ablation, the tumor grew very rapidly to 6 cm in diameter. After extended posterior sectorectomy of the liver, blood CEA levels were normalized. Resected specimen showed a massive tumor growth around the necrotic foci of radiofrequency ablation. Hepatectomy played significant roles in these patients with necrotic foci of the liver. Decision and timing of hepatectomy are very important to save the patient.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Catheter Ablation; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Necrosis; Organoplatinum Compounds

In a patient with multiple liver metastases of colorectal cancer whose tumor response had been achieved by 5-FU hepatic arterial infusion, a catheter for arterial infusion chemotherapy was occluded resulting in re-elevation of tumor marker levels. For this reason, a second-line IRIS therapy using S-1 and CPT-11 was started. IRIS therapy reduced tumor marker levels to a degree greater than that of previously achieved with 5-FU hepatic arterial infusion, and a diagnostic imaging allowed a judgment of partial response. Although a ratio of liver tumor volume to liver volume was 57% on admission of this patient, the ratio was reduced to 16% by the 14th course of 5-FU hepatic arterial infusion immediately before the catheter was occluded. The ratio was 18% after the 7th course of IRIS therapy, and the diagnostic imaging showed a partial response. Hepatic arterial infusion therapy is one of the treatment methods characterized by a lower incidence of adverse reactions, relatively low cost, and expectation of high anti-tumor efficacy as compared to chemotherapy such as FOLFIRI. IRIS therapy does not require a port insertion and it costs about a half of FOLFIRI therapy. When used as a second-line therapy for unresectable colorectal cancer, IRIS therapy has demonstrated non-inferiority compared to FOLFIRI in a phase III clinica (l FIRIS) study.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Combinations; Fluorouracil; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male; Oxonic Acid; Tegafur; Tumor Burden

We report 5 cases of colorectal liver metastases (CRLM) with hepatic arterial infusion (HAI) oxaliplatin after systemic infusion chemotherapy failure. Patients with unresectable CRLM and history of systemic chemotherapy failure were treated with HAI oxaliplatin (L-OHP 100 mg/body, 2 hours) combined with intravenous (iv) levofolinate calcium (175 mg/body, 2 hours) and iv bolus 5-FU (500 mg/body) every 2 weeks.. An average age was 58 years. All patients had previously received FOLFOX. Lung metastases had already existence before HAI oxaliplatin in 4 patients. A median of 10 treatments were administered (range 5-14). Serum level of CEA was decreased in 4 cases. In 2 patients, lung metastasis developed while a PR was obtained in the liver metastasis. Progress disease (PD) was confirmed in other 3 patients. No major toxicity was presented. The median time to progression free survival was 3.0 months and the median overall survival was 7.1 months.. HAI oxaliplatin might be beneficial as a salvage therapy for CRLM without extrahepatic metastasis, which demonstrated an acceptable tolerability and maintenance of QOL.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Salvage Therapy

Neoadjuavnt chemotherapy for liver metastasis of colorectal cancer implies issues about timing for resection and management for adverse events due to chemotherapy.. A 50-year-old male patient with synchronous liver metastasis from rectal cancer had a surgery for primary lesion followed by neo-adjuvant chemotherapy for liver resection. Chemotherapy of bevacizumab + mFOLFOX6 achieved a partial response for liver metastasis. When we planned a liver resection, platelet count decreased to 1.4 × 10(4)/µL. The patient was diagnosed as idiopathic thrombocytopenic purpura (ITP) by several examinations but medical control including steroids failed. Partial splenic artery embolization could recover platelet count successfully. However, during the period of therapy for ITP, liver metastasis became unresectable. The patient is currently treated by FOLFIRI and with stable disease for three months.. NeoPyloriadjuvant chemotherapy for respectable liver metastasis should be considered carefully in terms of timing for resection and prompt management for adverse events.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Embolization, Therapeutic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Purpura, Thrombocytopenic, Idiopathic; Rectal Neoplasms; Splenic Artery

We report here a case of rectal cancer with synchronous multiple liver metastases successfully treated with a combined chemotherapy of modified FOLFOX6 (mFOLFOX6) and bevacizumab. A 49-year-old man was admitted to our hospital due to constipation and anorexia. Abdominal ultrasonography and abdominal computed tomography (CT) scan revealed a rectal tumor (Rs) and abdominal abscess and 11 mm hepatic nodular lesion in S3 and 21 mm and 14 mm hepatic nodular lesions in S4. We diagnosed the patient had penetrated rectal cancer (Rs) and multiple liver metastases. We underwent a low anterior resection with D3 lymphadenectomy for the first time. After the operation, an 8 mm new liver metastasis in S6 appeared. We performed a combined therapy of mFOLFOX6 and bevacizumab 16 days after post operation. After the 8th course, there were a notable reduction in S3 and S4 liver metastases, and S6 liver metastasis was unidentifiable upon imaging. At this point, we underwent liver left lobectomy using the Liver Hanging Maneuver Method. After the second operation, there has been no recurrence and same chemotherapy is being continued.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms

Hepatic metastasis from colorectal cancer (mCRC) is best treated with a multidisciplinary approach. Conflicting data exist regarding the impact of preoperative chemotherapy on morbidity and mortality after hepatectomy. We hypothesized that preoperative chemotherapy does not adversely impact complications or mortality associated with hepatectomy. A retrospective analysis was performed and included patients with mCRC who underwent hepatectomy from 1996 to 2006. Patients were separated into two groups: those who received preoperative chemotherapy and those who did not. Univariate and multivariate analyses were performed to determine the factors associated with morbidity and mortality. Kaplan-Meier analyses were performed to determine disease-free survival (DFS) and overall survival (OS). One hundred eighty-six patients were analyzed: 112 (60%) received preoperative chemotherapy for a median of 4.2 months. Eighty patients (43%) underwent major hepatectomy. When comparing the two groups, there were no differences in hepatic tumor size (median 3 cm; p = 0.35), type of resection (p = 0.62), stage (p = 0.44) or location (p = 0.10) of the primary tumor, preoperative carcinoembryonic antigen (CEA) level (p = 0.80), or number of nodes in lymphadenectomy (p = 0.62). Only number of positive nodes after colectomy (p = 0.02), age (p < or = 0.0001), and combined resection/radiofrequency ablation (RFA) (p = 0.004) were statistically different between the two groups. There was no difference in rates of morbidity (p = 0.81), mortality (p = 0.29), DFS (p = 0.25) or OS (p = 0.30). We conclude that the use of preoperative chemotherapy did not increase the risk of complications or death for patients undergoing hepatectomy for metastatic colorectal cancer. Pre-hepatectomy chemotherapy appears to be safe and is an important part of the multidisciplinary approach for this disease.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colectomy; Colorectal Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Morbidity; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Preoperative Care; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate; Thalidomide; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Perioperative Care; Randomized Controlled Trials as Topic

It is known that tumors develop mechanisms to escape from the immune system and to inhibit antitumor responses. The aim of this study was to retrospectively assess changes of host immunity in relation to efficacy in liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by combined intra-arterial chemotherapy.. Thirty-seven adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 19 adult Japanese patients with chronic hepatitis C diagnosed by pathological examination of liver biopsy specimens. All control patients were stage 1 according to the fibrosis score of Desment.. Ten of the 37 patients (group PR) showed a partial response and 17 of the 37 patients (group SD) showed stable disease, but 10 of the 37 patients (group PD) showed no response. There were no significant differences in the percentage of Th1 cells between any of the groups either before or after chemotherapy. The percentage of Th2 cells was significantly higher in group PD before and after chemotherapy than in the control group (P < 0.05 by Tukey's test). Although there was no significant difference, the percentage of Th2 cells was higher in group SD than in group PR.. The percentage of Th2 cells increased in LC patients with aHCC as the efficacy of intra-arterial combination chemotherapy decreased. These results indicated that intra-arterial chemotherapy might be not useful for patients with aHCC, because it induces Th2 dominant host immunity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Case-Control Studies; Cisplatin; Female; Flow Cytometry; Fluorouracil; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunity; Infusions, Intra-Arterial; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Survival Rate; Th1 Cells; Th2 Cells; Treatment Outcome

Prognosis of patients following resection of CRC metastases to the liver has traditionally been predicted by clinical risk factors. In the era of neoadjuvant chemotherapy, determination of new prognostic indicators of outcome are necessary.. This retrospective study includes patients with CRC liver metastases, who received oxaliplatin or irinotecan based neoadjuvant chemotherapy and underwent R0 resection. Patients were followed by CT and PET-CT, before, during and after chemotherapy and surgery. The predictive value of the Memorial Sloan-Kettering Cancer Center Clinical Score (MSKCC-CS) and degree of response to chemotherapy (measured by CT and PET-CT), were analyzed by univariate and multivariate COX regression.. Included are 54 patients. Overall 1-, 2-, 3-year survival rates 88%, 70%, and 39%. Response to chemotherapy on CT was a significant predictor of survival on univariate (P = 0.03) and multivariate analysis (P = 0.03), whereas MSKCC-CS and response to chemotherapy on PET-CT were not. Multivariate analysis demonstrated response to chemotherapy as a predictor of time to recurrence on CT (P = 0.02) and PET-CT (P = 0.03), while the MSKCC-CS (P = 0.64) was not.. In this cohort of patients treated by neoadjuvant chemotherapy, the outcome was not predicted by the traditional clinical scoring system, but rather by response to chemotherapy as evaluated by CT and PET-CT.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Positron-Emission Tomography; Prognosis; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome; Young Adult

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Vasculitis, Leukocytoclastic, Cutaneous

The purpose of this study was to evaluate the efficacy of the combination of hepatic arterial infusion therapy and FOLFOX for colorectal cancer with multiple unresectable liver metastases causing severe liver dysfunction.. The subjects were 13 colorectal cancer patients who had undergone resection of the primary tumor, and showed multiple, unresectable liver metastases and severe liver dysfunction. They consisted of 8 men and 5 women, with a median age of 63(29-77)years. Of these patients, 7 and 6 had colon and rectum cancers, respectively. They had an average of 8(3-22)liver metastases of 4.6(1.5-14.5)cm in diameter. During surgery, extrahepatic lesions were found in 3 patients(P in 2, and CY in 1). The preoperative serum LDH and ALP levels were high, at 1,099 (322-1,418)and 1,011(644-2,384), respectively. The follow-up period was approximately 500(248-928)days. Only 5-FU in FOLFOX4 or 6 m therapy was infused into the hepatic artery, and LV and L-OHP were injected into the central venous port about every two weeks. Response rates and adverse events were evaluated according to the RECIST criteria and CTCAE ver 3.0, respectively.. The therapy was performed 14(6-22)times, with a response rate of 84.6% for liver metastases, facilitating hepatectomy in 1 patient. The overall response rate was 61.5%, with 1 patient dying of the primary cancer on the 265th day. Grade 3 adverse events were neutropenia and anorexia in only 1 patient each, and no adverse events were specific to hepatic arterial infusion.. Since the follow-up period after this therapy was still short, only 13 patients have received the therapy. However, it appears that it can be performed relatively safely, and is effective for the control of extrahepatic lesions as well. Therefore, this therapy provides good control, and can be a treatment option.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Colorectal Neoplasms; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Tomography, X-Ray Computed; Treatment Outcome

In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited.. Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST).. Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone.. This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chi-Square Distribution; Clinical Trials, Phase II as Topic; Colorectal Neoplasms; Deoxycytidine; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Liver Neoplasms; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaloacetates; Regression Analysis; Retrospective Studies; Statistics, Nonparametric; Treatment Outcome

Oxaliplatin in combination with 5-fluorouracil (5-FU) and Leucovorin (FOLFOX) currently represents a valid approach for treating advanced colorectal cancer. In Japan, it is generally performed. Gastrointestinal, hematological and neurosensory toxicities are the most common. However, information concerning the pulmonary toxicity of this regimen is very limited. We report here two cases of interstitial lung disease occurring in association with the use of this combination chemotherapy. Reports of interstitial lung disease due to FOLFOX are infrequent, but could lead to severe complications. It is important to perform an X-ray examination regularly and detect symptoms early.

Topics: Aged; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Organoplatinum Compounds; Rectal Neoplasms; Tomography, X-Ray Computed

Gastric carcinoma is often diagnosed at UICC stage 3 b or 4. R0 resection can be achieved only in very few such cases. Even for these patients the 5-year survival rate is less than 5 %. Surgical palliation is traditionally reserved for the treatment of severe tumour complications not responding to other forms of treatment.. We report on 21 patients who underwent palliative resection for gastric carcinoma at our institution between 2004 and 2007. Ten of these were assigned to palliative surgical treatment pre-operatively while this choice was made for 11 patients on the grounds of the intra-operative findings. We performed 17 gastrectomies, 3 proximal gastric resections and one distal gastric resection.. It has been shown that the patients have an improved overall survival time as compared to patients who received non-surgical treatment. The perioperative risk was reasonable when patients were carefully selected. Median survival for resected patients was 16 months. 80 % of patients were alive after 6 months and approximately 60 % of patients were alive after 12 months. The perioperative mortality was 0 % with a mean hospital stay of 12 days. All patients were discharged home with proper bowel passage and analgesia as individually required.. We are convinced that palliative gastric resection provides a pronounced survival benefit over any other palliative treatment options. Patients also have an improved quality of life.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Chemotherapy, Adjuvant; Female; Fluorouracil; Gastrectomy; Humans; Kaplan-Meier Estimate; Laparotomy; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Palliative Care; Patient Selection; Postoperative Care; Quality of Life; Stomach; Stomach Neoplasms; Time Factors

The GONO-FOLFOXIRI regimen improved the rate of R0 secondary resection of metastases in initially unresectable metastatic colorectal cancer. The objective of this study was to evaluate the long-term outcome of resected patients and the impact of FOLFOXIRI on perioperative morbidities, mortality, and chemotherapy induced hepatotoxicity.. Overall, 196 patients with initially unresectable metastatic colorectal cancer were treated with FOLFOXIRI in 2 phase II and 1 phase III trial. This regimen was associated with an elevated response rate (70.4%) and 37 patients (19%) could undergo a secondary R0 surgery on metastases. This study was registered with the Australian New Zealand Clinical Trials Registry Database at http://www.anzctr.org.au/Statistics.aspx and has ID number ACTRN12608000615381.. Main characteristics of the 37 radically resected patients were: median age 64 years (45-73), Eastern Cooperative Oncology Group Performance Status (ECOG) PS > or = 1 in 30%, synchronous metastases in 65%, multiple sites of disease in 22%, and metastases confined to the liver in 68%. Preoperative FOLFOXIRI was administered for a median of 5.5 months. There was no perioperative mortality and all morbidities (27% of patients) resolved without sequelae. After a median follow up of 67 months, 5-year and 8-year survival are 42% and 33% respectively. At 5 years, 29% of patients are free of disease. The analysis of treatment-induced liver injury showed neither G3 vascular toxicity nor G4 steatosis, and steato-hepatitis in only 5% of patients.. The GONO-FOLFOXIRI regimen allow an R0 surgery in approximately 1 out of 5 unselected patients with initially unresectable metastatic colorectal cancer, and the long-term survival of resected patients is considerable. Neoadjuvant FOLFOXIRI for 3-6 months is safe and not associated with severe liver injury.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pneumonectomy; Treatment Outcome

A 41-year-old man with multiple liver metastases from sigmoid colon cancer received a radical resection of the original tumor and 16 courses of weekly high-dose 5-FU(WHF)chemotherapy via hepatic arterial reservoir. The metastatic lesions showed stable disease(SD), and systemic chemotherapy by mFOLFOX6 was begun via CV port. After 14 courses of mFOLFOX4, abdominal CT revealed liver metastases were remarkably reduced in size. Hepatic resection of lateral segment and radio frequency ablation(RFA)for S6 were enforced, and the patient was uneventfully discharged. Pathological findings of lateral segment revealed no residual cancer cells, indicating that the histological effect of mFOLFOX6 was Grade 3.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Remission Induction; Tomography, X-Ray Computed

The purpose of this study was to assess retrospectively the sequential treatment of hepatic arterial infusion (HAI) chemotherapy followed by systemic therapy using oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin, namely, FOLFOX, for patients with liver metastases from colorectal cancer. We reviewed 20 patients with unresectable liver metastases from colorectal cancer. Patients were initially treated with HAI chemotherapy until disease progression (5-fluorouracil, 1000 mg/m(2) intra-arterial infusion, weekly) and then with FOLFOX thereafter (FOLFOX4, n = 13; modified FOLFOX6, n = 7). Adverse events, tumor response, and time to progression for each therapy were evaluated retrospectively, and overall survival was estimated. Toxicity of HAI chemotherapy was generally mild. Of 20 patients, adverse events leading to treatment discontinuation occurred in only 1 patient (5%) during initial therapy using HAI chemotherapy, while 9 patients (45%) exhibited adverse events during subsequent FOLFOX therapy. For HAI chemotherapy and FOLFOX, objective response rates were 85.0% and 35.0%, respectively, and median time to progression was 11.6 and 5.1 months, respectively. Median overall survival was 30.1 months. In conclusion, the sequence of HAI chemotherapy followed by FOLFOX is a promising treatment strategy for the long-term use of active chemotherapeutic agents, leading to a superior tumor response and fewer toxic effects in patients with unresectable liver metastases from colorectal cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Catheters, Indwelling; Colorectal Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate; Treatment Outcome

This prospective study evaluated the effect of bevacizumab on the hypertrophy of the future liver remnant (FLR) after portal vein occlusion (PVO) before major hepatectomy for colorectal liver metastases.. Twenty-seven patients with colorectal liver metastases treated with preoperative FOLFOX/FOLFIRI chemotherapy regimen since 2002 were evaluated for the degree of hypertrophy of the FLR after right PVO. The results were compared with a similar group of 13 patients treated since 2006 with a chemotherapeutic regimen including bevacizumab and PVO. The FLR was measured by volumetric computed tomography 4 weeks before and after PVO.. Before PVO, the FLR volumes were similar in the 13 patients who received bevacizumab (bev+) (mean +/- standard deviation, 497 +/- 136 cm(3)) and the 27 patients who did not receive bevacizumab (bev-) (511 +/- 222 cm(3), P = NS). After PVO, the increase in the FLR volume was significantly lower in the bev+ group (561 +/- 171 cm(3)) compared with the bev- group (667 +/- 213 cm(3), P < .031). In the bev+ group, patients who had received six or more cycles and were > or =60 years old experienced far lower hypertrophy. A right hepatectomy was performed in 29 patients (72%) without mortality and no clinically important differences in morbidity.. Bevacizumab may impair hypertrophy of the FLR after PVO in preparation for major hepatectomy particularly, in patients aged > or =60 years and those who receive six or more cycles of bevacizumab, suggesting that major liver resection should be considered with caution in patients who have received bevacizumab.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Hypertrophy; Leucovorin; Ligation; Liver; Liver Circulation; Liver Neoplasms; Liver Regeneration; Male; Middle Aged; Organoplatinum Compounds; Portal Vein; Preoperative Care; Prospective Studies; Young Adult

125 patients with hepatic neoplasms were observed during 1998-2008 years. Trisectionectomy was carried out to 84 patients with colorectal metastatic affection of liver, which amounted 67.2% of all cases. Hepatocellular carcinoma was the second most frequent malignancy to be observed--23 patients (18.4%). 6 patients (4.8%) with cholangiocellular carcinoma went further. 12 patients (9.6%) with non-colorectal metastatic tumors of liver were united into one group. In postoperative period adjuvant chemotherapy was carried out to 60 patients with colorectal metastatic affection of liver. In all patients with hepatic tumors undergoing trisectionectomy postoperative lethality amounted 6.4% (n=8), in patients with colorectal metastatic affection of liver--5.95% (n=5), in patients with primary hepatic tumors--3.45% (n=1), in patients with non-colorectal metastatic affection of liver--16.66% (n=2). Lethality was caused by acute hepatic failure in all observations. Postoperative complications were observed in 44.05% of patients with colorectal cancer and in 44.83% of patients with primary hepatic tumors. Hepatic failure was the most frequent complication. In case of colorectal metastatic affection three-year probability of survival amounted 30.94+/-6.6% in patients undergoing trisectionectomy, five-year--10.4+/-8%. Median 16 months. On conditions that adjuvant chemotherapy was carried out, three-year survival probability increased to 40.53+/-8.1%, five-year--to 10.4+/-8%. Median 17 months. One-year survival probability in patients with primary hepatic tumors undergoing trisectionectomy amounted 92.46+/-5.1%, three-year - 59.44+/-12.3%, five-year--44.58+/-15.8%. Median 42 months. Low level of postoperative lethality, allowable level of postoperative complications and good indices of survival probability in long-term period allow considering that trisectionectomy as a surgical technique is absolutely appropriate.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemotherapy, Adjuvant; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Postoperative Complications; Probability; Survival Analysis; Time Factors; Vitamin B Complex

We report a case of a woman in her sixties having primary duodenal carcinoma with multiple liver metastases who was treated with oxaliplatin in combination with infusional 5-fluorouracil/Leucovorin(FOLFOX regimen). After completing 2 courses of the chemotherapy, computed tomography showed a partial response without any severe adverse events. Now at 8 months, the PR stage has been maintained. So far, no standard therapeutic strategy for metastatic duodenal carcinoma has been developed. However, we suggest a FOLFOX regimen can be highly effective as a safe approach for continuously maintaining the quality of life of patients with this rare type of cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Duodenal Neoplasms; Duodenoscopy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Positron-Emission Tomography; Tomography, X-Ray Computed

A sixties-man had complained of melena. Colonoscopy revealed type 2 tumor at rectum. Computed tomography (CT)demonstrated lymph node metastasis in front of sacrum and two low density areas which were suspected metastases in the liver. The patient was diagnosed stageIV rectal cancer and resected primary focus and lymph node metastasis.[ Ra-RS, ant, type 2, moderately differentiated adenocarcinoma, ly1, v3, pSE, pN2, sH1(Grade C), sP0, pM1(No. 270)]without liver resection. It was due to high level of CEA and remote lymph node metastasis. The patient was treated with mFOLFOX6 and bevacizumab after the operation. The level of CEA decreased to normal level and CT revealed a partial response after 4 cycles of systemic chemotherapy. Liver resection was performed safely. Histological response was Grade 2 at liver metastases.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoembryonic Antigen; Fluorouracil; Humans; Immunotherapy; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms; Tomography, X-Ray Computed

Acinar cell carcinoma of the pancreas is rare tumour with a generally poor prognosis. There are very few reports of tumour regression following chemotherapy. In this case report, a patient with metastatic acinar cell carcinoma in the liver developed progressive disease after cisplatin/etoposide and then had progressive disease after weekly paclitaxel chemotherapy. However, his tumour then responded to gemcitibine/5-flourouracil/leucovorin chemotherapy. Herein, previously described chemotherapy regimens used for this rare tumour are reviewed. This case represents the first reported metastatic acinar cell carcinoma responding to this regimen.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Acinar Cell; Deoxycytidine; Drug Resistance, Neoplasm; Fluorouracil; Gemcitabine; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Treatment Outcome; Vitamin B Complex

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Skin Diseases; Treatment Outcome

Radiofrequency ablation (RFA) continues to evolve, improving the potentials of this technique. It is now a widely used procedure in the treatment of patients with unresectable colorectal liver metastases, increasing the number of potentially curable patients.. To evaluate the long-term survival of patients treated by RFA for colorectal liver metastases after downstaging by systemic chemotherapy.. In a retrospective review of our prospective colorectal liver metastasis RFA database, 36 patients (20 males, 16 females; median age 67 years) were identified during an 8-year period (1999-2007). All patients were initially unsuitable for local treatment, and referred to systemic chemotherapy by our multidisciplinary team. Multinodularity and/or location of tumor was the main cause of patients being unsuitable for local treatment. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined with oxaliplatin or irinotecan. After downstaging with chemotherapy, patients were treated by RFA. Patients with extrahepatic disease were excluded from RFA treatment. Pre- and posttreatment evaluation was performed with multidetector computed tomography (MDCT) scans.. The median time from diagnosis of hepatic metastases to first RFA was 10 months. A total of 158 tumors were treated with RFA during the study period. Median follow-up period was 27 months. The estimated median survival time after diagnosis of hepatic metastasis was 39 months, with a 5-year survival rate of 34%.. In selected patients with colorectal liver metastases downstaged by chemotherapy, RFA is an important modality that may contribute to improved survival. Furthermore, all patients responding to systemic chemotherapy should be re-evaluated by a multidisciplinary team.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheter Ablation; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

A 54-year-old man was referred to our hospital because of a huge, unresectable rectal cancer occupying his entire pelvic space with a solitary liver metastasis. He had undergone a laparotomy for surgical resection, but ended up with a sigmoid colostomy due to possible invasion into the urinary bladder and pelvic wall. At the completion of seven cycles of FOLFOX regimen, radiographic examination revealed remarkable reduction of the primary rectal tumor and regional lymph nodes, and also a complete response (CR) of the liver metastasis. The tumor was extirpated without any macroscopic residues by a low anterior resection of the rectum, along with a partial resection of the urinary bladder and seminal vesicles. Since pathological and immunohistochemical examinations showed no viable cancer cells in any parts of the resected specimens, the lesion was regarded as a pathologically CR. Analysis for single-nucleotide polymorphisms in the genes involved in nucleotide excision repair, excision repair cross-complementing group 1 and xeroderma pigmentosum group D, showed a genotypic pattern sensitive to oxaliplatin. To our knowledge, this is a rare case of an initially unresectable primary rectal cancer, which was down-staged to a pathologically CR by FOLFOX chemotherapy instead of chemoradiotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; DNA-Binding Proteins; Drug Resistance, Neoplasm; Endonucleases; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Rectal Neoplasms; Remission Induction; Xeroderma Pigmentosum Group D Protein

Liver resection is the only curative treatment offering a chance of long-term survival in patients with colorectal liver metastases (CRM). Recent data indicated that liver resection in patients with tumor progression while receiving chemotherapy was associated with poor outcome. The aim of the study was to identify risk factors for poor outcome in patients with pre-operative chemotherapy of CRM.. We analyzed 160 patients after liver resection for CRM with preoperative systemic. chemotherapy. Three groups of patients were identified: 44 patients (27.5%) had a tumor response, 20 (12.5%) showed stable disease, and 96 (60%) patients had tumor progression while on chemotherapy. Median follow-up was 2.4 years (range, 6 days-11.1 years). All available clinicopathologic variables possibly associated with outcome were evaluated.. Survival was 88%, 53%, and 37% at 1, 3, and 5 years. Noncurative resection, carcinoembryonic antigen levels >200 ng/ml, tumor grading, size of the largest tumor >5 cm, and number of metastases were associated with poor patient outcome. In the multivariate analysis, tumor free margin and tumor grading correlated with the outcome. Tumor progression while on chemotherapy had no influence on the long-term survival.. Liver resection offers a long-term survival benefit for patients with CRM, even when tumor growth proceeds during pre-operative chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colorectal Neoplasms; Combined Modality Therapy; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Retrospective Studies; Risk Factors; Treatment Outcome

Oxaliplatin has been shown to be valuable in the treatment of patients with colorectal cancer. Many of these patients will develop liver metastases during the course of their disease, with, in some cases, severe hepatic dysfunction. Although single agent oxaliplatin can be administered safely in patients with severely compromised liver function (as it is not metabolized by the liver), little is known of its safety in these patients when administered in the preferred combination with 5-fluorouracil (which is metabolized by the liver) and leucovorin (FOLFOX protocol). We report on a very sick patient with major liver dysfunction, a bilirubin of 11.2 mg/dl (190 micromol/dl) and an open abdominal wound, for whom palliative hospice care alone was originally proposed, who responded dramatically to the combination. His bilirubin fell to 0.6 mg/dl (10.2 micromol/dl) and his liver function tests returned to near normal levels. The combination was well tolerated and clinical improvement continued for more than 11 months before disease progression was observed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

The complete pathological response after primary chemotherapy could represent an important prognostic factor in patients affected by colorectal liver metastases. In recent studies, increasing complete pathological response seems to be correlated with longer overall survival periods and it is recognized as an important prognostic factor in patients treated with pre-operative chemotherapy. The correlation of radiological information on residual neoplastic disease after neoadjuvant treatment, obtained with CT and PET, has to be evaluated; in fact the complete disappearance of liver metastasis on radiological imaging does not always mean a complete disappearance of tumor tissue on histological examination; when it is documented with surgical procedures and confirmed by pathologist's examination, we can consider the complete pathological response. In recent years the addition of monoclonal antibodies to conventional chemotherapy may further increase the proportion of patients referred for surgery; bevacizumab before surgery has been shown to be feasible and safe, although concerns still exist regarding possible post-surgical and wound healing complications or bleeding. The limitation of the radiologic assessment of response as a surrogate for pathological response is even more relevant when antiangiogenic treatments are used. Excellent responses to bevacizumab-containing regimens do occur and referral to surgical oncology is a crucial step for documentation of complete pathological response.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Remission Induction

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Research Design; Retrospective Studies; SEER Program; Unnecessary Procedures

An increase in carcinoembryonic antigen (CEA) and/or carbohydrate antigen 19-9 (CA19-9) levels is generally considered as tumor progression in patients with metastatic colorectal cancer (MCRC). However, a transient CEA surge has been observed in patients with MCRC responding to chemotherapy. This study was to investigate the clinical significance of transient CEA/CA19-9 surges in Chinese MCRC patients.. One hundred and twenty-one MCRC patients with histologically proven adenocarcinoma and baseline ECOG performance status of < or =2 were treated with oxaplatin and (or) irinotecan-based chemotherapy regimens. Serum CEA and CA 19-9 levels were measured before and after chemotherapy.. Of the 121 patients, 14 (11.6%) had transient CEA surges with median baseline CEA level of 45 microg/L (9.67-2208 microg/L) and median surge peak level of 80.1 microg/L (13.38-4044 microg/L). The transient CEA surge occurred at a median of 4 weeks (2-6 weeks), and lasted for a medium of 6.5 weeks (4-14 weeks). Of the 14 patients, 11 received oxaplatin-based chemotherapy; three received irinotecan-based chemotherapy. All the 14 patients showed clinical benefit from chemotherapy, among which seven achieved partial response and seven had stable disease. In the meantime, five patients (3.8%) had transient CA19-9 surges. However, no significant correlation was found between an increase in the CA19-9 level and clinical benefits.. Transient CEA surges can be observed in Chinese MCRC patients receiving oxaplatin or irinotecan-based chemotherapy, which does not indicate tumor progression, but good therapeutic efficacy. A transient elevation of CA19-9 is not correlated to short-term clinical benefits.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; CA-19-9 Antigen; Camptothecin; Capecitabine; Carcinoembryonic Antigen; Child; Colonic Neoplasms; Deoxycytidine; Disease Progression; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Rectal Neoplasms; Remission Induction; Young Adult

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Node Excision; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Pneumonectomy; Survival Rate; Treatment Outcome

We report a case of a 71-year-old male with rectal cancer accompanied by liver metastases. Abdominal CT scan revealed a hepatic tumor (S2, 3) about 4 cm in diameter. We performed a Mile's operation and planned to resect the liver metastases after chemotherapy of modified FOLFOX6(mFOLFOX6)regimen: l-leucovorin (200 mg/m2) and oxaliplatin (85 mg/m/2) were given as a 2-hour infusion followed by bolus injection of 5-FU 400 mg/m2 and a 46-hour infusion 5-FU 2,400 mg/m2 every 2 weeks. An abdominal CT scan 6 months later demonstrated regression of the liver metastases. Hepatectomy was performed after chemotherapy, and no viable tumor cells were seen.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Rectal Neoplasms

To determine if neoadjuvant FOLFOX/FOLFIRI is associated with improved disease-free survival (DFS) or overall survival (OS) in patients with colorectal metastases (CRM) to the liver.. Ninety-nine patients (from 457 eligible) with CRM that underwent hepatic resection during 2000 to 2005 were included. Group 1 (n = 44) patients received neoadjuvant FOLFOX/FOLFIRI, and Group 2 (n = 55) did not receive neoadjuvant therapy.. There were 58% men. The median age for Group 1 was 58 and Group 2, 64 (p = 0.03). OS for Group 1 at 1, 3, and 5 years was 93%, 62%, and 51%, respectively, with a median OS of 5.8 years. In Group 2 survival at 1l, 3, and 5 years was 90%, 63%, and 45%, respectively, with a median OS of 3.7 years (HR 1.06, p = 0.87). The DFS for Group 1 at 1, 3, and 5 years was 51%, 20%, and 20%, with a median DFS of 1.1 years and Group 2 at 1, 3, and 5 years was 58%, 32%, and 32% (median DFS-1.2 years; HR = 1.24, p = 0.45).. Neoadjuvant FOLFOX/FOLFIRI was employed more frequently in younger patients with CRM; however, neoadjuvant chemotherapy for CRM was not significantly associated with an increase in OS or DFS, despite additional adjuvant therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Retrospective Studies

The case was a 69-year-old man with liver metastasis who had relapsed after the resection of rectal cancer. We treated the patient with FOLFIRI+bevacizumab(BV)after the failure of S-1+CPT-11, radiation, UFT/LV, FOLFOX and FOLFIRI regimen. The tumor marker level and accumulation of FDG-PET were rapidly decreased after initiating FOLFIRI+BV. There was no serious adverse event, and a remarkable improvement of QOL was observed. This case suggests that the BV combination regimen is useful even after the failure of FOLFOX and FOLFIRI regimen.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Quality of Life; Rectal Neoplasms; Recurrence; Salvage Therapy

The hypothesis was tested that systemic chemotherapy might contribute to improving overall survival (OS) of patients with unresectable colorectal liver metastases treated with hepatic arterial infusion (HAI).. We considered 153 consecutive patients retrospectively divided into group A (n=72) treated with HAI alone (floxuridine [FUDR] + leucovorin [LV]), and group B (n=81) treated with HAI combined with systemic chemotherapy (5-fluorouracil [5FU] + LV).. No significant difference in OS was observed between the two groups. Median OS was better in patients with <50% of liver involvement (21.3 vs. 13.2 months; p<0.0001) and in responders vs. non-responders (24.4 vs. 13.4 months; p<0.0001). The combination of low tumor load with good tumor response to HAI was the only variable retained on multivariate survival analysis, associated with a better clinical outcome (median OS: 34.2 months).. Our study does not support the use of FUDR-based HAI combined or not with 5FU-based systemic chemotherapy as the first-line therapeutic approach to unresectable colorectal cancer liver metastases. The identification of responsive patients would improve the therapeutic index of this HAI regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colorectal Neoplasms; Dexamethasone; Female; Floxuridine; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Retrospective Studies; Survival Rate; Treatment Outcome

Information concerning the pulmonary toxicity of oxaliplatin with infusional 5-fluorouracil plus leucovorin (FOLFOX) is very limited. We herein report the case of a patient with FOLFOX-induced interstitial pneumonia. An 82-year-old man with unresectable colon cancer liver metastases was referred to our department for chemotherapy with the FOLFOX protocol. After the administration of ten cycles, he visited our outpatient clinic with a 2-week history of coughing and shortness of breath; he was afebrile. A chest radiograph showed reticular shadows with ground-glass opacities mainly involving the middle and lower zones of the right lung. Computed tomography depicted ground-glass opacities with superimposed reticulation in the right lung. A diagnosis of FOLFOX-induced interstitial pneumonia was made based on the clinical course and imaging findings. The symptoms disappeared within 3 days after the cessation of the FOLFOX regimen and the initiation of high-dose corticosteroid treatment. Two months after the initiation of the corticosteroid treatment, complete remission of the radiological abnormalities was confirmed; thereafter, interstitial pneumonia did not recur despite the reintroduction of 5-fluorouracil/leucovorin alone, suggesting that 5-fluorouracil/leucovorin alone was not responsible for the development of the interstitial pneumonia. Thus, oxaliplatin, alone or in combination with 5-fluorouracil/leucovorin, may have caused the interstitial pneumonia in this patient. Once interstitial pneumonia has occurred, cessation of the regimen is mandatory, and high-dose corticosteroid treatment is commonly given to rescue patients from this potentially lethal complication.

Topics: Adrenal Cortex Hormones; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Male; Organoplatinum Compounds; Tomography, X-Ray Computed; Treatment Outcome

The patient was a 51-year-old male diagnosed with gastric cancer in July 1999 by endoscopic examination, revealing multiple liver metastasis with abdominal computed tomography (CT). The serum levels of alpha-fetoprotein (AFP)were determined to be 91 ng/mL, and tumors were histopathologically identified as AFP-producing gastric cancer by immunohistological staining. We started combination chemotherapy with 5-fluorouracil (5-FU), Leucovorin (LV), etoposide (VP-16) and cis-diaminedichloroplatinum (CDDP) (designated as FLEP)in August 1999. The serum AFP value was normalized after two courses, and the liver metastases disappeared. The primary gastric tumor became a ulcer, and disappearance of the cancer was confirmed histologically. We continued adjuvant chemotherapy with S-1 as an outpatient. In April 2000, there was no sign of the liver metastases, but endoscopic examination showed IIc-like lesion in the stomach. We performed 2 courses of FLEP, but the tumor did not disappear. He underwent total gastrectomy with D2 dissection in June 2001. The pathological diagnosis was por 1, ss, ly2, v1, n(1+). He was still alive with no sign of recurrence 84 months after surgery. We experienced this AFP-producing gastric cancer in which CR was possible by FLEP. There was no recurrence after total gastrectomy for local recurrence.

Topics: Adenocarcinoma; alpha-Fetoproteins; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Drug Combinations; Etoposide; Fluorouracil; Gastrectomy; Humans; Immunohistochemistry; Leucovorin; Liver Neoplasms; Male; Middle Aged; Oxonic Acid; Remission Induction; Stomach Neoplasms; Tegafur

A 60-year-old man was referred to our hospital since his stool examination was positive for occult blood. Colonoscopy showed a tumor of Bauhin's valve and terminal ileum. Biopsy of the tumor was performed and pathological examination revealed adenocarcinoma. No other lesions were detected by gastroduodenoscopy and double-balloon enteroscopy. CT also showed multiple liver metastases. Ileocecal resection was performed because of severe stenosis of the terminal ileum. Histopathological examination revealed moderately-differentiated adenocarcinoma of Bauhin's valve and the terminal ileum, and no adenocarcinoma was found in the cecum and ascending colon. He was diagnosed with primary adenocarcinoma of the ileum with multiple liver metastases. Chemotherapy with mFOLFOX6 was performed after surgical resection. After 5 courses of chemotherapy, abdominal CT showed marked regression of the liver metastases, and tumor marker (CA19-9) was normalized from 1,100 U/mL to 36 U/mL. Effectiveness of mFOLFOX6 for primary adenocarcinoma of small intestine is suggested.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Ileal Neoplasms; Leucovorin; Liver Neoplasms; Male; Middle Aged; Paclitaxel

Recently, an increased number of reports have been published on liver resection following neoadjuvant chemotherapy ( NAC) in patients with initially unresectable colorectal liver metastases (IUCLM). However, the definition of unresectable liver metastases differs among institutions. The size of liver tumor B5 cm and number of tumors B5 is commonly a contraindication for resection of liver metastases. The present study was performed to compare the short and longterm results between patients who underwent liver resection following NAC for IUCLM and those with multiple bilobar metastases for initially resectable liver metastases.. Twenty-seven patients with multiple bilobar liver metastases between 1994 and 2007 were divided into two groups, i. e. 11 patients who underwent liver resection following NAC for IUCLM and 16 patients who initially underwent liver resection. NAC was used in three in J-IFL and eight cases in mFOLFOX6.. All eleven patients with IUCLM were H3/grade C. The median course of NAC was 6 (4-6 courses, Mean+/-SD: 6+/-2 courses). The objective overall response rate was 100% (11/11). H3 of eleven patients was changed to two in H1 and nine in H2 after chemotherapy. Grade C of 11 patients was down-staged in 4 in grade Band 2 in grade A. The H factors and grade of 16 patients who initially underwent liver resection were H16H28H32 and grade A4/B6/C6, respectively. The disease-free and overall survival after resection of colorectal liver metastases between patients with initially unresectable and resectable liver metastases were not significantly different.. NAC enables liver resection in some patients with IUCLM. It should be performed not only preoperatively but also postoperatively for IUCLM because of better survival after surgery.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds

A 64 -year-old female received oral S-1 chemotherapy followed by mFOLFOX6 chemotherapy for postoperative liver and lung metastasis of sigmoid colon cancer. The tumor progression was observed after twelve courses of mFOLFOX6 chemotherapy, and then FOLFIRI+bevacizumab chemotherapy was performed. After two courses of FOLFIRI+bevacizumab chemotherapy, leucopenia was observed. The chemotherapy was then discontinued and G-CSF was administered. Two days later she complained of high fever and dry cough, and was admitted to the hospital. A diffuse ground-glass appearance of bilateral lung was observed on chest X-ray and CT. Drug-induced interstitial pneumonitis was suspected, and Pneumocystis carini pneumonia was considered in the differential diagnosis. Oral administration of prednisolone and sulfamethoxazole/trimethoprim did not improve the symptoms, so steroid pulse therapy was performed. Steroid pulse therapy improved respiratory symptoms, but CT findings did not change remarkably. After nine weeks in the hospital, she was discharged with home oxygen therapy. Interstitial pneumonitis induced by FOLFIRI+bevacizumab chemotherapy is rare, but the number of cases may increase with increased use of this regimen. The possibility of interstitial pneumonitis should always be considered when the patient presents with a respiratory disorder while receiving systemic chemotherapy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Diseases, Interstitial; Lung Neoplasms; Middle Aged; Sigmoid Neoplasms

We analyzed a treatment outcome and the effect of FOLFOX and FOLFIRI neo-adjuvant chemotherapy (NAC) for patient with liver metastasis of colorectal cancer. Eleven patients undergoing hepatectomy after NAC were investigated. FOLFOX was performed for 8 patients, and FOLFIRI was for 3 patients. The response rate was 45.5% (PR 5, SD 6), and the reduction rate was 37.7%. The average ICG R15 value before hepatectomy was 13.7%. A complication during and after operations was not recognized. The average observation period was 19.8 months (8-45 months). Now, 9 patients are alive with no recurrence. NAC by FOLFOX for liver metastasis of colorectal cancer showed a high reduction rate, and there was a little influence to hepatectomy indicating that FOLFOX could be an effective therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds

This retrospective study was performed to examine the outcomes of patients with liver metastasis of colorectal cancer, who received mFOLFOX6 regimen prior to hepatic metastatectomy. The reasons for introducing mFOLFOX6 prior to hepatectomy were unresectable hepatic lesions in two patients, presence or suspicion of extrahepatic lesions in four patients, and patient's refusal for hepatectomy in one patient. The mean number of cycles of administering mFOLFOX6 was 12.7 (range 10-18), two patients received additional FOLFIRI regimen after mFOLFOX6 treatment. The therapeutic efficacy revealed complete response in two, partial response in two, and stable disease in two by RECIST criteria. Histological examination revealed that six from 15 resected nodules were classified into grade 3. Histological examination of the non-cancerous liver tissue revealed stage I sinusoidal dilation (Rubbia-Brandt's classification) in five and grade 1 steatohepatitis (Brunt's classification) in two who received additional FOLFIRI regimen. Blood loss and duration of surgery of the subjects were identical to those (n=17) who underwent hepatic metastatectomy without preoperative chemotherapy during the same study period. It does not seem easy to determine the optimal timing of hepatic metastatectomy after FOLFOX treatment in clinical practice. However, our results suggest that preoperative FOLFOX treatment may have little adverse impact on the safety of hepatic metastatectomy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Direct intrahepatic arterial infusion of 5-FU produced a significantly higher response rate than systemic infusion of FOLFOX in the treatment of hepatic metastases from colorectal carcinoma. Fourteen patients switched over from systemic FOLFOX therapy to intrahepatic protracted 5-FU infusion after a progression of liver metastases treated with systemic therapy. Of the 14 patients whose tumors had initially failed to respond to systemic FOLFOX therapy, 12 (85%) had a partial response, and 13 (93%) had a reduction in their tumor marker (CEA, CA19-9, TPA) when the treatment was switched to intrahepatic 5-FU therapy. Traditional chemotherapy toxicity, such as myelosuppression, nausea, vomiting and neurotoxicity did not occur in the intrahepatic group. Three out of 14 patients survived more than a year, and the longest was 18 months. A better survival rate can be achieved with the use of hepatic artery infusion therapy.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Organoplatinum Compounds

We report a case of multiple liver metastases of rectsigmoid colon cancer treated with systemic chemotherapy and hepatectomy. A 40s woman had undergone anterior resection of rectum for rectsigmoid colon cancer with multiple liver metastases. Then FOLFOX4 regimen was performed fifteen times, and FOLFIRI regimen was performed eleven times. After chemotherapy was enforced, an abdominal CT revealed that liver metastases were reduced in size (effect judgment of partial response). Hepatic resection of the right lobe and partial of S2 segment were performed. Pathological findings of the resected liver revealed no residual cancer cells, indicating that the histological effect of chemotherapy was complete response (CR).

Topics: Adult; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Organoplatinum Compounds; Rectal Neoplasms; Sigmoid Neoplasms

A man in his fifties with rectal cancer underwent low anterior resection in another Hospital in January 2006. He was finally diagnosed with Stage III a (pA, pN1, H0, P0). The patient who had postoperative complication such as ruptured suture left the hospital in May 2006, when he was detected with multiple liver metastases and was referred to our hospital for systemic chemotherapy. Systemic chemotherapy with mFOLFOX6 was performed from May 2006. Grade 3 diarrhea and grade 2 peripheral neuropathy, nausea and vomiting were observed. After 6 courses of mFOLFOX6, MRI revealed metastasis had been disappeared and levels of CEA and CA19-9 were decreased below normal. The treatment has been discontinued. Recurrence was not observed for 30 months.

Topics: Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms; Treatment Outcome