levoleucovorin and Colonic-Neoplasms

Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies.. PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022.. Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event.. Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Placenta Growth Factor; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms

Chemotherapy plus antiangiogenic agents, including bevacizumab, ramucirumab and aflibercept, is a standard second-line treatment for patients with metastatic colorectal cancer, but which specific agents should be selected is ambiguous due to a lack of clear evidence from prospective studies. Previous reports have suggested ramucirumab and aflibercept could be more effective than bevacizumab in patients with high VEGF-D and high VEGF-A, respectively. JCOG2004 is a three-arm, randomized, phase II study to identify predictive biomarkers for these agents in patients who have failed first-line treatment. The study will enroll 345 patients from 52 institutions for 2 years, with progression-free survival in high VEGF-D (bevacizumab vs ramucirumab) and high VEGF-A (bevacizumab vs aflibercept) serving as the primary end point.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Camptothecin; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Oxaliplatin; Prospective Studies; Rectal Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor D

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Randomized Controlled Trials as Topic

The meta-analysis aimed to assess the clinical efficacy of chemotherapeutic triplet-drug regimen combined with anti-EGFR antibody in patients with initially unresectable metastatic colorectal cancer (mCRC). A systematic literature search was performed in PubMed Publisher. Studies evaluating FOLFOXIRI combine with panitumumab or cetuximab as the therapy for initially unresectable mCRC were included. The primary outcome was objective response rate (ORR) and rate of R0 resections. The secondary outcomes included overall survival (OS), progression-free survival (PFS), and grades 3 or 4 adverse events. R software (version 4.0.2) and RevMan (version 5.3) were used to analyze the extracted data. The studies included were published between 2010 and 2021, involving four single-arm phase II trials and two randomized phase II trials. A total of 6 studies with 282 patients were included. The data showed a significant benefit for the FOLFOXIRI + anti-EGFR antibody arm compared with FOLFOXIRI arm (RR 1.33; 95% CI, 1.13-1.58; I

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Panitumumab; Randomized Controlled Trials as Topic; Rectal Neoplasms; Treatment Outcome

To develop recommendations for adjuvant therapy for patients with resected stage II colon cancer.. ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice.. Twenty-one observational studies and six randomized controlled trials met the systematic review inclusion criteria.. Adjuvant chemotherapy (ACT) is not routinely recommended for patients with stage II colon cancer who are not in a high-risk subgroup. Patients with T4 tumors are at higher risk of recurrence and should be offered ACT, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphovascular invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT. The addition of oxaliplatin to fluoropyrimidine-based ACT is not routinely recommended, but may be offered as a result of shared decision making. Patients with mismatch repair deficiency/microsatellite instability tumors should not be routinely offered ACT; if the combination of mismatch repair deficiency/microsatellite instability and high-risk factors results in a decision to offer ACT, oxaliplatin-containing chemotherapy is recommended. Duration of oxaliplatin-containing chemotherapy is also addressed, with recommendations for 3 or 6 months of treatment with capecitabine and oxaliplatin or fluorouracil, leucovorin, and oxaliplatin, with decision making informed by key evidence of 5-year disease-free survival in each treatment subgroup and the rate of adverse events, including peripheral neuropathy.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Oxaliplatin

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

Metastasectomy in patients with metastatic colorectal cancer (mCRC) confers a significant survival benefit. We hypothesized that conversion to resectability (C2R) correlates with superior overall survival (OS) in patients with unresectable mCRC.. A prospectively registered systematic review (PROSPERO CRD42015024104) of randomized clinical trials published after 2003 was conducted. Exposure of interest was C2R with a primary outcome of OS. Clinical trials were classified based on difference in C2R between study arms (<2%, 2% to 2.9%, ≥3%). Generalized estimating equations were used to measure associations while adjusting for multiple observations from the same trial.. Of 2902 studies reviewed, 30 satisfied selection criteria (n=13,618 patients). Median C2R was 7.3% (interquartile range [IQR]: 5% to 12.9%), with maximum C2R in the FOLFOX/FOLFIRI+cetuximab arm (28.6%). The median difference in C2R between 2 arms of the same study was 2.3% (IQR: 1.3% to 3.4%) with a maximum difference of 15.4% seen in FOLFOX/FOLFIRI+cetuximab versus FOLFOX/FOLFIRI. Median OS for the entire patient cohort was 20.7 months (IQR: 18.9 to 22.7 mo), with a between group difference of 1.3 months (IQR: -1.2 to 3.6 mo). The median survival difference between the 2 study arms with <2% C2R difference was 0.8 months versus 1.6 months with ≥3% C2R rates . Increasing C2R had an incremental dose-effect response on OS ( P =0.021), and higher response rates correlated with C2R rates ( P =0.003).. C2R occurs infrequently and variably in clinical trials enrolling patients with unresectable mCRC. Prioritization of chemotherapeutic agents that enhance C2R might improve OS of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms

To provide guidance for the management of RAS wild-type (wt) metastatic colorectal cancer (mCRC) in daily practice.. Nominal group and Delphi techniques were used. A steering committee of seven experts analyzed the current management of RAS wt mCRC, through which they identified controversies, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a group of 30 experts (the expert panel) was selected to test agreement with the statements, through two Delphi rounds. The following response categories were established in both rounds: 1 = totally agree, 2 = basically agree, 3 = basically disagree, 4 = totally disagree. Agreement was defined if ≥ 75% of answers were in categories 1 and 2 (consensus with the agreement) or 3 and 4 (consensus with the disagreement).. Overall, 71 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) tumor location; (3) triplets; (4) maintenance; (5) second-line and beyond treatments; (6) Rechallenge and liquid biopsy. After the two Delphi rounds, only six statements maintained a lack of clear consensus.. This document aims to describe the expert's attitude when dealing with several common clinical questions regarding patients with RAS wt mCRC.

Topics: Advisory Committees; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colon, Ascending; Colon, Transverse; Colonic Neoplasms; Colorectal Neoplasms; Consensus; Delphi Technique; ErbB Receptors; Fluorouracil; Genes, ras; Genotype; Humans; Leucovorin; Liquid Biopsy; Maintenance Chemotherapy; Organoplatinum Compounds; Proto-Oncogene Proteins B-raf; Retreatment

Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen.. Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade.. A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HR. Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints.. NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Oxaliplatin

The MSI phenotype in colon cancer is a good prognostic factor, with an impact probably more pronounced for stage II than stage III tumor. This survival advantage may be related to the tumor-infiltrating lymphocytes observed in MSI tumors, thus explaining the existence of a probably more effective anti-tumor immune response. In addition, the MSI status would also be a biomarker able to predict the lack of efficacy of adjuvant 5-fluorouracil (5FU) chemotherapy. In contrast, as observed in MSS colon cancer, the MSI tumors would have a survival benefit with the addition of oxaliplatin to adjuvant 5FU chemotherapy. Based on these data, the "French National Thesaurus of Digestive Oncology" suggests for patients with MSI colon cancer, an adjuvant chemotherapy combining fluoropyrimidine and oxaliplatin for stage III, and surgery alone without adjuvant chemotherapy for stage II (excepted for pT4b tumors in which the combination of fluoropyrimidine and oxaliplatin may be a therapeutic option). Beyond these recommendations, the discussion of adjuvant treatment in MSI tumors should also include other factors such as the patient's age and comorbidities. The duration of the adjuvant treatment (3 or 6 months) and the regimen used (FOLFOX or XELOX) should be based on the recommendations of the international IDEA consortium pending the results of the translational studies of this trial. Finally, the promising results of immunotherapy in metastatic MSI colorectal led to the development of clinical trials evaluating "immune checkpoint blockers" in combination with FOLFOX in the treatment of stage III MSI colon cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Immunotherapy; Leucovorin; Lymphocytes, Tumor-Infiltrating; Microsatellite Instability; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Phenotype; Prognosis; Pyrimidines

The results from the recent International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration have led some clinicians to adopt shorter durations of adjuvant chemotherapy for patients with stage III colon cancer. The extent to which these findings are supported by other data is unknown.. To conduct a systematic review and meta-analysis of randomized and observational studies investigating the association between the duration of adjuvant chemotherapy and survival among individuals diagnosed as having stage II and III colon cancer (PROSPERO protocol CRD42018108711]).. Abstracts published in English between 2003 and 2018 within the MEDLINE, Embase, CENTRAL, and CINAHL databases were reviewed by 2 authors. Also searched were conference proceedings and the indexes of high-impact oncology journals.. Studies were excluded if they did not present original data; focused on animal populations, on cancers in sites other than the colon, or on patients with stage 0, I, or IV disease; did not examine a 5-flourouracil-based monotherapy or combination therapy; or did not evaluate the association between treatment duration and survival. The search identified 2341 articles, from which 2 randomized trials and 20 observational studies were included in the meta-analysis.. This study followed the PRISMA and MOOSE reporting guidelines. The risk of bias was assessed by 2 authors using the Cochrane and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) tools. The results were synthesized using a random-effects model.. The primary and secondary outcomes were overall survival and disease-free survival, respectively. It was hypothesized a priori that 3 months of chemotherapy would be as effective as 6 months of chemotherapy.. Twenty-two studies were included in the meta-analysis, representing 43 671 patients. The inclusion of patients with stage II disease or with rectal cancer was identified as a source of heterogeneity. After restricting the analysis to patients with stage III colon cancer, there was no association between the duration of chemotherapy and overall survival among studies involving FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin) regimens (hazard ratio [HR], 0.80; 95% CI, 0.58-1.09). Among studies focused exclusively on monotherapy, the standard 6-month regimen relative to a 3-month regimen was associated with improved survival (HR, 0.59; 95% CI, 0.52-0.68).. Shortened durations of chemotherapy may reduce survival among patients with stage III colon cancer prescribed monotherapy but not a combination regimen.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Leucovorin; Neoplasm Staging; Observational Studies as Topic; Organoplatinum Compounds; Oxaliplatin; Progression-Free Survival; Randomized Controlled Trials as Topic; Time Factors

The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial.. To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX.. The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009.. Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study.. Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status.. Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P = .03).. The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy.. clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair; DNA Mutational Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Neoplastic Syndromes, Hereditary; Organoplatinum Compounds; Randomized Controlled Trials as Topic; Treatment Outcome

Oxaliplatin-based chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin] or XELOX [oxaliplatin, capecitabine; also called CAPOX]) for 6 months is the current standard for adjuvant therapy of stage III colon cancer patients with good performance status. However, these regimens are associated with significant toxicities, including myelosuppression, diarrhea, and oxaliplatin-induced, cumulative, dose-dependent neurotoxicity. A reduced duration of adjuvant therapy, which would reduce overall toxicity while maintaining overall clinical efficacy, would be optimal. The goal of the International Duration Evaluation of Adjuvant (IDEA) study was to evaluate the noninferiority of 3-month compared with 6-month adjuvant oxaliplatin-based treatment in stage III colon cancer using a prospectively designed pooled analysis of 6 concurrently conducted phase III randomized trials. Herein, we review the findings of the IDEA study and discuss the optimal duration of oxaliplatin-based adjuvant chemotherapy using patient-based risk factors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Drug-Related Side Effects and Adverse Reactions; Fluorouracil; Humans; Leucovorin; Medication Therapy Management; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Time Factors; Treatment Outcome

A 60-year-old woman was administered mFOLFOX6 therapy as postoperative adjuvant chemotherapy for fStage III a ascending colon cancer. The patient developed a disorder of consciousness(Japan Coma Scale[JCS]III-200)immediately after the completion of the therapy. Blood ammonia levels were high at 319 mg/dL, and a diagnosis of disturbance of consciousness due to hyperammonemia was made. The patient's state of consciousness improved on the following day as blood ammonia levels decreased due to treatment with branched chain amino acid(BCAA)formulation and oxygen. Two months later, mFOLFOX6 therapy was again administered with strengthening measures for side effects to nausea and vomiting and reducing 5-FU, but the patient again developed a disorder of consciousness(JCS III-200). The 5-FU administration rate was considered as a potential cause of hyperammonemia. Hyperammonemia induced by 5-FU is relatively rare, with a reported incidence of 5-9%; however, caution is required with high dosage regimens of 5-FU that are currently recommended for colorectal cancer therapy because hyperammonemia is an important side effect.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Diseases; Chemotherapy, Adjuvant; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Middle Aged; Organoplatinum Compounds

Multiple primary malignancy is defined as two or more malignancies detected in an individual person. In particular, synchronous quintuple primary malignancy is extremely rare. A 52-year-old male with anal pain and intermittent blood-tinged stool was diagnosed with malignancies in the stomach, jejunum, ascending colon, transverse colon and rectum. He underwent a subtotal gastrectomy, segmental resection of the jejunum and total protocolectomy with end ileostomy. The postoperative pathologic findings were moderate differentiated gastric adenocarcinoma (pT1bN0M0, pStageIA), combined adenocarcinoma and neuroendocrine carcinoma of the jejunum (pT3N0M0, pStageIIA), three mucinous adenocarcinoma of the ascending colon (pT3N0M0, pStageIIA), transverse colon (pT1N0M0, pStageI) and rectum (pT3N1aM0, pStageIIIB). The tumors did not lack MLH-1 and MSH-2 expression, as the markers (bat26, D5S346, bat25, D2S123) suggest MSI-H presence. Adjuvant chemoradiotherapy was started according to regimen, FOLFOX 4 for advanced rectal cancer. Six years post-operation, the patient is currently attending regular follow-ups without recurrence or metastasis.

Topics: Adenocarcinoma, Mucinous; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cancer Pain; Chemoradiotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Endoscopy, Gastrointestinal; Fluorouracil; Gastrectomy; Gastrointestinal Hemorrhage; Humans; Ileostomy; Jejunal Neoplasms; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Rectal Neoplasms; Stomach Neoplasms; Tomography, X-Ray Computed

5-Fluorouracil (5-FU) is combined with folinic acid (FA) for enhancing its cytotoxic effects in the colon cancer chemotherapy treatment. Folinic acid has rarely been involved in hypersensitivity reactions. Here, we report a case of FA hypersensitivity in an adult patient initially attributed to oxaliplatin administered concurrently. A 56-year-old male patient diagnosed with colon cancer received twelve cycles of FOLFOX4, one cycle of FOLFIRI plus cetuximab and nine cycles of FOLFOX6 uneventful. At the tenth cycle of FOLFOX6 chemotherapy, after 15 minutes of starting the infusion of oxaliplatin and FA, the patient reported flushing, pruritus and abdominal pain and erythema and oedema developed over the face and thorax. After progression, FOLFIRI plus aflibercept was scheduled and another reaction occurred. At this time, FA was discontinued and the patient received another cycle consisted on irinotecan plus 5-FU without incidences. This episode of hypersensitivity reaction following FA infusion with no oxaliplatin empirically confirmed that the hypersensitivity reaction was secondary to FA. Clinicians should be aware of hypersensitivity reaction with FA, especially when FA is administered concomitantly with oxaliplatin, despite its lower risk to cause hypersensitivity reactions. Furthermore, the similar signs and symptoms associated to the hypersensitivity reactions of each agent, highlight the importance of having a specialised allergist team for to make a prompt diagnose of the causative agent in order to prevent patient harm and proceed properly without unnecessary delays in the scheduled chemotherapy treatments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Hypersensitivity; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

Colorectal cancer (CRC) is the third most common cancer in the western world and also in Japan. The key factors in curing CRC are early detection, surgery and adequate adjuvant chemotherapy if needed.. Based on the results of following pivotal adjuvant trials, FOLFOX or XELOX are considered standard adjuvant chemotherapy for patients with stage III colon cancer in the western countries. On the other hand, 5-FU based monotherapies showed favorable results as adjuvant chemotherapy in Japan providing comparable results to doublet strategies in the western countries. There are two key factors that could provide better outcome: D3 lymph node dissection (LND) and thorough pathological examinations.. I believe that oxaliplatin based adjuvant chemotherapy may not be suitable for at least substage IIIA patients who underwent D3 surgery and were diagnosed by thorough pathological examinations for the following two reasons: toxicities and strongly stage-dependent added benefit of oxaliplatin in overall survival. We are awaiting the final results of three Japanese ongoing trials focusing on oxaliplatin based adjuvant chemotherapy. These results will hopefully help us create and implement global guidelines for truly standardizing the management of colon cancer prevalent all over the world, and help physicians recommend the treatment strategy available to each patient.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Deoxycytidine; Fluorouracil; Humans; Japan; Leucovorin; Lymph Node Excision; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates

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

Topics: Adenocarcinoma, Mucinous; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Combined Modality Therapy; Diagnosis, Differential; Female; Fluorouracil; Gallbladder; Genes, ras; Humans; Hyperthermia, Induced; Intestines; Leucovorin; Middle Aged; Neoadjuvant Therapy; Omentum; Organoplatinum Compounds; Ovarian Neoplasms; Peritoneal Neoplasms; Remission Induction; Round Ligaments; Second-Look Surgery

A 71-year-old woman was admitted for fever and appetite loss. She was diagnosed with ascending colon cancer, with portal vein tumor thromboembolism extending to the portosplenic junction. This was deemed unresectable despite the absence of distant metastasis. She underwent 16 courses of mFOLFOX6 therapy, and because the effect of chemotherapy was PR, right hemicolectomy with high ligation of the ileocolic vessels and the right branch of the middle colic vessels was performed. The tumor stage was yp-T3N1bM0, StageⅢB with a few remaining cancer cells in the portal venous system. Staging after chemotherapy effect was Grade 1a. Postoperatively, 13 courses of mFOLFOX6 were administered. A repeat CT scan showed lymph node recurrence along the SMV, which was subsequently resected again. After the second operation, 9 courses of the DeGramont regimen was administered and discontinued. Five years after the last operation, the patient remains well and without any recurrences. Colonic carcinoma with portal venous tumor thromboembolism has been reported in 9 cases, including ours. Among these, 8 cases involved the ascending colon. Seven of the affected patients were female while 3 were poorly differentiated adenocarcinoma. None of the other patients, except for our case, reported a 5 year patient survival rate without recurrence.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Organoplatinum Compounds; Portal Vein; Time Factors; Treatment Outcome; Venous Thromboembolism

A 67-year-old man was diagnosed with pulmonary metastasis from advanced transverse colon cancer. Thus, a local resection was performed. Adjuvant chemotherapy with mFOLFOX6 was started. Sixteen courses were carried out without problems. However, he complained of chills and chest discomfort 2 hours after beginning the 17th course of chemotherapy. Laboratory data showed remarkable thrombocytopenia, and platelet-associated IgG level was high. After administration of steroids and platelet transfusions, the platelet count improved. Therefore, we diagnosed drug-induced thrombocytopenia resulting from sensitivity to oxaliplatin (L-OHP). Since then, sLV5FU2 therapy was started, and the patient received the whole adjuvant chemotherapy without problems. Thrombocytopenia resulting from sensitivity to L-OHP is a relatively rare side effect. We herein report this case with a review of the relevant literature.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colon, Transverse; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Platelet Transfusion; Pneumonectomy; Thrombocytopenia

In October 2008, a 66-year-old male patient underwent resection of the right half of the colon for ascending colon cancer. Histopathological examination revealed a tumor classification of tub2, pSE, ly1, v0, PM0, DM0, RM0, pN1(2/23), H0 , P0 , Stage III a. The patient was treated with uracil/tegafur plus Leucovorin(UFT/LV)chemotherapy after surgery. However, he developed Grade 2 liver dysfunction after completion of 1 course, so UFT/LV was discontinued. In June 2009, a rise in the carcinoembryonic antigen(CEA)level was observed, and computed tomography(CT)and positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-D-glucose(FDG-PET)showed a single enlarged lymph node, 2 cm in diameter, located around the aorta. We informed the patient of the therapeutic effect of anticancer drug treatment and surgery, risk of adverse events, and other management methods, and UFT/LV chemotherapy was selected as treatment. After 3 courses, the lymph node had completely disappeared, and UFT/LV was discontinued in April 2011, as there was no sign of recurrence. The patient remains alive and well. We report a case of para-aortic lymph node metastasis after surgery, treated with UFT/LV, which led to a complete response without major adverse events.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Aorta; Colonic Neoplasms; Humans; Leucovorin; Lymphatic Metastasis; Male; Remission Induction; Tegafur; Uracil

Currently, the backbone of therapy for metastatic disease is cytotoxic chemotherapy, along with the recent addition of targeted therapy based on molecular markers with KRAS testing. Despite the improvement in survival for metastatic colon cancer, newer agents are still needed. The clinical activity of TroVax in metastatic colon cancer has been studied in a small number of clinical trials. There is evidence that supports the vaccine's ability to induce humoral and cellular responses, as demonstrated by positive 5T4 and MVA-specific antibody titers and cellular proliferation assays. Future strategies should focus on investigating the immunomodulatory effects of chemotherapy in conjunction with TroVax, understanding the optimal dosing and schedule of the combination, and examining potential predictive biomarkers to determine which patients may benefit from immunotherapy from those who do not.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cancer Vaccines; Carcinoembryonic Antigen; Carcinoma, Renal Cell; Colonic Neoplasms; Fluorouracil; Humans; Immunotherapy; Kidney Neoplasms; Leucovorin; Membrane Glycoproteins; Organoplatinum Compounds; Vaccination; Vaccines, DNA; Vaccinia virus

We report a case of recurrent colon cancer successfully treated by mFOLFOX6 and FOLFIRI, and maintaining a complete response(CR)over the long-term. A 60-year-old woman complained of abdominal discomfort 18 months after surgery for advanced descending colon cancer(tub2, pT3, pN2, cM0, fStage IIIb). A pelvic mass was demonstrated by abdominal computed tomography(CT)scan, and relapse of the cancer was suspected. Positron emission tomography-CT fusion image revealed metastases at Douglas' pouch, liver, right ovary and right inguinal lymph nodes. Systemic chemotherapy followed by mFOLFOX6 regimen was started. After 8 courses of mFOLFOX6, severe neuralgic side effects forced us to change the regimen to FOLFIRI. After completion of 4 courses of FOLFIRI, CR was proved by CT scan. Chemotherapy was stopped after an additional 4 courses of FOLFIRI. CR has been maintained for 4 years and 4 months after confirmation of CR. There were 18 cases reported in the literature that had CR by FOLFOX and/or FOLFIRI. Among those reports, our case was considered to have kept CR for the longest duration of time.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Recurrence; Time Factors

Colon cancer is among the most common cancers in the United States, and the median age of patients at diagnosis is 70. Medical oncologists are commonly asked to comprehensively evaluate elderly patients to estimate individual risk/benefit ratios for adjuvant treatment. Although 40% of patients with colon cancer are elderly, clinical trials enroll mainly younger patients. Consequently, we are forced to depend on subgroup analyses, observational studies, and personal experience to guide recommendations. Decision-making in adjuvant therapy for colon cancer is increasingly complex, as we subdivide patients with stage II to III colon cancer by molecular as well as anatomic staging to predict which are likely to benefit from chemotherapy and then whether the addition of oxaliplatin to 5-fluorouracil (5-FU) is worth the toxicity. It is likely that the tumor biology of younger and older patients differs, and more research is needed to dissect out the biologic heterogeneity of both the tumors and their elderly hosts to help guide treatment. We recognize that our evaluations should not solely be based on temporal age and factor physiology, pharmacology, psychology, functional status, and social support into these considerations. Older patients who are treated must be monitored closely for toxicities when undergoing treatment. Although there is a clear need for clinical trials in this population, treatment decisions confront us today in the absence of definitive evidence. How can we help our patients navigate through these important choices?

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Fluorouracil; Geriatric Assessment; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Patient Selection; Predictive Value of Tests; Risk Assessment; Risk Factors; Treatment Outcome

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

The standard treatment for colon cancer is surgical excision. Adjuvant chemotherapy is intended to reduce the risk of relapse, which is responsible for the death of nearly half of all patients treated surgically for localised disease. After surgery for stage III disease (node involvement without metastases), the 5-year survival rate is about 63% with adjuvant chemotherapy combining fluorouracil and folinic acid, versus 51% with placebo, a statistically significant difference. After surgery for stage II disease (tumour spread beyond the intestinal wall but no node involvement), a meta-analysis updated in 2008 showed no impact of adjuvant chemotherapy on the overall survival rate. Fluorouracil + folinic acid administration according to the de Gramont protocol is the standard adjuvant treatment. The addition of regional fluorouracil chemotherapy did not further improve outcome in a trial in 1501 patients with stage II or stage III disease. The fluorouracil precursors, capecitabine and tegafur, provide no advantages in terms of efficacy or tolerability. These oral drugs have not been compared with the de Gramont protocol. A trial comparing raltitrexed versus fluorouracil + folinic acid was stopped because of an excess of deaths in the raltitrexed arm. In two large trials, each including more than 2000 patients, the addition of oxaliplatin to the fluorouracil + folinic acid combination (Folfox 4 protocol) in patients with stage III disease appeared to slightly improve overall survival in patients under 65 years of age, but severe neuropathy, diarrhoea, nausea and vomiting were more frequent. In three trials in a total of more than 3000 patients with stage III disease, the addition of irinotecan did not improve the efficacy of the fluorouracil + folinic acid combination, while serious adverse effects were more frequent. No new drugs intended for the treatment of colon cancer have been introduced since 2006, but better evaluation of existing drugs means that patients with stage III colorectal cancer can now be offered a choice between standard intravenous fluorouracil and oral capecitabine or tegafur. Oxaliplatin adjunction is another option for patients under 65. The adverse effect profile is an important factor in the choice of treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Neoplasm Staging; Survival Rate

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

Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials.. We assessed 14,611 patients (1218 black and 13,393 white) who received standardized adjuvant treatment in 12 randomized controlled clinical trials conducted in North America for resected stage II and stage III colon cancer between 1977 and 2002. Individual patient data on covariates and outcomes were extracted from the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database. The endpoints examined in this meta-analysis were overall survival (time to death), recurrence-free survival (time to recurrence or death), and recurrence-free interval (time to recurrence). Cox models were stratified by study and controlled for sex, stage, age, and treatment to determine the effect of race. Kaplan-Meier estimates were adjusted for similar covariates to control for confounding. All statistical tests were two-sided.. Black patients were younger than whites (median age, 58 vs 61 years, respectively; P < .001) and more likely to be female (55% vs 45%, respectively; P < .001). Overall survival was worse in black patients than whites (hazard ratio [HR] of death = 1.22, 95% confidence interval [CI] = 1.11 to 1.34, P < .001). Five-year overall survival rates for blacks and whites were 68.2% and 72.8%, respectively. When subsets defined by sex, stage, and age were analyzed, overall survival was consistently worse in black patients. Recurrence-free survival was worse in black patients than whites (HR of recurrence or death = 1.14, 95% CI = 1.04 to 1.24, P = .0045). Three-year recurrence-free survival rates in blacks and whites were 68.4% and 72.1%, respectively. In contrast, recurrence-free interval was similar in black and white patients (HR of recurrence = 1.08, 95% CI = 0.97 to 1.19, P = .15). Three-year recurrence-free interval rates in blacks and whites were 71.3% and 74.2%, respectively.. Black patients with resected stage II and stage III colon cancer who were treated with the same therapy as white patients experienced worse overall and recurrence-free survival, but similar recurrence-free interval, compared with white patients. The differences in survival may be mostly because of factors unrelated to the patients' adjuvant colon cancer treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Confounding Factors, Epidemiologic; Disease-Free Survival; Female; Fluorouracil; Health Status Disparities; Healthcare Disparities; Humans; Kaplan-Meier Estimate; Leucovorin; Levamisole; Lomustine; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Odds Ratio; Proportional Hazards Models; Randomized Controlled Trials as Topic; Treatment Outcome; United States; Vincristine; White People

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA-Binding Proteins; Endonucleases; Fluorouracil; Humans; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Organic Anion Transporters; Organoplatinum Compounds; Thymidylate Synthase; Xeroderma Pigmentosum Group D Protein

While many patients with early-stage colon cancer are cured with surgery alone, the standard of care remains a uniform approach to adjuvant chemotherapy based primarily on tumor stage. Recently, increasing awareness of the need for more individualized decision-making in cancer care has led to the development of several potential prognostic and predictive markers in colon cancer. While adjuvant chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin is clearly beneficial to patients with stage III disease, well-validated molecular markers might help define which patients with stage II disease are likely to benefit from adjuvant therapy as well. Here, we review the data on the clinical development of molecular markers to individualize adjuvant therapy in colon cancer.

Topics: Adjuvants, Immunologic; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Chromosomal Instability; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Prognosis; Rectal Neoplasms; Risk Factors

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Semustine; Survival Rate; Vincristine

A woman in her fifties underwent a right hemicolectomy (D3) for cancer of the ascending colon in October 2007, definitively and pathologically diagnosed as papillary adenocarcinoma invading to the subserosa, and no metastasis was detected to lymph node. But 13 months after the surgery, she was found to have a mass near the anastomosis by an abdominal CT scan. Colonoscopy showed an evaluating lesion with ulcer in the anal side of the anastomosis. We tried to resect the metastasis, but it was not resectable because of the invasion to the pancreas. The mFOLFOX regimen was effective. After the chemotherapy (6 courses), we decided to perform a radical resection. We conducted pancreatoduodenectomy in May 2009. She is still alive 12 months after surgery.

Topics: Adenocarcinoma, Papillary; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Duodenum; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Pancreatectomy; Pancreatic Neoplasms

Colorectal cancer (CRC) represents a major public health problem accounting for > 1 million cases of new cancers and about half a million deaths worldwide. The risk of recurrence remains high despite curative surgery in early disease stages. The incremental benefit in absolute recurrence-free survival from 5-fluorouracil (5-FU)-based regimens in young patients with high-risk colon cancer is not insignificant. We present a case of a 57-year-old otherwise healthy white man who was treated with adjuvant chemotherapy consisting of modified 5-FU/leucovorin/oxaliplatin (FOLFOX6) regimen for stage III colon cancer. He experienced significant cardiotoxicity related to infusional 5-FU. Because of his young age and high-risk cancer, the patient opted to continue with adjuvant bolus 5-FU-containing chemotherapy after a lengthy discussion. With close cardiac monitoring and treatment with calcium channel blocker to prevent coronary vasospasm, he was able to successfully complete adjuvant chemotherapy. Currently, there are no guidelines for predicting a patient's risk for 5-FU-induced cardiotoxicity. Similarly, there is no uniform management of this 5-FU-related induced cardiotoxicity. We believe that our case report, with a brief review of related literature, might help fill some of this vacuum.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Coronary Vasospasm; Electrocardiography; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Myocardial Stunning; Neoplasm Staging; Organoplatinum Compounds

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

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

A 62-year-old man was referred to our hospital with the chief complaint of a palpable abdominal mass. Type 1 tumor was found in the ascending colon on fiberscopic examination, and pathologic examination revealed moderate to highly differentiated adenocarcinoma. Computed tomography of the abdomen demonstrated a main tumor and an adjacent large mass which was suspected to be lymph node metastasis. The tumor invaded the superior mesenteric vein( SMV) and pancreas. On the first laparotomy, a curative resection was difficult, and chemotherapy was planned. The FOLFIRI regimen was effective, but adverse events such as fever and general fatigue gradually became pronounced. Even after the change to FOLFOX, these adverse events did not improve, and we therefore decided to perform a radical resection. The patient is still alive and disease-free 8 months after surgery.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Pancreaticoduodenectomy

Colon cancer is a public health problem worldwide. Although potentially curable at early stages, a substantial number of patients will inevitably present with or eventually develop metastatic disease, which is often incurable. Despite the progress achieved with the introduction of new cytotoxic agents, recurrence rates for patients with resected stage II/III disease remain > 20%. Therefore, a great deal of effort and resources have been put into improving early diagnosis and prevention tools as well as the efficacy of adjuvant treatment. Oxaliplatin-based chemotherapy is now considered the standard of care in node-positive colon cancer, but there remains controversy with regard to the indication and type of adjuvant treatment in patients with nodenegative disease. Oral fluoropyrimidines play a growing role in the management of colorectal cancer and can be currently considered an alternative to 5-fluorouracil. Numerous reports have suggested that elderly patients benefit equally from chemotherapy, but the growing numbers of octogenarian and nonagenarian patients in our clinics, many of whom occasionally struggle through treatment, are a reminder of the challenges ahead. Finally, as we might have reached a plateau in terms of cytotoxic chemotherapy, numerous clinical trials are now focusing on the role of biologic agents in the adjuvant setting.

Topics: Age Factors; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

The MOSAIC trial showed that the use of adjuvant oxaliplatin and an infusional regimen of 5-FU/LV in the treatment of stage II/III colon cancer improved disease-free survival (DFS). The NSABP's C-07 trial evaluated the addition of oxaliplatin to a weekly Roswell Park regimen of bolus 5-FU/LV and found a similar improvement in DFS. The benefit of oxaliplatin appears to be independent of the 5-FU/LV regimen used. This paper reviews the efficacy and toxicities of these two regimens and is meant to serve as a guide for clinical practice.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Survival Rate

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Tegafur; Uracil

This manuscript summarizes recent progress in the adjuvant treatment of colon cancer. 5-Fluorouracil plus leucovorin, that have been considered standard therapy over the last 15 years, have now been replaced by combination chemotherapy, at least in stage III disease. The treatment of stage II disease is still somewhat less established. Prognostic and predictive biological markers are urgently needed for further fine-tuning of therapy. Molecular targeted agents have been developed with proven activity in advanced disease and are now being assessed in the adjuvant setting. It is expected that the inclusion of these new agents will lead to a further enhancement of treatment outcome. Those involved in the treatment of colorectal cancer should be encouraged to continue to provide optimal patient care and to participate in clinical trials in order to increase the evidence on which they can base their clinical judgement and to make further progress.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; ErbB Receptors; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Levamisole; Organoplatinum Compounds; Oxaliplatin; Survival Rate

Chemotherapy that targets metastatic colorectal cancer originally developed in Europe and the US, and was introduced to Japan in April, 2005, where it has since headed toward full scale clinical applications. This event created an opportunity to re-evaluate the role of postoperative adjuvant chemotherapy in Japan. In Europe and the US, adjuvant therapy has centered on the intravenous administration of leucovorin/fluorouracil, while in Japan, it has been long-term continuous administration of oral fluoropyrimidine preparations. Despite this difference in historical background,guidelines created in 2005 recommend both LV/5-FU and LV/UFT regimens and there has been increased application of evidence-based adjuvant chemotherapy. The benefits of postoperative adjuvant chemotherapy in stage II and III (high risk of recurrence) colorectal cancer patients have also come to be recognized. Examination of a new survey of 100 medical specialists on the current state of adjuvant chemotherapy for colorectal cancer in Japanese clinical settings revealed that for stage III patients, there is a tendency to choose treatment based on evidence gathered from both home and abroad. In contrast, a solid majority (60%) of stage II patients are treated exclusively with oral fluoropyrimidine despite a lack of, or limited evidence of efficacy. At the same time, half of the physicians who treated stage II patients with adjuvant chemotherapy initially attempted to identify those with a high risk of cancer recurrence and treat them accordingly; which was a breakthrough in the clinical treatment approach. While ongoing comparative Japanese clinical studies that use adjuvant chemotherapy for the treatment of colorectal cancer were noted, consideration was also given to the desired future direction clinical research should take.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Europe; Evidence-Based Medicine; Fluorouracil; Humans; Irinotecan; Japan; Leucovorin; Neoplasm Staging; Oxonic Acid; Practice Guidelines as Topic; Rectal Neoplasms; Tegafur; United States; Uracil

Angiogenesis is one of the hallmarks of cancer. Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) is a crucial regulator of angiogenesis in normal and malignant tissue. Increased expression of VEGF has been detected in most tumors of humans, and it is associated with increased risks of recurrence, metastasis, and death. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody targeting VEGF, has been evaluated in various solid tumors. Some pivotal phase III trials demonstrated that the addition of bevacizumab to conventional chemotherapy showed a survival benefit with acceptable toxicity. The United States Food and Drug Administration approved the use of bevacizumab for patients with unresectable colorectal cancer and unresectable non-squamous, non small cell lung cancer. In April 2007, the Japanese Ministry of Health, Labour and Welfare approved bevacizumab for patients with unresectable colorectal cancer. The usage of bevacizumab will be stipulated in combination with 5-fluorouracil containing chemotherapy at a dose of 5 mg/kg or 10 mg/kg given every 14 days. To know its efficacy and safety of bevacizumab is necessary for Japanese patients in the clinical practice.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Drug Administration Schedule; Drug Approval; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Vascular Endothelial Growth Factor A

Topics: Age Factors; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Vascular Endothelial Growth Factor A

Surgical resection of the primary and regional lymph nodes is still, at this time, the standard treatment of colon cancer. However, the risk of recurrence is still high in many patients. Efforts of the past decades have proved the role of systemic chemotherapy in the adjuvant setting in improving the curative rates. The combination of 5-fluorouracil (5-FU)and leucovorin (LV) remains the cornestorne of colon cancer chemotherapy worldwide. The addition of Oxaliplatin to infusional 5FU/LV has been shown to prolong significantly disease-free survival and capecitabine may be considered as an alternative to 5-FU/LV in the adjuvant therapy of stage III colon cancer. Novel molecular and biological-oriented agents are being studied, with promising date.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin

Irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and Leucovorin (LV) became the standard first-line chemotherapy for colorectal cancer in the U.S. and Europe in 2000, largely owing to the results of controlled randomized phase III trials of 5-FU/LV with or without CPT-11. One of the regimens for CPT-11 plus infusional 5-FU/LV therapy is the FOLFIRI regimen. This regimen consists of CPT-11 180 mg/m(2) as a 90-min infusion on day 1 and l-LV 200 mg/m(2) as a 2-h infusion during CPT-11, immediately followed by a bolus dose of 5-FU 400 mg/m(2) and a 46-h continuous infusion of 2,400 mg/m(2) every 2 weeks. FOLFIRI, as well as oxaliplatin/5-FU/LV therapy (FOLFOX), is an internationally accepted standard chemotherapy for metastatic colorectal cancer. Safe use of this effective regimen requires adequate supportive therapy in Japan, as well as in Western countries.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Randomized Controlled Trials as Topic; Rectal Neoplasms

The X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) trial compared the efficacy and safety of the oral fluoropyrimidine capecitabine with bolus 5-fluorouracil (5-FU)/leucovorin (LV; Mayo Clinic regimen) as adjuvant therapy for stage III colon cancer. A total of 1987 patients were enrolled at 164 centers worldwide. Disease-free survival (primary study endpoint) in the capecitabine arm was at least equivalent to that in the 5-FU/LV arm; the upper limit of the hazard ratio was significantly (P < 0.001) below the predefined margins for noninferiority. Capecitabine was also associated with significantly fewer fluoropyrimidine-related grade 3/4 adverse events (AEs; P < 0.001) and fewer AE-related hospital admissions/days than 5-FU/LV. Pharmacoeconomic analyses performed in several countries show that the savings in direct costs (drug administration and AE-related costs) associated with capecitabine versus 5-FU/LV offset the acquisition costs of the drug. Furthermore, capecitabine reduces patient travel time and costs, making it a "dominant" strategy (ie, less costly and more effective) in the adjuvant setting. In conclusion, efficacy, safety, convenience, and cost findings from the X-ACT trial show that capecitabine offers at least equivalent clinical benefit compared with bolus 5-FU/LV and can replace intravenous 5-FU/LV in the adjuvant treatment of stage III colon cancer. The X-ACT trial has not only helped to better define the role of capecitabine but has also broadened the options available to patients with early-stage disease to include a uniquely effective oral outpatient treatment.

Topics: Antimetabolites, Antineoplastic; Capecitabine; Clinical Trials as Topic; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Neoplasm Staging

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Rate

Postoperative adjuvant chemotherapy is benefit to survival of stage III colon cancer patients. Regimens containing 5-fluorouracil (5-FU) are used as the main therapy, including 5-FU/Lev, Mayo (FU/LV), protracted venous infusion of 5-FU, orally administered fluorouracil (UFT, Xeloda), and so on. 5-FU combined with oxaliplatin may improve therapeutic efficacy; however, further study on therapeutic efficacy of 5-FU combined with irinotecan is needed. The survival benefit of postoperative adjuvant chemotherapy for stage II colon cancer is controversial now; while postoperative adjuvant chemotherapy for high-risk colon cancer patients should be considered. The progression of postoperative adjuvant chemotherapy for colon cancer patients was reviewed in the article.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Levamisole; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain.. Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets.. Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients.. Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs. This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Medical Records; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Proportional Hazards Models; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Analysis; United States

This article summarizes the progress of adjuvant systemic chemotherapy of colon cancer. The study by Moertel et al that showed that the combination of 5-fluorouracil (5-FU) and levamisole in the adjuvant setting reduced mortality by 33% in stage III colon cancer; 5-FU/leucovorin (LV) became the standard of care in the adjuvant treatment of colon cancer after it showed superiority to 5-FU/levamisole. However, no standard schedule of 5-FU/LV has been established. The fortnightly regimen of bolus 5-FU/LV and continuous infusion 5-FU (LV5FU2) has the same efficacy as and is less toxic than the monthly regimen of bolus 5-FU/LV. Oxaliplatin combined with 5-FU and LV (FOLFOX4) is the first combination to demonstrate significant superiority in 3-year disease-free survival as compared with 5-FU/LV in the adjuvant treatment of colon cancer. Three-year disease-free survival is an excellent predictor of 5-year overall survival and, in future studies, can serve as a reliable endpoint that is associated with reproducible 5-year overall survival. Results of studies testing irinotecan combined with 5-FU and LV are not yet available. Adjuvant chemotherapy for patients with stage II colon cancer is a controversial subject. Because the available data suggest that stage II patients benefit from adjuvant chemotherapy, although to a lesser extent than patients with stage III disease, all patients with stage III and high-risk stage II disease should be offered adjuvant treatment with the new standard of care, FOLFOX4. Future studies in adjuvant therapy for colon cancer will explore oxaliplatin and 5-FU with or without antiangiogenesis or anti-epidermal growth factor agents.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Levamisole; Organoplatinum Compounds; Oxaliplatin; Prognosis; Randomized Controlled Trials as Topic

At present, standard adjuvant treatment for patients with stage III colon cancer after surgical resection is represented by 6 months of chemotherapy based on 5-fluorouracil/leucovorin regimens. Even elderly patients enjoy the benefit of chemotherapy in terms of superior overall survival with no detrimental effects on quality of life. More questionable is the role of adjuvant chemotherapy for stage II colon cancer patients, the standard of care for whom is surgical resection alone. Although a majority of patients will be cured with resection, a significant minority will ultimately relapse, suggesting the need to identify patients who may benefit from adjuvant therapy. Putative prognostic markers for stage II patients, as well as the state-of-the-art of the adjuvant treatment in this setting, are reviewed in this paper.

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Immunotherapy; Leucovorin; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Postoperative Care; Quality of Life; Secondary Prevention

This article reviews the available data regarding the acticity of postoperative adjuvant systemic therapy for colorectal cancer as first and second-line treatment in metastatic disease. The efficacy of adjuvant treatment of patients with stage III colorectal cancer is well established. 5-fluorouracil (5-FU) and folic acid over 6 months (still) represent todays standard and should serve as comparison in randomized studies. The risk of relapse is low in stage II colon carcinoma and consequently the efficacy is relatively small compared to stage III. New investigation indicate, Capecitabene has the potential to replace 5-FU/FS as standard treatment for patients with colon cancer. Efficacy results are expected to be available in 2004. In metastatic disease combination of 5-FU/folic acid plus CPT-11 or OXA are treatment of choice for the first-line therapy of metastatic colorectal carcinoma. FOLFOX is high-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second- line therapy for metastatic colorectal cancer. It resulted in prolongation of the median progress free survival from 6,8 to 8,8 months and increased the survival for 4,5 months. New perspectives are novel chemotherapeutic and targeted agents in metastatic colorectal cancer: For the first time, there has been a targeted therapy shown convincingly to prolong survival for patients with unresectable metastatic colorectal cancer in a well-performed Phase III trial. This agent is bevacizumab, a humanised monoclonal antibody targeting the circulating proangiogenic growth factor vascular endothelial growth factor. Results with bevacizumab should lead to rapid expansion of the number of strategies targeting tumour neovasculature. Additionally, an antibody against the epidermal growth factor, cetuximab, has been shown to have both single-agent activity and the potential ability to partially reverse resistance to a chemotherapy drug. These advancements, as well as data on other novel treatment agents that have been studied specifically in patients with colorectal neoplasms, are discussed in detail.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colon; Colonic Neoplasms; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Folic Acid; Humans; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Palliative Care; Postoperative Care; Randomized Controlled Trials as Topic; Time Factors

Topics: Administration, Oral; Adolescent; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colon; Colonic Neoplasms; Contraindications; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Meta-Analysis as Topic; Middle Aged; Multicenter Studies as Topic; Neoplasm Staging; Organoplatinum Compounds; Patient Selection; Pharmacogenetics; Prognosis; Randomized Controlled Trials as Topic; Sentinel Lymph Node Biopsy; Time Factors

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Survival Rate

Over the last 12 years, numerous randomized trials have addressed the role of adjuvant chemotherapy in resected colon cancer. Together, these studies give conclusive evidence of the benefit of adjuvant 5-fluorouracil combined with folinic acid in stage III (node positive) disease and this is now considered the standard of care. The chemotherapy appears to be equally effective whether it is given daily for 5 days per month or on a weekly schedule. The overall effect is a relative reduction in tumour -recurrence of 25% or an absolute improvement in survival of 10%. However, doubt remains as to the role of adjuvant chemotherapy in stage II colon cancer. To date, most of the randomized trials have demonstrated a relative reduction in tumour recurrence but have not shown any significant impact on survival. It seems likely that this inability to demonstrate a survival benefit from adjuvant chemotherapy in stage II disease relates to the fact that the trials have been underpowered to do so. Nevertheless, the absolute survival advantage is only about 2% and clinicians need to weigh this against the costs and toxicities of the treatment when managing these patients.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; Evidence-Based Medicine; Fluorouracil; Humans; Leucovorin; Levamisole; Neoplasm Staging; Randomized Controlled Trials as Topic

Topics: Adenocarcinoma; Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Randomized Controlled Trials as Topic

A significant proportion of patients with colon cancer who undergo curative surgical resection develop metastatic disease. Over the last 20 years large prospective randomised studies have demonstrated a clear survival benefit for patients with stage III colon cancer who are treated with adjuvant 5FU based chemotherapy. At the present time 6 months of 5FU and leucovorin is generally considered the standard adjuvant therapy. For stage II disease the routine use of adjuvant treatment remains controversial. Newer drugs such as oxaliplatin, irinotecan, and the oral fluoropyrimidines have proven active in advanced colorectal cancer and are currently being evaluated in the adjuvant setting. Molecular markers for this disease are being identified and may help define those patients who would benefit from therapy. The integration of adjuvant immunotherapy with conventional chemotherapy offers the potential to improve the long-term outcome for surgically resected colon cancer.

Topics: Adjuvants, Immunologic; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Therapy, Combination; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Levamisole; Neoplasm Staging; Randomized Controlled Trials as Topic

We report a very unusual case of malignant sigmoidoduodenal communication. To the best of our knowledge, this is the first documentation of this entity in the English language literature. A 76-year-old man presented with weakness, severe weight loss, foul-smelling eructations, anemia, constipation, and episodes of diarrhea. A sigmoidoduodenal fistula was found by barium enema, and a diagnosis of ulcerative colonic adenocarcinoma was made from the colonoscopy findings. Thus, we performed sigmoid colectomy with resection of the fistula and the involved anterior wall of the third duodenal part, followed by primary closure of the duodenal defect. Histological examination confirmed a Dukes' B (Stage II - T(4)N(0)M(0)) colonic adenocarcinoma, and the excision margins of the resected duodenal specimen were clear. We gave adjuvant chemotherapy with 5-fluorouracil and leucovorin. The patient is still alive and disease-free, 2 years postoperatively.

Topics: Adenocarcinoma; Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Duodenal Diseases; Fluorouracil; Humans; Intestinal Fistula; Leucovorin; Male; Sigmoid Diseases

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; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Tegafur; Treatment Outcome; Uracil

Although the benefit from adjuvant chemotherapy has been established clearly in patients with Stage III colon carcinoma, the degree to which elderly patients with colon carcinoma can tolerate such therapy generally has remained unknown.. The authors reviewed all patients in their Tumor Registry with Stage II and Stage III adenocarcinoma of the colon who underwent potentially curative resection for their disease at the Geisinger Medical Center between January 1990 and September 2000. One hundred twenty patients underwent complete resection of their colon carcinoma and received 5-fluorouracil-based (5-FU) adjuvant chemotherapy.. The 5-year disease free survival rate for patients age > or =65 years (Group A) was 70% compared with 56% for patients age < 65 years (Group B) (P = 0.085). The 5-year overall survival rate for patients in Group B was 77% compared with 62% for the patients in Group A (P = 0.143). In a Cox regression model, age was not a predictor of disease free survival (P = 0.633) or overall survival (P = 0.900) when it was analyzed as a continuous variable. Only 19 patients were age > 75 years, and the disease free and overall survival rates for this group were similar but were underpowered compared with the rates for the patients ages between 65-75 years. When gender and disease stage were included in the model, age remained a nonsignificant variable (P = 0.400 for disease free survival; P = 0.615 for overall survival). Nine of 56 patients in Group A (16%) experienced Grade 3-4 toxicity compared with 14 of 64 patients in Group B (22%) (P = 0.420). The lack of a correlation between toxicity and age was maintained after controlling for disease stage and patient gender (P = 0.343). There were no correlations between preoperative carcinoembryonic antigen level, tumor grade, or lymph node involvement and patient age (P = 0.258, P = 0.256, and P = 0.519, respectively).. Elderly patients with Stage II and Stage III colon carcinoma benefit from 5-FU-based adjuvant therapy without a significant increase in toxicity compared with their younger counterparts. Adjuvant chemotherapy should be presented to elderly patients with high-risk, resected colon carcinoma. The data regarding age cannot be generalized to patients age > 75 years.

Topics: Adenocarcinoma; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Lymph Nodes; Male; Middle Aged; Neoplasm Staging; Registries; Survival Rate

Colorectal cancer is one of the most frequent cancers in the world, especially in occidental countries. The primary curative therapy is surgical resection of the tumour. Within the last 15 years, appropriately powered prospective randomized trials have demonstrated that adjuvant post-operative chemotherapy should be the standard treatment for stage III cancers (node-positive disease). 5-Fluorouracil(5FU)/levamisole was used in the early 1990s but has now been replaced by 5FU/leucovorin. The recommended duration of treatment is 6 months. Combining levamisole with 5FU/leucovorin does not improve efficacy. In patients with stage II colon cancer it is still unclear whether adjuvant chemotherapy is effective. In an attempt to define groups of stage II cases that may benefit from adjuvant chemotherapy, considerable efforts have been made to determine molecular genetic factors (tumour-ploidy and mutations or alterations in oncogenes and tumour-suppressor genes). Regional therapy (particularly portal vein infusion) is one of the other therapeutic strategies still considered to be investigational. Current clinical trials are evaluating the role of non-fluorinated pyrimidine agents in an adjuvant setting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Immunotherapy; Leucovorin; Levamisole; Neoplasm Staging; 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

The primary curative therapy of colorectal cancer is surgical resection. However, within the last 15 years, prospectively randomized appropriately powered clinical trials have convincingly demonstrated that adjunctive postoperative adjuvant chemotherapy is of benefit to all patients with node-positive disease (stage III) and arguably to high-risk node-negative (stage II) cases. In the United States, the clinical trials encompassing greater than 5,000 cases have demonstrated that fluorouracil (5-FU)/leucovorin used in a variety of doses and schedules improves disease-free and overall survival in resected node-positive (stage III) colorectal cancer. The postoperative use of 5-FU/leucovorin for approximately 6 months represents standard of care for such patients. Current clinical trials are evaluating the role of nonfluorinated pyrimidine chemotherapeutic agents in adjuvant chemotherapy for resected large bowel cancer. 5-FU/leucovorin combined with irinotecan (CPT-11) versus 5-FU/leucovorin are being tested in a national intergroup clinical trial. Another trial is evaluating 5-FU/leucovorin plus oxaliplatin versus 5-FU/leucovorin alone. These clinical trials will be important in defining the appropriate standard of care for patients with resected colorectal cancer, since recent studies in advanced colorectal cancer in the United States and in Western Europe have demonstrated that combinations of 5-FU/leucovorin and CPT-11 or 5-FU/ leucovorin and oxaliplatin are superior to 5-FU/leucovorin alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Survival Rate

Adjuvant chemotherapy is standard treatment for patients with resected colon cancer who are at high risk for recurrence, but the efficacy and toxicity of such treatment in patients more than 70 years of age are controversial.. We performed a pooled analysis, based on the intention to treat, of individual patient data from seven phase 3 randomized trials (involving 3351 patients) in which the effects of postoperative fluorouracil plus leucovorin (five trials) or fluorouracil plus levamisole (two trials) were compared with the effects of surgery alone in patients with stage II or III colon cancer. The patients were grouped into four age categories of equal size, and analyses were repeated with 10-year age ranges (< or =50, 51 to 60, 61 to 70, and >70 years), with the same conclusions. The toxic effects measured in all trials were nausea or vomiting, diarrhea, stomatitis, and leukopenia. Patients in the fluorouracil-plus-leucovorin and fluorouracil-plus-levamisole groups were combined for the efficacy analysis but kept separate for toxicity analyses.. Adjuvant treatment had a significant positive effect on both overall survival and time to tumor recurrence (P<0.001 for each, with hazard ratios of death and recurrence of 0.76 [95 percent confidence interval, 0.68 to 0.85] and 0.68 [95 percent confidence interval, 0.60 to 0.76], respectively). The five-year overall survival was 71 percent for those who received adjuvant therapy, as compared with 64 percent for those untreated. No significant interaction was observed between age and the efficacy of treatment. The incidence of toxic effects was not increased among the elderly (age >70 years), except for leukopenia in one study.. Selected elderly patients with colon cancer can receive the same benefit from fluorouracil-based adjuvant therapy as their younger counterparts, without a significant increase in toxic effects.

Topics: Adenocarcinoma; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Levamisole; Multivariate Analysis; Neoplasm Recurrence, Local; Randomized Controlled Trials as Topic; Survival Analysis

Capecitabine is a novel fluoropyrimidine carbamate, orally administered and rationally designed to undergo tumor-selective activation. Some studies have been proven it to be safe for outpatient treatment and to have significant antitumor activity in colorectal and breast cancer patients. Randomized trials of patients with advanced colorectal cancer using capecitabine versus Leucovorin (LV).5-FU were studied in two groups. Capecitabine results in both a higher response rate and a more favorable toxicity profile than LV.5-FU. In women aged 55 years or more with breast cancer, capecitabine showed at least comparable efficacy to CMF combination therapy. Capecitabine offers a new effective oral treatment option as a single agent for patients with advanced colorectal or breast cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Randomized Controlled Trials as Topic; Rectal Neoplasms

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Germany; Humans; Incidence; Irinotecan; Leucovorin; Lymphatic Metastasis; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Prodrugs

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Immunotherapy; Leucovorin; Levamisole

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

The majority of colorectal neoplasms diagnosed are adenocarcinomas. Other histologies such as squamous, adenosquamous, carcinoid tumors, or lymphoid tumors are occasionally identified. Given the rarity of squamous-cell tumors, it is very difficult to study their natural course and response to therapy. An attempt is made to describe the frequency, anatomic location, and response to therapy with a review of the literature.. From the Cancer Registry at the University of Missouri-Columbia Ellis Fischel Cancer Center, tumors of the colon identified above the dentate line were selected for chart review. Data were extracted from cases between the years 1940 and 1996. The key terms used to identify cases were epidermoid, squamous cell, and cancer of the rectum or colon. Using this approach, forty patients were identified and each record was reviewed.. The majority of these cases were anal cancers with proximal extension into the rectum and were excluded. Of 4,561 cases of epithelial colon and rectal cancers identified, only one additional case of squamous-cell cancer could be verified. In this report we describe a patient with a primary squamous-cell carcinoma of the sigmoid colon with metastatic disease to the liver at diagnosis who responded to systemic chemotherapy. We believe this to be the first reported case of this rare tumor type in which the patient's tumor responded to systemic chemotherapy. Two cases with a thorough review of literature are presented.. Primary squamous-cell carcinoma of the colon is a rare malignancy of unknown cause and pathogenesis. Metastatic tumors to the colon should be ruled out in all cases before therapy. Early detection and surgery remain the main therapeutic options, but as presented in our case, response to chemotherapy in advanced disease is encouraging.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Carcinoma, Squamous Cell; Cisplatin; Colonic Neoplasms; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment.. The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV.. Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors.. Patients with Dukes' B colon cancer benefit from adjuvant chemotherapy and should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.

Topics: Adenocarcinoma; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Randomized Controlled Trials as Topic; Semustine; Survival Analysis; Vincristine

The goal of this analysis was to determine whether fluorouracil (FU) and folinic acid (leucovorin, LV) is an effective adjuvant therapy for patients after potentially curative resection of colon cancer in patients with B2 tumors.. One thousand sixteen patients with B2 colon cancer entered onto five separate trials were randomized to FU + LV or observation. A pooled analysis for event-free (EFS) and overall survival (OS) using a stratified log-rank and Cox model was performed.. The median follow-up duration was 5.75 years. Patients receiving FU + LV did not experience a significant increase in EFS or OS. The hazards ratio at 5 years was 0.83 (90% confidence interval, 0.72 to 1.07) for EFS and 0.86 (90% confidence interval, 0.68 to 1.07) for OS. The 5-year EFS was 73% for controls and 76% for FU + LV. The 5-year OS was 80% for controls and 82% for FU + LV. Increasing age and poorly differentiated tumors were significant indicators of poor prognosis (P < .02).. This data set does not support the routine use of FU + LV in all patients with B2 colon cancer. Longer follow-up may identify a small benefit. At present, studies in B2 colon cancer designed with a no-treatment control arm should be considered appropriate.

Topics: Age Factors; Antidotes; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Proportional Hazards Models; Survival Analysis

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Palliative Care; Prognosis; Quality of Life; Rectal Neoplasms

5-Fluorouracil (5-FU) has been available for over 40 years and has been used in a wide variety of different regimens for the treatment of advanced colorectal cancer, a malignancy with a poor prognosis that is common in industrialized countries. However, despite numerous clinical trials in which 5-FU has been used alone and in combination with a variety of modulating agents [chiefly leucovorin (LV)], and has been administered by bolus injection and i.v. infusion, the optimal regimen for the management of advanced colorectal cancer remains unclear, and there are notable national and international variations in clinical practice. The toxicity of 5-FU also remains an obstacle to the achievement of overall clinical benefit in many patients. The introduction of novel chemotherapeutic agents may make it necessary to reassess the place of 5-FU in the treatment of advanced colorectal cancer. This article debates these issues with a review of clinical trials of 5-FU, and concludes that the future lies in the utilization of novel and established agents in combinations that may significantly improve outcomes, rather than in continuing experimentation with various schedules of 5-FU and LV.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Rectal Neoplasms

Systemic palliative chemotherapy is usually regarded as ineffective in disseminated colorectal cancer, and the risk of toxic adverse effects is often considered a contraindication, as many patients are old and cannot be offered curative treatment. Randomized trials during the last decade have shown, however, that an effect on both survival and quality of life can be expected. Only casuistic reports of total remission have been published but a partial tumour response can be expected in 20-50% of patients. Toxicity is related to palliative chemotherapy and accelerated with old age (> 70 years). When disseminated colorectal cancer is diagnosed the possibility of palliative chemotherapy should be conferred with an oncologist.

Topics: Age Factors; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Meta-Analysis as Topic; Palliative Care; Quality of Life; Randomized Controlled Trials as Topic; Rectal Neoplasms

Evaluation of surgery and multidisciplinary treatment for colorectal cancer was performed based on the review of the results of clinical trials. Although most improvement in prognosis for colorectal cancer patients was obtained by the development of surgical techniques until the mid-70's, further extended surgery could not have demonstrated the obvious improvement in survival after the 80's. In this regard, various multidisciplinary treatments were evaluated by a meta-analysis of clinical trials. Among those modalities, preoperative irradiation for rectal cancer, postoperative adjuvant chemotherapy for resected colorectal cancer and biochemical modulation of 5-fluorouracil by methotrexate or leucovorin for advanced colorectal cancers proved to be significantly effective for improvement of prognosis. Clinical trials of immunochemotherapy using either levamisole or PSK for resected colorectal cancers, a trial of hepatic artery infusion for liver metastasis, and a trial of an adjuvant monoclonal antibody treatment, were also reported to demonstrate significant effects. For further progress in multidisciplinary treatment for colorectal cancers, standardization of the appropriate surgical technique for each stage of the disease is much anticipated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Immunologic Factors; Leucovorin; Meta-Analysis as Topic; Rectal Neoplasms; Survival Rate

Topics: Adjuvants, Immunologic; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Germany; Humans; Immunotherapy; Leucovorin; Levamisole; Practice Guidelines as Topic; Prognosis; Societies, Medical

Since its introduction in 1953, 5-fluorouracil based chemotherapy remained the standard treatment in advanced colorectal cancer. Continuous infusion or biochemical modulation by folinic acid enhanced the therapeutic efficacy of this agent. Quality of life is limited by the toxicity of these regimens as well as by the frequent visits to the hospital during each cycle. Raltitrexed, a thymidylate synthase inhibitor, offers similar antitumoral activity together with a tolerability in comparison to standard 5-fluorouracil based chemotherapy and its simple dosage schedule also contributes to better quality of life. New chemotherapeutic agents are currently in development for the treatment of patients refractory to 5-fluorouracil. Irinotecan and oxaliplatin demonstrate promising activity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Colonic Neoplasms; Enzyme Inhibitors; Fluorouracil; Hospitalization; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Quality of Life; Quinazolines; Rectal Neoplasms; Thiophenes; Thymidylate Synthase; Topoisomerase I Inhibitors

Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Levamisole; Neoplasm Staging; Randomized Controlled Trials as Topic; Russia; Survival Analysis; Treatment Outcome; United States

Approximately 141,000 patients will develop colorectal cancer each year and 45% will have positive lymph nodes, one of the most significant predictors of survival. Now there is evidence that systemic chemotherapy with fluorouracil (FU) and leucovorin, levamisole, or FU and leucovorin with decrease recurrence and increase survival for patients with Dukes' C colon cancer. In patients with Dukes' B or C rectal cancer, combined radiation and FU increase survival and decrease local and distal recurrence.

Topics: Adjuvants, Immunologic; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Forecasting; Humans; Infusions, Intravenous; Leucovorin; Levamisole; Lymph Nodes; Lymphatic Metastasis; Neoplasm Recurrence, Local; Portal Vein; Prognosis; Radiotherapy, Adjuvant; Rectal Neoplasms; Survival Rate

Topics: Animals; Antimetabolites, Antineoplastic; Colonic Neoplasms; Colorectal Neoplasms; Floxuridine; Fluorouracil; Humans; Leucovorin

The prognosis for patients with cancer of the colon is dubious. An intendedly curative colon resection is performed in two-thirds of these patients, but half of them will subsequently die from metastatic disease. Randomized trials of adjuvant therapy with fluorouracil in combination with levamisole or leucovorin have shown significant benefit in terms of increased disease-free survival and overall survival. In 1990 adjuvant treatment was recommended as routine therapy in high risk patients in USA. A number of European countries are routinely treating high risk patients with Dukes' C coloncarcinoma. The recommendations are based on results from several cooperative trials reviewed in this article. Treatment related toxicity accelerates with increasing age but was acceptable in the reviewed trials. Adjuvant therapy is widely accepted as an important supplement to surgery in high risk patients. A Conference on the results and experiences now available should take place in the near future in order to establish a national consensus on adjuvant chemotherapy in Denmark. Patients with resected Dukes' C coloncarcinoma should receive adjuvant chemotherapy including 5-fluorouracil and leucovorin. Randomized trials are needed to establish the most effective regimens but "no-treatment" controls are no longer ethically acceptable.

Topics: Adjuvants, Immunologic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Levamisole; Prognosis

Topics: Antinematodal Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Levamisole

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

An important advance in cancer treatment has been made in recent years with the finding that adjuvant therapy can significantly improve the survival of patients with colorectal cancer. In patients with resected lymph node-positive colon carcinomas (TNM stage 3), adjuvant 5-fluorouracil and levamisole produced an unequivocal survival advantage that established this combination as the standard of clinical practice. Given that biochemical modulation of fluorouracil by leucovorin can increase response rates in advanced disease, this combination is undergoing evaluation as an adjuvant treatment. Preliminary results indicate that 5-fluorouracil and leucovorin are effective in reducing disease relapse; however, the effect of this regimen on patient survival rates awaits extended follow-up. In the treatment of stages 2 and 3 rectal cancer, significant reductions in local recurrence and death rates have been achieved with the combination of 5-fluorouracil and radiation therapy. Immunologic approaches and newer chemotherapeutic agents may further improve patient outcome and are under investigation, as are efforts to reduce the toxic effects of cancer chemotherapy. Increased understanding of the biology of these diseases is likely to yield prognostic markers capable of identifying subgroups of earlier stage patients at high risk of disease relapse who may also benefit from adjuvant therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Immunotherapy; Leucovorin; Levamisole; Lymphatic Metastasis; Prognosis; Radiotherapy, Adjuvant; Rectal Neoplasms

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

The recurrence-free and overall survival of patients with colon carcinoma in UICC stage III can be improved under a postoperative chemotherapy with 5-fluorouracil combined with the unspecific immune-modulator levamisole. The pharmacological interaction of both components is however disputed. The point is whether the therapeutic effect is achieved only through a high dose monotherapy with 5-FU or whether it can also be achieved by the specific modulation of the 5-FU with folinic acid. Possibly the prognosis for a subgroup of patients in stage II (Dukes B2) could be improved with this combination of drugs. Additionally, there are clinical experiences that the postoperative tumor cell vaccination (ASI) or the treatment with monoclonal antibodies against tumor-associated antigens (CA17-1A) might reveal more specific possibilities in immunotherapy than are provided with levamisole so far. An answer to these questions can therefore only be given by well designed and performed prospective trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Immunotherapy; Leucovorin; Levamisole; Neoplasm Staging; Survival Rate

Colorectal cancer is one of the leading causes of death in western countries. The prognosis is strongly correlated to the TNM-staging system and patients with stage T3-4 and/or N positive disease have a high risk for local or distant relapse. It is now widely accepted that patients with stage III disease should be offered postoperative adjuvant chemotherapy with 5-fluorouracil (5-FU) and levamisole by which cancer related death is reduced by 32%. The use of 5-FU plus folinic acid is based on the experience gathered in metastatic disease where its superiority over 5-FU alone has been proven in randomized trials. In the adjuvant setting, however, this regimen has only been studied in comparison to untreated controls of combined stage II and stage III patients. Due to different patient selection criteria, data are currently not directly comparable to standard 5-FU/levamisole and the results of the intergroup trial 0089 have to mature. Regional short term adjuvant treatment (7 days) seems to be as effective as long term systemic therapy (12 months). Knowledge has been accumulated within at least 8 randomized trials and the NSABP-CO2 trial, with more than 1000 patients, is now demonstrating improved survival with regional therapy applied shortly after curative resection. The EORTC has just started to randomize patients to receive systemic vs. regional therapy or both modalities and will hopefully clarify the role of either strategy. Immunotherapy with autologous tumor cell-BCG or monoclonal antibody treatment also improves patients survival and is currently investigated in randomized comparison to standard 5-FU/levamisole.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Immunotherapy; Leucovorin; Levamisole; Mitomycin; Randomized Controlled Trials as Topic

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Immunotherapy; Interferons; Interleukin-2; Leucovorin; Phosphonoacetic Acid

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colonic Neoplasms; Fluorouracil; Humans; Interferons; Leucovorin; Methotrexate; Neoplasm Metastasis; Phosphonoacetic Acid; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Randomized Controlled Trials as Topic

In the HCT 116 human colon carcinoma cell line, dipyridamole, an inhibitor of nucleoside transport, increases the toxicity of 5-fluorouracil (5-FU) in a dose-dependent manner. While dipyridamole inhibits thymidine transport, interference with thymidine salvage did not appear to be a critical factor. Dipyridamole altered 5-FU metabolism, producing a selective increase in fluorodeoxyuridine monophosphate levels by blocking the efflux of fluorodeoxyuridine. Deoxyuridine monophosphate levels were greatly increased when cells were exposed to 5-FU alone, and were even larger with the addition of dipyridamole. Dipyridamole did not alter the absolute amount of 5-FU incorporated into either RNA or DNA. Exposure to either 5-FU or dipyridamole alone was associated with the generation of alkaline labile sites in newly synthesized DNA. Concurrent exposure to 5-FU with dipyridamole resulted in a striking increase in the alkaline labile sites. Thus, increased DNA damage appears to correlate with the enhanced cytotoxicity of this combination. The results of a clinical trial evaluating concurrent intravenous infusion of 5-FU with dipyridamole over 72 hours are reviewed. At maximally tolerated doses of infusional dipyridamole, the steady-state concentration of bioactive, non-protein-bound drug is in the range of 25 nM. While this concentration may be sufficient to perturb thymidine salvage in some cell types, it is 20-fold lower than the optimal concentration of bioactive dipyridamole needed to modulate 5-FU toxicity, metabolism and DNA damage in the HCT 116 tissue culture model. In addition, an unexpected pharmacokinetic interaction was seen: dipyridamole increased 5-FU clearance and decreased its steady-state plasma concentration. It remains to be determined whether dipyridamole with 5-FU alone or with leucovorin will translate into an improved therapeutic outcome.

Topics: Colonic Neoplasms; Deoxyuridine; Dipyridamole; DNA Damage; DNA, Neoplasm; Drug Interactions; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Methotrexate; Nucleosides; Nucleotides; RNA, Neoplasm; Thymidine; Tumor Cells, Cultured; Uridine Monophosphate

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Levamisole; Portal Vein; Prospective Studies; Randomized Controlled Trials as Topic

Topics: Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Methotrexate; Phosphonoacetic Acid; Rectal Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Cytarabine; Dipyridamole; Drug Interactions; Etoposide; Fluorouracil; Humans; Leucovorin; Methotrexate

Topics: Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Levamisole; Postoperative Care; Recurrence; Semustine

In vitro results have clearly demonstrated that leucovorin (LV) can enhance the growth inhibitory effects of 5-fluorouracil (5FU) but in vivo potentiation of the antitumor effect of 5FU by LV has not yet been defined in animal models. The antitumor effect and the toxicity of the LV-5FU combination was studied in mice bearing the colon carcinomas, Colon 26 and Colon 38. Mice were treated weekly with 5FU at the maximum tolerated dose (100 mg/kg) alone or with LV at different doses and schedules. Pretreatment with LV followed 1 hr later by a second LV injection together with 5FU clearly potentiated the antitumor effect of 5FU in both murine tumor lines. Comparable results were obtained with total LV doses of 100 and 200 mg/kg. The effect of 5FU pretreatment was studied by randomization of 5FU pretreated Colon 38-bearing mice in 2 groups, one treated with 5FU and the other with LV-LV + 5FU. Again, LV potentiated the effect of 5FU. Also in a Colon 38 tumor which had developed resistance against 5FU and which was reimplanted, LV potentiated the antitumor activity of 5FU. Weight loss of the combination was slightly higher than for 5FU alone. A moderate leukopenia (nadir 40%) and mild anemia were observed, which were less than for 5FU alone. The combination did not cause thrombocytopenia. In conclusion, LV can potentiate the therapeutic efficacy of 5FU in murine colon carcinoma.

Topics: Adenocarcinoma; Animals; Carcinoma; Colonic Neoplasms; Disease Models, Animal; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Forecasting; Humans; Leucovorin; Rectal 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

Fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab is the standard second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) who are refractory or intolerant to fluoropyrimidines and oxaliplatin. However, the benefits of incorporating fluoropyrimidines into second-line chemotherapy for patients with mCRC who are refractory to fluoropyrimidines are unknown.. We retrospectively evaluated patients with mCRC who were administered irinotecan plus bevacizumab or FOLFIRI plus bevacizumab as second-line chemotherapy at a single institution from January 2010 to April 2020. We compared the efficacy and safety of irinotecan plus bevacizumab (IRI group) with those of FOLFIRI plus bevacizumab (FOLFIRI group).. Of the 255 enrolled patients, 107 (IRI/FOLFIRI group, 31/76 patients) were eligible for analysis. After a median follow-up of 13.1 months (range 1.2-48.4) and 14.3 months (range 0.9-46.5) for the IRI and FOLFIRI groups, respectively, the median progression-free survival was 6.4 months and 5.8 months [adjusted hazard ratio (aHR), 0.82; 95% confidence interval (CI) 0.50-1.34, p = 0.44] and the median overall survival was 16.6 months and 16.5 months (aHR, 1.01; 95% CI 0.59-1.69; p = 0.97) in the IRI and FOLFIRI groups, respectively. All-grade nausea, stomatitis, neutropenia, thrombocytopenia, Grade 3/4 neutropenia, and febrile neutropenia occurred more frequently in the FOLFIRI group than in the IRI group.. Our study suggests omitting fluorouracil from FOLFIRI plus bevacizumab as the second-line chemotherapy decreases adverse events without affecting the treatment efficacy in patients with mCRC who are refractory to fluoropyrimidines. Further randomized prospective studies are warranted to validate our result.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neutropenia; Rectal Neoplasms; Retrospective Studies

Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients.. The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled.. The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2.. No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Frailty; Humans; Leucovorin; Neoplasm Staging; Oxaliplatin

Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer.. This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy.. From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging

In patients with RAS wild-type metastatic colorectal cancer, depth of response (DpR) has gained importance as a novel end-point in clinical trials. We investigated the overall DpR, as well as the prognostic and predictive impact of DpR to induction therapy (six cycles of 5-fluorouracil, leucovorin [FU/FA], oxaliplatin [FOLFOX] and panitumumab [Pmab]) on consecutive maintenance therapy (FU/FA plus Pmab or FU/FA alone) in patients treated within the PanaMa trial.. Central radiological assessment was performed according to RECIST 1.1. DpR was defined as percentage change in tumour diameter within defined time intervals (induction therapy, maintenance therapy, total course of therapy). For prognostic and predictive analyses, median DpR (

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Panitumumab; Rectal Neoplasms

Napabucasin is an investigational, orally administered reactive oxygen species generator bioactivated by intracellular antioxidant NAD(P)H:quinone oxidoreductase 1 that has been evaluated in various solid tumors, including metastatic colorectal cancer (mCRC). Phosphorylated signal transducer and activator of transcription 3 (pSTAT3) is hypothesized to predict response in napabucasin-treated patients with mCRC.. In the multi-center, open-label, phase III CanStem303C (NCT02753127) study, adults with histologically confirmed mCRC that progressed on first-line fluoropyrimidine plus oxaliplatin ± bevacizumab were randomized to twice-daily napabucasin plus FOLFIRI (napabucasin) or FOLFIRI alone (control). The primary endpoint was overall survival (OS) in the general study population and in patients with pSTAT3-positive tumors (biomarker-positive).. In the general study population (napabucasin, n = 624; control, n = 629), median OS was 14.3 months for napabucasin and 13.8 months for control (hazard ratio [HR], 0.976, one-sided P = .74). Overall, 44% of patients were biomarker-positive (napabucasin, n = 275; control, n = 272). In the biomarker-positive population, median OS was 13.2 months for napabucasin and 12.1 months for control (HR, 0.969; one-sided P > .99). In the control arm, median OS was shorter for biomarker-positive versus biomarker negative patients (12.1 vs. 18.5 months; HR, 1.518; nominal 2-sided P = .0002). The most common treatment-emergent adverse events (TEAEs) were diarrhea (napabucasin, 84.6%; control, 53.9%), nausea (60.5%, 50.5%), vomiting (41.2%, 29.3%), and abdominal pain (41.0%, 25.2%). Grade ≥3 TEAEs occurred in 73.8% of napabucasin-treated and 66.7% of control-treated patients, most commonly diarrhea (21.2%, 7.0%), neutrophil count decreased (13.7%, 19.2%), and neutropenia (13.3%, 15.2%). Safety was similar in biomarker-positive patients.. In patients with previously treated mCRC, adding napabucasin to FOLFIRI did not improve OS. Results from the control arm indicate that pSTAT3 is an adverse prognostic factor in mCRC.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms

Differential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that is easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer.. Individual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab+FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses.. Patients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter ( P <0.001) median progression-free survival (PFS) of 7.27 months (95% CI, 6.12-7.96 mo) and overall survival (OS) of 16.0 months (95% CI, 13.8-18.2 mo) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95% CI, 8.75-10.89 mo) and OS of 22.4 months (95% CI, 20.1-26.7 mo), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (hazard ratio, 4.17; 95% CI, 2.49-6.99; P <0.001) and shorter OS (hazard ratio, 2.57; 95% CI, 1.64-4.01; P <0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts.. Tumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with metastatic colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Oxaliplatin; Prognosis; Rectal Neoplasms; Treatment Outcome

Analysis of methylation markers in liquid biopsies is a promising technique for the follow-up of patients with metastatic colorectal cancer (mCRC), because they can be used in all patients, regardless of their mutational status. Therefore, we studied the value of NPY methylation analysis in circulating tumor DNA (ctDNA) for accurate response monitoring in patients with mCRC in the PANIB trial.. The PANIB trial was a randomized phase II trial designed to compare FOLFOX plus panitumumab and FOLFOX plus bevacizumab in patients with RAS wild-type unresectable mCRC. The results of sequential liquid biopsies were correlated with results of imaging.. Forty patients were included from six Belgian hospitals. Analysis of the liquid biopsies revealed that higher baseline levels of methylated ctDNA was associated with a significantly shorter overall survival [HR, 1.015; 95% confidence interval (CI), 1.005-1.025; P = 0.002]. Furthermore, 37 patients provided at least two liquid biopsies. Thirty-one of them showed a decrease in the methylation ratio after the start of therapy, which corresponded with stable disease or response on imaging at the first evaluation. When comparing the panitumumab and bevacizumab arm, significantly higher objective response and early tumor shrinkage rates were observed in the panitumumab arm (P = 0.048 and 0.015, respectively). However, due to a small study population, the trial was underpowered to detect a significant difference in survival.. The results of this study confirm that baseline methylated ctDNA is a prognostic marker and indicate that NPY methylation is a promising marker for response monitoring in patients with mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Panitumumab; Rectal Neoplasms

Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody-drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated.. Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression.. Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm.. In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Prognosis; Rectal Neoplasms

AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC.. Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg).. DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup.. DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms; Transcriptome

For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined.. To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer.. Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022).. Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days.. The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate.. In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%).. Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population.. ClinicalTrials.gov Identifier: NCT02394795.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; ErbB Receptors; Female; Fluorouracil; Humans; Leucovorin; Male; Oxaliplatin; Panitumumab; Vascular Endothelial Growth Factors

In clinical trials, the assessment of safety is traditionally focused on the overall rate of high-grade and serious adverse events (AEs). A new approach to AEs evaluation, taking into account chronic low-grade AEs, single patient's perspective, and time-related information, such as ToxT analysis, should be considered especially for less intense but potentially long-lasting treatments, such as maintenance strategies in metastatic colorectal cancer (mCRC).. We applied ToxT (Toxicity over Time) evaluation to a large cohort of mCRC patients enroled in randomised TRIBE, TRIBE2, and VALENTINO studies, in order to longitudinally describe AEs throughout the whole treatment duration and to compare AEs evolution over cycles between induction and maintenance strategies, providing numerical and graphical results overall and per single patient. After 4-6 months of combination therapy, 5-fluorouracil/leucovorin (5-FU/LV) + bevacizumab or panitumumab was recommended in all studies except for the 50% of patients in the VALENTINO trial who received panitumumab alone.. Out of 1400 patients included, 42% received FOLFOXIRI (5-FU/LV, oxaliplatin, and irinotecan)/bevacizumab, 18% FOLFIRI/bevacizumab, 24% FOLFOX/bevacizumab, 16% FOLFOX/panitumumab. Mean grade of general and haematological AEs was higher in the first cycles, then progressively decreasing after the end of induction (p < 0.001), and always remaining at the highest levels with FOLFOXIRI/bevacizumab (p < 0.001). Neurotoxicity became more frequent over the cycles with late high-grade episodes (p < 0.001), while the incidence but not the grade of hand-and-foot syndrome gradually increased (p = 0.91). Anti-VEGF-related AEs were more severe in the first cycles, then setting over at low levels (p = 0.03), while anti-EGFR-related AEs still affected patients during maintenance.. Most of chemotherapy-related AEs (except for HFS and neuropathy) reach the highest level in the first cycles, then decrease, probably due to their active clinical management. Transition to maintenance allows relief from most AEs, especially with bevacizumab-based regimens, while anti-EGFR-related AEs may persist.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Panitumumab; Rectal Neoplasms

In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points.. Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52;. To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of

Topics: Adenosine Triphosphate; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Prospective Studies; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest.. PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy.. In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis.. In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Panitumumab; Treatment Outcome

Anti-EGFR antibodies plus doublet chemotherapy is the standard of care in RAS/BRAF wild-type metastatic colorectal cancer (mCRC). No phase-3 level of evidence is available to guide treatment de-escalation after anti-EGFR-based first-line. Several randomised clinical trials investigated de-intensification strategies with 5-fluorouracil/leucovorin (5-FU/LV) and/or anti-EGFR.. We performed an individual patient data pooled analysis of Valentino, Panama, MACRO-2, COIN-B trials including RAS wild-type mCRC patients who received first-line therapy with FOLFOX plus panitumumab or cetuximab followed by pre-specified maintenance strategy. Only patients who started maintenance according to the assigned arm were included. Patients were categorised by type of maintenance (i.e. 5-FU/LV, anti-EGFR or 5-FU/LV + anti-EGFR). Progression-free survival (PFS) and overall survival (OS) were calculated from the start of maintenance; toxicity was evaluated for the maintenance treatment period.. A total of 518 patients were included in the pooled analysis. Overall, 123, 185 and 210 patients received maintenance with 5-FU/LV, anti-EGFR, 5-FU/LV + anti-EGFR, respectively. Median PFS was 5.6, 6.0 and 9.0 (P = 0.009) and OS was 25.7, 24.0 and 28.0 months (P = 0.134) in 5-FU/LV, anti-EGFR and 5-FU/LV + anti-EGFR arms, respectively. Monotherapy maintenance (either 5-FU/LV or anti-EGFR) was inferior to combination in terms of PFS (hazard ratios [HR] 1.26, P = 0.016) and non-significantly trending also in OS (HR 1.20, P = 0.111). An increase of overall any grade and grade ≥ 3 AEs and selected AEs was reported in combination compared to either 5-FU/LV or anti-EGFR arms.. This pooled analysis including four randomised phase II supports the use of 5-FU/LV plus anti-EGFR as the preferred maintenance regimen. Data provide rational for a more individualised maintenance treatment approach based on tumour and patients features.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Rectal Neoplasms

The PanaMa trial demonstrated significant benefit in progression-free survival with the addition of panitumumab (Pmab) to fluorouracil and folinic acid (FU/FA) as maintenance therapy following first-line induction therapy with FOLFOX/Pmab in patients with RAS wild-type metastatic colorectal cancer. Here, we report health-related quality of life (HRQOL) analyses from the PanaMa trial.. HRQOL outcomes were evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) at every cycle of therapy until disease progression/death. HRQOL outcomes were mean and individual changes in EORTC QLQ-C30 from baselines (before induction therapy and before maintenance therapy) to each cycle of treatment. Comparative analyses were performed by randomisation status and treatment arm for induction- and maintenance-therapy, respectively. The trial is registered with clinicaltrials.gov (NCT01991873).. At least one HRQOL questionnaire was completed by a total of 349/377 (93%) patients who received induction therapy, and by 237/248 (96%) patients who were randomised and received maintenance therapy. During induction therapy, most HRQOL dimensions remained stable or showed improvement, while appetite loss and diarrhoea significantly deteriorated. During maintenance therapy, HRQOL dimensions remained stable, while those that deteriorated during induction therapy showed significant improvement, without significant differences between the treatment arms.. Maintenance therapy improves HRQOL dimensions that initially deteriorated during induction therapy while stabilising HRQOL in other dimensions. The addition of Pmab to FU/FA as maintenance therapy in patients with RAS wild-type metastatic colorectal cancer prolongs progression-free survival without negative impact on HRQOL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Panitumumab; Quality of Life; Rectal Neoplasms

Triplet chemotherapy might be more effective than doublet chemotherapy in metastatic colorectal cancer (mCRC), but it may also be marked by increased toxicity. To investigate whether. Seventy patients with mCRC were randomly assigned (1:1) to receive FOLFOXIRI plus either. The addition of

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Oxaliplatin; Rectal Neoplasms; Tocotrienols; Young Adult

There are multiple approaches to modeling the relationship between longitudinal tumor measurements obtained from serial imaging and overall survival. Many require strong assumptions that are untestable and debatable. We illustrate how to apply a novel, more flexible approach, the partly conditional (PC) survival model, using images acquired during a phase III, randomized clinical trial in colorectal cancer as an example.. PC survival approaches were used to model longitudinal volumetric computed tomography data of 1,025 patients in the completed VELOUR trial, which evaluated adding aflibercept to infusional fluorouracil, leucovorin, and irinotecan for treating metastatic colorectal cancer. PC survival modeling is a semiparametric approach to estimating associations of longitudinal measurements with time-to-event outcomes. Overall survival was our outcome. Covariates included baseline tumor burden, change in tumor burden from baseline to each follow-up time, and treatment. Both unstratified and time-stratified models were investigated.. Without making assumptions about the distribution of the tumor growth process, we characterized associations between the change in tumor burden and survival. This change was significantly associated with survival (hazard ratio [HR], 1.04; 95% CI, 1.02 to 1.05;. The PC modeling approach offers flexible characterization of associations between longitudinal covariates, such as serially assessed tumor burden, and survival time. It can be applied to a variety of data of this nature and used as clinical trials are ongoing to incorporate new disease assessment information as it is accumulated, as indicated by an example from colorectal cancer.

Topics: Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin

The optimal maintenance strategy after induction chemotherapy with anti-epidermal growth factor receptor antibody for patients with RAS wild-type metastatic colorectal cancer (mCRC) remains to be debated.. To evaluate the efficacy and safety of maintenance therapy with single-agent cetuximab after FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) plus cetuximab induction therapy.. The TIME (Treatment After Irinotecan-Based Frontline Therapy: Maintenance With Erbitux]) (PRODIGE 28 [Partenariat de Recherche en Oncologie Digestive]-UCGI 27 [UniCancer GastroIntestinal Group]) phase 2 noncomparative, multicenter randomized clinical trial was conducted from January 15, 2014, to November 23, 2018, among 139 patients with unresectable RAS wild-type mCRC. The cutoff date for analysis was July 21, 2022.. After first-line induction therapy with 8 cycles of FOLFIRI plus cetuximab, patients without disease progression were randomized (1:1) to biweekly maintenance with cetuximab or observation. On disease progression, the same induction regimen was recommended for 16 weeks followed by further maintenance with cetuximab or observation until disease progression under the full induction regimen.. The primary end point was the 6-month progression-free rate from randomization. Analysis was performed on an intention-to-treat basis. An exploratory biomolecular analysis, using next-generation sequencing, investigated the putative prognostic value of the tumor mutation profile.. Of 214 patients enrolled (141 men [65.9%]; median age, 67 years [range, 23-85 years]), 139 were randomized to receive cetuximab (n = 67; 45 men [67.2%]; median age, 64 years [range, 34-85 years]) or to be observed (n = 72; 50 men [69.4%]; median age, 68 years [23-85 years]). The 6-month progression-free rate was 38.8% ([26 of 67] 95% CI, 27.1%-51.5%) in the cetuximab group and 5.6% ([4 of 72] 95% CI, 1.5%-13.6%) in the observation group. At a median follow-up of 40.5 months (95% CI, 33.6-47.5 months), median progression-free survival (PFS) from randomization was 5.3 months (95% CI, 3.7-7.4 months) in the cetuximab group and 2.0 months (95% CI, 1.8-2.7 months) in the observation group. Median overall survival (OS) was 24.8 months (95% CI, 18.7-30.4 months) in the cetuximab group and 19.7 months (95% CI, 13.3-24.4 months) in the observation group. In an exploratory multivariate analysis, any tumor-activating mutation in the mitogen-activated protein kinase (MAPK) pathway genes was associated with shorter PFS from randomization regardless of treatment group (hazard ratio, 1.63 [95% CI, 1.01-2.62]; P = .04). The most frequent grade 3 or 4 treatment-related toxic effect in the cetuximab group during maintenance therapy was rash (8 of 67 [11.9%]).. The randomized clinical trial did not meet its primary end point but suggests clinically meaningful PFS and OS benefits associated with cetuximab maintenance therapy. However, maintenance cetuximab or treatment breaks after first-line combination FOLFIRI-cetuximab therapy seems inappropriate for patients with MAPK-mutated independently of the side of primary tumor. A more complete assessment of MAPK pathway mutations warrants further investigation to the refine treatment strategy for patients with RAS wild-type mCRC.. ClinicalTrials.gov Identifier: NCT02404935.

Topics: Aged; Cetuximab; Colonic Neoplasms; Disease Progression; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Rectal Neoplasms

The TIMELESS-TIPIN complex protects the replication fork from replication stress induced by chemotherapeutic drugs. We hypothesised genetic polymorphisms of the TIMELESS-TIPIN complex may affect the response, progression-free survival (PFS), and overall survival (OS) of cytotoxic drugs in patients with metastatic colorectal cancer (mCRC).. We analysed data from the MAVERICC trial, which compared FOLFOX/bevacizumab and FOLFIRI/bevacizumab in untreated patients with mCRC. Genomic DNA extracted from blood samples was genotyped using an OncoArray. Eight functional single nucleotide polymorphisms (SNPs) in TIMELESS and TIPIN were tested for associations with clinical outcomes.. In total, 324 patients were included (FOLFOX/bevacizumab arm, n = 161; FOLFIRI/bevacizumab arm, n = 163). In the FOLFOX/bevacizumab arm, no SNPs displayed confirmed associations with survival outcomes. In the FOLFIRI/bevacizumab arm, TIMELESS rs2291739 was significantly associated with OS in multivariate analysis (G/G vs. any A allele, hazard ratio = 3.06, 95% confidence interval = 1.49-6.25, p = 0.004). TIMELESS rs2291739 displayed significant interactions with treatment regarding both PFS and OS.. TIMELESS rs2291739 might have different effects on therapeutic efficacy between oxaliplatin- and irinotecan-based chemotherapies. Upon further validation, our findings may be useful for personalised approaches in the first-line treatment of mCRC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Cell Cycle Proteins; Colonic Neoplasms; DNA Replication; DNA-Binding Proteins; Female; Fluorouracil; Germ-Line Mutation; Humans; Intracellular Signaling Peptides and Proteins; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Survival Rate

The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors.. We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm.. Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW.. Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes.. Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Humans; Japan; Leucovorin; Lymph Node Excision; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Propensity Score; Prospective Studies; Risk Factors; Survival Rate; Tegafur; Treatment Outcome; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Dipeptides; Fluorouracil; Glutamine; Humans; Incidence; Leucovorin; Organoplatinum Compounds; Quality of Life

Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients.. Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events.. We enrolled 102 patients with a median age of 80 years (range, 75-88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, -0.06; P = 0.56) adverse events.. The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Fatigue; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms

The phase III ACHIEVE trial conducted in Japan was one of six prospective studies included in the International Duration Evaluation of Adjuvant Therapy collaboration, which explored whether 3 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) therapy would be noninferior to 6 months of treatment in patients with curatively resected stage III colon cancer. We report the final analyses of survival and long-term safety.. Eligible patients were randomly assigned (1:1) to either 3 or 6 months of adjuvant chemotherapy (modified [m]FOLFOX6 or CAPOX, as selected by the treating physician). Random assignment was stratified according to number of involved lymph nodes, center, regimen, primary site, and age. The primary end point was disease-free survival, assessed in the modified intention-to-treat population. Overall survival (OS) was a secondary end point.. The modified intention-to-treat population comprised 1,291 patients: 641 in the 6-month treatment group and 650 in the 3-month treatment group. Median follow-up for this analysis was 74.7 months. Five-year OS rates were comparable: 87.0% in the 3-month treatment group and 86.4% in the 6-month treatment group (hazard ratio, 0.91; 95% CI, 0.69 to 1.20;. In Asian patients, shortening adjuvant therapy duration from 6 to 3 months did not compromise efficacy and reduced the rate of long-lasting peripheral sensory neuropathy. In this setting, 3 months of CAPOX therapy is an appropriate adjuvant treatment option.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Prospective Studies

The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients' age and sidedness of primary tumour.. The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan-Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.. Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).. In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.. FIRE-3 (NCT00433927).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms; Retrospective Studies

Reactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC).. We analyzed genomic and clinical data from FIRE-3, a phase III trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes.. In total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129; FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06-5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03).. TXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Germ Cells; Humans; Leucovorin; Rectal Neoplasms

This multicenter single-arm, phase II study evaluated the efficacy and safety of uninterrupted panitumumab usage combined with cytotoxic doublets for unresectable/metastatic colorectal cancer (mCRC). Additionally, clinical value of the RAS/BRAF mutation status in circulating cell-free DNA (ccfDNA) was evaluated; this evaluation was measured independently of the protocol treatment. Eligible patients with RAS wild-type mCRC who had received the first-line panitumumab plus FOLFOX treatment were recruited and administered continuous panitumumab combined with FOLFIRI. Progression-free survival (PFS) at 6 months was the primary endpoint, with threshold and expected values of 35% and 50%, respectively. In total, 54 patients were enrolled between October 2017 and October 2019. The crude 6-month PFS rate was 37.0%, with a 4.8-month median PFS. The response rate and disease control rate were 16.7% and 50.0%, respectively. Notably, of the 54 participants, 17 showed RAS/BRAF mutations until the end of the protocol treatment and of the 22 patients with progressive disease as their best response, 10 possessed RAS/BRAF mutations in their plasma ccfDNA at baseline. The median PFS significantly differed among patients harboring tumors with BRAF and RAS mutations and those with wild-type tumors. In conclusion, our study failed to show the expected efficacy of the continuous panitumumab use in the second-line treatment. Liquid biopsy discriminated the duration of PFS according to the mutation status. The effectiveness of continuous treatment with panitumumab should be evaluated in patients with RAS/BRAF wild-type mCRC determined by liquid biopsy at the start of the second-line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell-Free Nucleic Acids; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mutation; Panitumumab; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

Cetuximab in combination with chemotherapy is a standard first-line treatment regimen for patients with metastatic colorectal cancer (mCRC) RAS wild-type (wt); however, the efficacy of cetuximab plus leucovorin, fluorouracil and oxaliplatin (FOLFOX) had never been demonstrated in a prospective, randomized, controlled phase III study. The TAILOR study is the first randomized, multicenter, prospective Phase III study evaluating the addition of cetuximab to FOLFOX in a RAS wt Chinese population and thus providing confirmatory data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Prospective Studies; Rectal Neoplasms

Panitumumab plus FOLFOX (P-FOLFOX) is standard first-line treatment for RAS wild-type (WT) metastatic colorectal cancer. The value of panitumumab rechallenge is currently unknown. We assessed addition of panitumumab to FOLFIRI (P-FOLFIRI) beyond progression to P-FOLFOX in patients with no RAS mutations in liquid biopsy (LB).. In this randomized phase II trial, patients were assigned (3:2 ratio) to second-line P-FOLFIRI (arm A) or FOLFIRI alone (arm B). LB for circulating tumor DNA analysis was collected at study entry and at disease progression. Primary endpoint was 6-month progression-free survival. Two-stage Simon design required 85 patients to be included (EudraCT 2017-004519-38).. Between February 2019 and November 2020, 49 patients were screened (16 RAS mutations in LB detected) and 31 included (18 assigned to arm A and 13 to arm B). The study was prematurely closed due to inadequate recruitment. Serious adverse events were more frequent in arm A (44% vs. 23%). Overall response rate was 33% (arm A) vs. 7.7% (arm B). Six-month progression-free survival rate was 66.7% (arm A) and 38.5% (arm B). Median progression-free survival was 11.0 months (arm A) and 4.0 months (arm B) (hazard ratio, 0.58). At disease progression, RAS or BRAF mutations in LB were found in 4/11 patients (36%) in arm A and 2/10 (20%) in arm B.. The BEYOND study suggests a meaningful benefit of P-FOLFIRI beyond progression to P-FOLFOX in metastatic colorectal cancer patients with WT RAS status selected by LB. This strategy deserves further investigation.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Circulating Tumor DNA; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Fluorouracil; Humans; Leucovorin; Panitumumab; Proto-Oncogene Proteins B-raf; Rectal Neoplasms

The combination of oxaliplatin and fluoropyrimidine for 6 months is one of the standard options for adjuvant therapy for high-risk stage II and III colorectal cancers (CRCs). The optimal duration of oxaliplatin to diminish neurotoxicity without compromising efficacy needs to be clarified.. This open-label, randomized, phase III, noninferiority trial randomly assigned patients with high-risk stage II and III CRC to 3 and 6 months of oxaliplatin with 6 months of fluoropyrimidine groups (3- and 6-month arms, respectively). The primary end point was disease-free survival (DFS), and the noninferiority margin was a hazard ratio (HR) of 1.25.. In total, 1,788 patients were randomly assigned to the 6-month (n = 895) and 3-month (n = 893) arms, and 83.6% in the 6-month arm and 85.7% in the 3-month arm completed the treatment. The neuropathy rates with any grade were higher in the 6-month arm than in the 3-month arm (69.5%. This study suggests that adding 3 months of oxaliplatin to 6 months of capecitabine could be considered an alternative adjuvant treatment for stage III CRC (ClinicalTrials.gov identifier: NCT01092481).

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms

To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC).. Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription.. The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only.. High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Glucosephosphate Dehydrogenase; Humans; Leucovorin; Rectal Neoplasms

The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups.. Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%).. Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points.. In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours.. Trial registration ID (clinicaltrials.gov) NCT01249638.

Topics: Aged; Antimetabolites; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Randomized Controlled Trials as Topic; Rectal Neoplasms

The ability to detect circulating tumor DNA (ctDNA), a novel surrogate for minimal residual disease (MRD) for patients with solid tumors, has significantly evolved over the past decade. Several studies have shown that ctDNA may provide clinical insight into the biological dynamics of MRD. The CIRCULATE-US (NRG-GI008; NCT05174169) trial will aim to address the role of ctDNA for risk stratification to intensify and deintensify adjuvant chemotherapy for patients with early-stage colon cancer.. CIRCULATE-US, a prospective phase 2/3 randomized trial, is investigating the molecular dynamics and prognostic role of ctDNA (evaluated by Natera's Signatera assay) for patients with resected colon cancer. Patients with negative postoperative ctDNA will be enrolled in cohort A and randomized to receive either immediate treatment with 5-fluorouracil and folinic acid or capecitabine plus oxaliplatin (FOLFOX6 or CAPEOX; Arm 1) or serial ctDNA surveillance with delayed adjuvant therapy (Arm 2). Patients randomized to Arm 2 with subsequent positive ctDNA results will be enrolled in cohort B for a second randomization to receive either FOLFOX6/CAPEOX (Arm 3) or 5-fluorouracil, folinic acid, oxaliplatin, and irinotecan (FOLFIRINOX; Arm 4) for 6 months. Patients with positive postoperative ctDNA results will be directly enrolled in cohort B and randomized to receive either FOLFOX6/CAPEOX (Arm 3) or FOLFIRINOX (Arm 4). Patients with stage II or stage IIIC colon cancer with positive ctDNA results (tested as standard of care with commercial testing) will be eligible for enrollment in cohort B. The primary end point for cohort A is time to positive ctDNA status for phase 2 and disease-free survival for phase 3 with a noninferiority design. The primary end point for cohort B is disease-free survival for both phase 2 and phase 3 with a superiority design.. CIRCULATE-US will aim to understand postoperative ctDNA dynamics in early-stage colon cancer and will investigate escalation and de-escalation approaches by using ctDNA status as a surrogate for MRD status.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Circulating Tumor DNA; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Prospective Studies

The addition of aflibercept to the fluorouracil and irinotecan (FOLFIRI) regimen significantly improved clinical outcomes in patients with metastatic colorectal cancer (CRC) previously treated with oxaliplatin. We aimed to investigate the efficacy and safety of second-line FOLFIRI and aflibercept combination in patients with metastatic CRC in real-life experience.. Four hundred and thirty-three patients who treated with FOLFIRI and aflibercept in the second-line were included in the study. The clinical and pathological features of the patients were recorded retrospectively. Survival (overall and progression-free survival [PFS]), response rates, and safety data were analyzed.. The median age was 61. Majority of patients (87.5%) received first-line bevacizumab and 10.1% of patients received anti-epidermal growth factor receptor agents. About 80% of patients had KRAS, 18.6% of patients had NRAS, and 6.4% of patients had BRAF mutations. The median OS was 11.6 months (95% confidence interval [CI], 10.6-12.6) and the median PFS was 6 months (95% CI, 5.5-6.5). About 4.6% of patients had complete response and 30.6% of patients had partial response as best tumor response. Grade 1-2 toxicities were seen in 33.4% of patients, while grade 3-4 toxicities were recorded in 27% of patients. Eight patients (2%) died due to treatment toxicity.. Overall and PFS were similar in routine clinical practice compared to phase III pivotal VELOUR trial. However, response rates were found to be higher. It was observed that there were fewer adverse events compared to the VELOUR trial.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Middle Aged; Rectal Neoplasms; Retrospective Studies

Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties.. To evaluate PTX effects on colon cancer patients treated with chemotherapy.. Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX).. Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group.. PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.

Topics: Aged; Antineoplastic Agents; Cachexia; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Pentoxifylline; Stomatitis; Weight Gain

Oxaliplatin-based adjuvant chemotherapy may be associated with debilitating peripheral sensory neuropathy (PSN) in patients with high-risk stage II colon cancer. This open-label, multicenter, randomized phase III trial was conducted as a prospective pooled analysis to investigate the non-inferiority of 3 versus 6 months of adjuvant oxaliplatin-based chemotherapy.. From 12 February 2014 to 31 January 2017, 525 Asian patients with high-risk stage II colon cancer were randomly assigned to 3- and 6-month treatment arms. The treatment consisted of either modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine combined with oxaliplatin (CAPOX). The primary end point was disease-free survival (DFS). The secondary end points were treatment compliance and safety.. Of the 525 randomized patients, 11 were not treated. Among the 514 participating patients (255 in the 3-month arm; 259 in the 6-month arm), 432 (84%) received CAPOX, and 184 (36%) presented with T4 as a high-risk factor for recurrence. The 3-year DFS rate was 88.2% in the 3-month arm and 87.9% in the 6-month arm [hazard ratio (HR), 1.12; 95% confidence interval (CI), 0.67-1.87]. With CAPOX, the 3-year DFS rate was 88.2% in the 3-month arm and 88.4% in the 6-month arm (HR, 1.13; 95% CI, 0.65-1.96). The discontinuation rate in the 3- and 6-month arms was 10% and 31% for mFOLFOX6 (P = 0.0193), and 15% and 35% for CAPOX (P < 0.0001), respectively. The incidence of grade ≥2 PSN was significantly lower in the 3-month arm than in the 6-month arm (16% and 43%, respectively, P < 0.0001).. Three months of combination therapy presented significantly less grade ≥2 PSN than the respective 6-month regimen. The shortened therapy duration did not affect the 3-year DFS rate, suggesting that a 3-month course of CAPOX can be an effective treatment option.. UMIN Clinical Trials Registry, UMIN000013036 and Japan Registry of Clinical Trials, jRCTs031180128.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Japan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies

Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial.. PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR).. Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed.. Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis

Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Medication Adherence; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Treatment Outcome; Young Adult

In colon cancer (CC), surgery remains the mainstay of treatment with curative intent. Despite several clinical trials comparing open and laparoscopic approaches, data on long-term outcomes for stage III CC are lacking.. This post-hoc analysis of the European PETACC8 randomized phase 3 trial included patients from 340 sites between December 2005 and November 2009, with long follow-up (median 7.56 years). Patients were randomly assigned to FOLFOX or FOLFOX+cetuximab after colonic resection. The surgical approach was left to the referring surgeon's discretion.. Among 2555 patients included, 1796 (70.29%) were operated on by open surgery and 759 (29.71%) by laparoscopy. The 5-year OS rate was better after laparoscopic resection (85.4%, 95%CI 82.5-87.7) than after open surgery (80.2%, 95%CI 78.2-82.0; p = 0.002). The 5-year DFS rate was also better after laparoscopy (p = 0.016). However, in multivariate analysis using a propensity matching, the surgical approach was not found to be an independent prognostic factor for OS or DFS. OS (p = 0.0243) and DFS (p = 0.035) were increased after laparoscopic surgery in KRAS/BRAF WT sub-group CONCLUSION: We showed that laparoscopic resection has comparable long-term outcomes to open surgery in patients with stage III CC. For those with RAS and BRAF WT CC, laparoscopic colectomy may favorably impact survival.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colectomy; Colonic Neoplasms; Disease-Free Survival; Europe; Female; Fluorouracil; Follow-Up Studies; Humans; Laparoscopy; Leucovorin; Male; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Propensity Score; Survival Rate; Treatment Outcome

SCOT was an international, randomized phase 3 trial of 3 months vs 6 months of adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine in patients with colorectal cancer. We sought patients' preferences for 3 months vs 6 months of adjuvant chemotherapy in the SCOT trial.. SCOT participants from Australia and New Zealand completed a validated questionnaire (at 3 and 18 months) to elicit the minimum survival benefits judged necessary to make an extra 3 months of adjuvant chemotherapy worthwhile, based on their experience. Standardized hypothetical scenarios used the following baseline survivals (with 3 months of chemotherapy): life expectancies (LE) of 5 years and 15 years and 5-year survival rates (5YS) of 65% and 85%.. Of the 160 participants, 82 were assigned 3 months adjuvant chemotherapy, and 78 were assigned 6 months. Adjuvant chemotherapy was FOLFOX in 121 (75.6%) and XELOX in 39 (24.4%). Preferences varied substantially and did not differ according to treatment group. The median survival benefits judged necessary to make the extra 3 months of chemotherapy worthwhile were an extra 3 years beyond a LE of 5 years; 3 years beyond a LE of 15 years; 15% beyond a 5YS of 65%; and 5% beyond a 5YS of 85%. Preferences were similar at 3 months and 18 months. Preferences were not predicted by participants' baseline characteristics.. Preferences varied substantially, and the benefits many required to warrant an extra 3 months of adjuvant chemotherapy were larger than the benefits of an extra 3 months of chemotherapy calculated in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) meta-analysis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Life Expectancy; Male; Middle Aged; New Zealand; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Patient Preference; Prospective Studies; Surveys and Questionnaires; Survival Rate

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

The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT).. Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab.. A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III.. S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths.. NCT00112918.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds

Adjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy.. This national, phase III trial (NCT00002019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity. Recruitement began End of January 2020.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Chemotherapy, Adjuvant; Circulating Tumor DNA; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Treatment Outcome; Young Adult

Chemotherapy with oxaliplatin is known to induce sinusoidal obstruction syndrome (SOS). In a previous single-center study, we reported that oxaliplatin-induced increase in splenic volume (SV) is strongly indicative of SOS, and that this increase in SV persisted for > 1 year after completing chemotherapy. The aim of this study was to confirm the oxaliplatin-induced SV change in a multicenter study in patients with stage III colon cancer in Japan.. We enrolled 59 patients who underwent curative resection for stage III colon cancer in the FACOS study in a phase II multi-center clinical study. Participants received mFOLFOX6 or CAPOX as adjuvant chemotherapy. SV change was assessed three times by computed tomographic volumetry: before surgery, on completion of adjuvant chemotherapy, and 1 year after completing adjuvant chemotherapy.. SV on completing and 1 year after chemotherapy was significantly higher than that before surgery (P < 0.001). Oxaliplatin-induced SOS persisted for > 1 year after the completion of adjuvant chemotherapy in half of the patients. There was no difference in 3-year disease-free survival with respect to the presence or absence of increased SV. An increase in SV was observed in 72% of patients treated with mFOLFOX6 and 94% of patients treated with CAPOX (P = 0.13).. This study can be verified the findings observed in our previous single-center study, oxaliplatin-based adjuvant chemotherapy was associated with an increase in SV. Furthermore, this increase can persist for > 1 year. The continuous presence of SOS may have a negative impact on prognosis in patients that develop recurrent disease.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Splenic Diseases

The purpose of this clinical study was to be the first to explore whether ART-123, a recombinant human soluble thrombomodulin, prevents oxaliplatin-induced peripheral neuropathy (OIPN).. This randomized, phase IIa trial enrolled stage II/III colon cancer patients who received adjuvant mFOLFOX6 chemotherapy. Participants were randomly allocated to 3 arms in a double-blind manner: placebo (placebo: days 1-3); 1-day ART (ART-123: day 1, placebo: days 2-3); and 3-day ART (ART-123: days 1-3). ART-123 (380 U/kg/day) or placebo was infused intravenously before each 2-week cycle of mFOLFOX6. OIPN was assessed with the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) score by participants and the NCI Common Terminology Criteria for Adverse Events (NCI-CTCAE) by investigators.. Seventy-nine participants (placebo n = 28, 1-day ART n = 27, 3-day ART n = 24) received study drugs. The least-squares mean FACT/GOG-Ntx-12 scores at cycle 12 from the mixed effect model for repeated measures were 28.9 with placebo, 36.3 with 1-day ART (vs. placebo: 7.3 [95% CI 1.9 to12.8, p = 0.009]), and 32.3 with 3-day ART (vs. placebo: 3.4 [95% CI -.1 to 9.0, p = 0.222]). The cumulative incidence of NCI-CTCAE grade ≥ 2 sensory neuropathy at cycle 12 was 64.3% with placebo, 40.7% with 1-day ART (vs. placebo: -23.5 [95% CI -48.4 to 4.0], p = 0.108), and 45.8% with 3-day ART (vs. placebo: -18.5 [95% CI -44.2 to 9.4], p = 0.264). Common adverse events were consistent with those reported with mFOLFOX6; no severe bleeding adverse events occurred.. ART-123 showed a potential preventive effect against OIPN with good tolerability. A larger study with 1-day ART is warranted. NCT02792842, registration date: June 8, 2016.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Incidence; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Placebos; Recombinant Proteins; Self Report; Severity of Illness Index; Thrombomodulin; Treatment Outcome

Estimates of cancer therapy effects can differ in clinical trials and clinical practice, partly due to underrepresentation of certain patient subgroups in trials. We utilize a hybrid approach, combining clinical trial and real-world data, to estimate the comparative effectiveness of two adjuvant chemotherapy regimens for colon cancer.. We identified patients aged 66 and older enrolled in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer. Similar patients were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, initiating adjuvant chemotherapy with either 5-fluorouracil (5FU) alone or in combination with oxaliplatin (FOLFOX). We used logistic regression to estimate the likelihood of trial enrollment as a function of age, sex, and substage. Using inverse odds of sampling weights (IOSW), we compared 5-year mortality in patients randomized to FOLFOX vs 5FU using weighted Cox proportional hazards regression, the Nelson-Aalen estimator for cumulative hazards, and bootstrapping for 95% confidence intervals (CIs).. There were 690 trial participants and 3834 SEER-Medicare patients. The SEER-Medicare population was older and had a higher proportion of stage IIIB and IIIC patients than the trial. After controlling for differences between populations, the IOSW 5-year HR was 1.21 (0.89, 1.65), slightly farther from the null than the trial estimate (HR = 1.14, 95%CI: 0.87, 1.49).. This study supports mounting evidence of little to no incremental reduction in 5-year mortality for FOLFOX vs 5FU in older adults with stage II-III colon cancer, emphasizing the importance of combining clinical trial and real-world data to support such conclusions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Medicare; Neoplasm Staging; Organoplatinum Compounds; Treatment Outcome; United States

In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.. To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.. This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.. Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.. The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.. The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.. In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.. ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Proportional Hazards Models; Treatment Outcome

Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC).. The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC.. This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery.. A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group.. Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colectomy; Colonic Neoplasms; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Tomography, X-Ray Computed

Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Multidrug Resistance-Associated Protein 2; Neoplasm Proteins; Organoplatinum Compounds; Oxaloacetates; Pharmacogenomic Testing; Polymorphism, Single Nucleotide; Sex Characteristics

Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer.. To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy.. An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018.. Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician.. The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival.. Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02).. The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease.. UMIN Clinical Trials Registry: UMIN000008543.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asian People; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Oxaliplatin; Peripheral Nervous System Diseases

Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer.. Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated.. Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2).. Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Incidence; Japan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Peripheral Nervous System Diseases; Severity of Illness Index; Time Factors; Young Adult

A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients.. Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS.. A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS.. Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Digestive System Surgical Procedures; Disease-Free Survival; Female; Fluorouracil; Humans; Japan; Leucovorin; Lymph Node Excision; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Risk Factors; Time Factors; Withholding Treatment

Microsatellite instable/deficient mismatch repair (MSI/dMMR) metastatic colorectal cancers have been reported to have a poor prognosis. Frequent co-occurrence of MSI/dMMR and BRAFV600E complicates the association.. Patients with resected stage III colon cancer (CC) from seven adjuvant studies with available data for disease recurrence and MMR and BRAFV600E status were analyzed. The primary end point was survival after recurrence (SAR). Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for age, gender, performance status, T stage, N stage, primary tumor location, grade, KRAS status, and timing of recurrence.. Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI/dMMR tumors had significantly longer SAR than did patients with microsatellite stable/proficient MMR tumors (MSS/pMMR) (adjusted hazard ratio [aHR], 0.82; 95% CI [confidence interval], 0.69-0.98; P = 0.029). This finding remained when looking at patients treated with standard oxaliplatin-based adjuvant chemotherapy regimens only (aHR, 0.76; 95% CI, 0.58-1.00; P = 0.048). Same trends for SAR were observed when analyzing MSI/dMMR versus MSS/pMMR tumor subgroups lacking BRAFV600E (aHR, 0.84; P = 0.10) or those harboring BRAFV600E (aHR, 0.88; P = 0.43), without reaching statistical significance. Furthermore, SAR was significantly shorter in tumors with BRAFV600E versus those lacking this mutation (aHR, 2.06; 95% CI, 1.73-2.46; P < 0.0001), even in the subgroup of MSI/dMMR tumors (aHR, 2.65; 95% CI, 1.67-4.21; P < 0.0001). Other factors associated with a shorter SAR were as follows: older age, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence.. In stage III CC patients recurring after adjuvant chemotherapy, and before the era of immunotherapy, the MSI/dMMR phenotype was associated with a better SAR compared with MSS/pMMR. BRAFV600E mutation was a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.. NCT00079274, NCT00265811, NCT00004931, NCT00004931, NCT00026273, NCT00096278, NCT00112918.

Topics: Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome; Young Adult

We tested the association of colon tumour sidedness with prognosis and with molecular subtypes recently shown to be predictive of oxaliplatin benefit in stage III colon cancer.. NSABP/NRG C-07 trial (N=1603) was used to determine association of tumour sidedness with molecular subtypes and recurrence-free survival (RFS) and overall survival (OS).. Sidedness was associated with molecular subtypes except stem-like/CMS4 subtype. Patients with stage III, left-sided tumours showed superior OS but not RFS. Sidedness was not associated with prediction of oxaliplatin benefit when combined with 5-Fu+LV. However, greater benefit from oxaliplatin was observed in a small subset of stage III patients with left-sided, enterocyte-subtype tumours (interaction HR=0.17, P=0.01).. Sidedness was associated with molecular subtypes and was predictive of OS in stage III colon cancer but was not predictive of RFS or oxaliplatin benefit in C-07. Molecular subtypes may provide more predictive value for oxaliplatin benefit than tumour sidedness.

Topics: Biomarkers, Tumor; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Oxaliplatin; Prognosis; Survival Analysis; Treatment Outcome

Adjuvant chemotherapy with oxaliplatin combined with a fluoropyrimidine derivative is widely accepted as standard therapy for patients with stage III colon cancer, since few clinical data are available for Japanese patients. The FACOS trial investigated the tolerability of modified FOLFOX6 (mFOLFOX6) and XELOX regimens in Japanese colon cancer patients.. Twelve cycles of mFOLFOX6 or 8 cycles of XELOX were given to patients with eligibility: stage III curatively resected colon cancer, performance status of 0-1, age from 20 to 75 years, and adequate organ function. The primary endpoint was 3-year disease-free survival. Secondary endpoints were the incidence of adverse events (AEs) and the completion rate of study therapy.. From April 2010 to April 2014, a total of 132 patients were enrolled. Safety was analyzed in 130 patients, with finalized data from 73 patients receiving mFOLFOX6 and 57 patients receiving XELOX. A total of 130 patients (100%) experienced AEs (any grade), and 52 patients (40.0%) experienced AEs of grade ≥ 3. No significant difference in the frequency of grade ≥ 3 AEs was observed between mFOLFOX6 and XELOX groups. Continuation of the planned cycle rate of protocol treatment was 69.9% in the mFOLFOX6 group and 68.4% in the XELOX group. Treatment was discontinued because of AEs in 14 patients (19.2%) in the mFOLFOX6 group and 8 (14.0%) in the XELOX group. Mean relative dose intensity for oxaliplatin was 78.0% in the mFOLFOX6 group and 82.8% in the XELOX group.. As adjuvant chemotherapy for stage III colon cancer, mFOLFOX6/XELOX regimens are acceptable.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Withholding Treatment

Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.. We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.. After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).. Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Intention to Treat Analysis; Leucovorin; Male; Medication Adherence; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Prospective Studies; Randomized Controlled Trials as Topic; Young Adult

Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Italy; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Time Factors; Treatment Outcome

Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines ± oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3-month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Time Factors; Treatment Outcome

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; CpG Islands; Disease-Free Survival; DNA Methylation; DNA Mismatch Repair; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Phenotype; Prognosis

The NORDIC-VII study is a randomised phase III trial of cetuximab plus continuous or intermittent fluorouracil, folinic acid, and oxaliplatin (Nordic FLOX) vs FLOX alone in first-line treatment of metastatic colorectal cancer. The present report presents an updated and final survival analysis with BRAF and extended RAS mutational status, 5 years after the primary analysis.. A total of 566 patients were included in the intention-to-treat (ITT) population of the NORDIC-VII study. Updated survival status was obtained from 176 patients who were alive in the primary survival analyses. Samples from 223 tumours previously found to be KRAS (exon 2) and BRAF (V600E) wild-type, were re-analysed for KRAS (exons 3 and 4) and NRAS (exons 2-4) mutations.. Including the extended RAS analyses, RAS and BRAF mutational status was available from 457 patients (81% of the ITT population). RAS was mutated in 46% and BRAF in 12% of the tumours. RAS and BRAF, if mutated, were negative prognostic factors. The updated analyses confirmed the finding of the primary report that cetuximab did not provide any additional benefit when added to FLOX in patients with RAS/BRAF wild-type tumours, neither on progression-free nor overall survival. However, the outcomes in a subset of patients, which, after the first eight treatment cycles, received cetuximab alone, suggested a beneficial effect of cetuximab monotherapy.. Adding cetuximab to Nordic FLOX did not provide any clinical benefit, but the data suggested an effect of cetuximab monotherapy in patients with RAS/BRAF wild-type tumours in the NORDIC-VII cohort. The data were compatible with a negative interaction between cetuximab and the Nordic FLOX chemotherapy backbone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Female; Fluorouracil; GTP Phosphohydrolases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Membrane Proteins; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Rectal Neoplasms; Survival Rate; Young Adult

The association of biomarkers with patient survival after recurrence (SAR) of cancer is poorly understood but may guide management and treatment.. To determine the association of DNA mismatch repair (MMR) status and somatic mutation in the B-Raf proto-oncogene (c.1799T>A [V600E]; BRAFV600E) or exon 2 of the KRAS proto-oncogene (KRAS) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant chemotherapy.. Patients with resected stage III colon cancers were randomized to adjuvant FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) chemotherapy with or without cetuximab (North Central Cancer Treatment Group N0147 trial) or adjuvant FOLFOX chemotherapy with or without bevacizumab (National Surgical Adjuvant Breast and Bowel Project C-08 trial). Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features and time to recurrence (data collected February 10, 2004, to August 7, 2015).. The primary study outcome was survival after recurrence of cancer. A secondary outcome measure was the effect of the site of the primary tumor on the association of biomarkers with SAR.. Among 871 patients with cancer recurrence in the N0147 trial (472 men [54.2%] and 399 women [45.8%]; mean [SD] age, 57.8 [11.2] years) and 524 in the C-08 trial (269 men [51.3%] and 255 women [48.7%]; mean [SD] age, 57.0 [11.7] years), multivariable analysis revealed that patients whose tumors had deficient vs proficient MMR had significantly better SAR (adjusted hazard ratio [AHR], 0.70; 95% CI, 0.52-0.96; P = .03). Patients whose tumors harbored mutant BRAFV600E (AHR, 2.45; 95% CI, 1.85-3.25; P < .001) or mutant KRAS (AHR, 1.21; 95% CI, 1.00-1.47; P = .052) had worse SAR compared with those whose tumors had wild-type copies of both genes, although only results for BRAFV600E achieved statistical significance. Significant interactions were found for MMR (P = .03) and KRAS (P = .02) by primary tumor site for SAR. Improved SAR was observed for patients with deficient MMR tumors of the proximal vs distal colon (AHR, 0.57; 95% CI, 0.40-0.83; P = .003), and worse SAR was observed for tumors of the distal colon with mutant KRAS in codon 12 (AHR, 1.76; 95% CI, 1.30-2.38; P < .001) and codon 13 (AHR, 1.76; 95% CI, 1.08-2.86; P = .02).. In patients with recurrence of stage III colon cancer, deficient MMR was significantly associated with better SAR, and this benefit was limited to primary tumors of the proximal colon. Mutations in BRAFV600E were significantly associated with worse SAR, and worse SAR for BRAFV600E or KRAS mutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence.. clinicaltrials.gov Identifiers: NCT00079274 and NCT00096278.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Cetuximab; Colonic Neoplasms; DNA Mismatch Repair; DNA Mutational Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Proportional Hazards Models; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Analysis

RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer.. Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested.. Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations.. Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting.. This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins B-raf; ras Proteins; Young Adult

The prognostic value of BRAF and KRAS mutations within microsatellite-unstable (MSI) and microsatellite-stable (MSS) subgroups of resected colon carcinoma patients remains controversial. We examined this question in prospectively collected biospecimens from stage III colon cancer with separate analysis of MSI and MSS tumors from patients receiving adjuvant FOLFOX +/- cetuximab in two adjuvant therapy trials.. Three groups were defined: BRAF Mutant, KRAS Mutant, and double wild-type. The analytic strategy involved estimation of study-specific effects, assessment of homogeneity of results, and then analysis of pooled data as no differences in patient outcome were found between treatment arms in both trials. Associations of mutations with patient outcome were analyzed, and multivariable models were adjusted for treatment and relevant factors.. Four thousand four hundred eleven tumors were evaluable for BRAF and KRAS mutations and mismatch repair status; 3934 were MSS and 477 were MSI. In MSS patients, all BRAF V600E mutations (hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.23 to 1.92, P < .001), KRAS codon 12 alterations, and p.G13D mutations (HR = 1.60, 95% CI = 1.40 to 1.83, P < .001) were associated with shorter time to recurrence (TTR) and shorter survival after relapse (SAR; HR = 3.02 , 95% CI = 2.32 to 3.93, P < .001, and HR = 1.20, 95% CI = 1.01 to 1.44, P = .04, respectively). Overall survival (OS) in MSS patients was poorer for BRAF-mutant patients (HR = 2.01, 95% CI = 1.56 to 2.57, P < .001) and KRAS-mutant patients (HR = 1.62, 95% CI = 1.38 to 1.91, P < .001) vs wild-type. No prognostic role of KRAS or BRAF mutations was seen in MSI patients. Furthermore, no interaction was found between treatment arm (with or without cetuximab) and KRAS and BRAF mutations for TTR or OS in MSS patients.. In a pooled analysis of resected stage III colon cancer patients receiving adjuvant FOLFOX, BRAF or KRAS mutations are independently associated with shorter TTR, SAR, and OS in patients with MSS, but not MSI, tumors. Future clinical trials in the adjuvant setting should consider these mutations as important stratification factors.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Survival Rate; Time Factors; Young Adult

The optimal time to initiate adjuvant chemotherapy after surgery in patients with colon cancer is not clear. We investigated the benefit of combined intraportal chemotherapy administered during radical surgery with adjuvant chemotherapy for treating stage II and III colon cancer.. Patients were randomly assigned to OCTREE arm (intraportal chemotherapy plus mFOLFOX6) or a standard adjuvant chemotherapy arm (mFOLFOX6). The primary study endpoint was disease-free survival. The secondary endpoints included metastasis-free survival, overall survival, and safety.. The intent-to-treat population comprised 237 patients. With a median follow-up of 44 months, the hazard ratio (OCTREE vs mFOLFOX6) was 0.66 (95% confidence interval, 0.43-0.90), a 34% risk reduction in favor of OCTREE (P = 0.016). The 3-year disease-free survival rate was 85.2% for OCTREE and 75.6% for mFOLFOX6 alone (P = 0.030). The 3-year metastasis-free survival rates were 87.6% for OCTREE and 78.0% for mFOLFOX6 (P = 0.035). Patients had lower distant metastatic rate in the OCTREE arm (12.7% vs 22.7%; P = 0.044), when compared with the mFOLFOX6 arm. The 3-year overall survival was no significant difference between 2 arms (P = 0.178). Neutropenia occurred in 12.7% of the patients receiving OCTREE and in 2.5% of the patients receiving mFOLFOX6 (P = 0.003) within 2 weeks of surgery, and grade 3 or 4 toxicity event was no difference between 2 regimens.. Combination of intraoperative intraportal chemotherapy with mFOLFOX6 reduced the occurrence of distant metastases and improved disease-free survival in patients with stage II and stage III colon cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Tomography, X-Ray Computed; Treatment Outcome

Topics: Activities of Daily Living; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Digestive System Surgical Procedures; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Quality of Life; Treatment Outcome

Irinotecan is approved and widely administered to metastatic colorectal cancer (mCRC) patients; however, it can cause severe toxicities including neutropenia and diarrhea. The polymorphisms of genes encoding drug-metabolizing enzymes can play a crucial role in the increased susceptibility of cancer patients to chemotherapy toxicity. Therefore, we plan to explore the effect of the genetic polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) for irinotecan detoxification in mCRC patients. This trial will compare the clinical outcomes and side effects observed in mCRC patients treated with bevacizumab plus 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) with and without UGT1A1 genotyping and irinotecan dose escalation. A total of 400 mCRC patients were randomized into a study group and a control group.. This trial is a prospective, multicenter, randomized clinical trial comparing UGT1A1 promoter polymorphism for irinotecan dose escalation in mCRC patients administered with bevacizumab plus FOLFIRI as the first-line setting. The enrolled patients were randomly assigned to one of two groups, a study group and a control group, on the basis of receiving UGT1A1 genotyping or not. The study group receive a biweekly FOLFIRI regimen, with irinotecan dose escalation based on UGT1A1 genotyping; whereas the control group receive the conventional biweekly FOLFIRI regimen without UGT1A1 genotyping. The clinicopathological features, response rates, toxicity, and progression-free survival or overall survival will be compared between the two groups.. Patients with mCRC undergoing UGT1A1 genotyping may receive escalated doses of irinotecan for a potentially more favorable clinical response and outcome, in addition to comparable toxicities. Such personalized medicine based on genotyping may be feasible for clinical practice.. NCT02256800 . Date of registration: 3 October 2014. Date of first patient randomized: 16 January 2015.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Outcome Assessment, Health Care; Polymorphism, Genetic; Promoter Regions, Genetic; Prospective Studies

Oxaliplatin added to fluorouracil plus leucovorin therapy for patients with colon cancer has been shown to provide significant but modest absolute benefit for disease-free survival. However, acute and chronic neurotoxic effects from this regimen underscore the need for markers that predict oxaliplatin benefit.. To test our hypothesis that molecular subtypes of colon cancer would be associated with differential prognosis and benefit from oxaliplatin added to fluorouracil plus leucovorin therapy.. Participants in the NSABP C-07 trial were divided into discovery (n = 848) and validation (n = 881) cohorts based on the order of tissue block submission. A reestimated centroid using 72 genes was used to determine Colorectal Cancer Assigner subtypes and their association with oxaliplatin benefit in the discovery cohort. The validation cohort was examined with a locked-down algorithm for subtype classification and statistical analysis plan. Post hoc analysis included examination of the entire cohort with Colorectal Cancer Assigner, Colorectal Cancer Subtype (CCS), and Consensus Molecular Subtype (CMS) methods.. Fluorouracil plus leucovorin with or without oxaliplatin.. Percent recurrence-free survival.. Among 1729 patients, 744 (43%) were female and mean (SD) age was 58 (11) years. Although C-07 participants with stage III disease with an enterocyte subtype showed a statistically significant benefit from oxaliplatin in the discovery cohort (hazard ratio, 0.22 [95% CI, 0.09-0.56]; P = .001 [N = 65]), no statistically significant benefit was observed in the validation cohort (hazard ratio, 0.53 [95% CI, 0.22-1.24]; P = .14 [N = 70]). The stemlike subtype was associated with poor prognosis and lack of benefit from oxaliplatin treatment (HR, 0.99 [95% CI, 0.73-1.34]; P = .96 [N = 367]). Examination of the different subtyping methods shows that all 3 methods robustly identified patients with poor prognosis (stemlike, CCS-3, and CMS-4) in both stage II and III.. Patients with stemlike tumors may be appropriate for clinical trials testing experimental therapies because stemlike tumors were robustly identified and associated with a poor prognosis regardless of stage or chemotherapy regimen. The clinical utility of using subtyping for the identification of patients for treatment with oxaliplatin requires validation in independent clinical trial cohorts.. clinicaltrials.gov Identifier: NCT00004931.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Class I Phosphatidylinositol 3-Kinases; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Enterocytes; Female; Fluorouracil; Gene Expression Profiling; Goblet Cells; GTP Phosphohydrolases; Humans; Inflammation; Leucovorin; Male; Membrane Proteins; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Phosphatidylinositol 3-Kinases; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras)

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

Six months of oxaliplatin-based adjuvant chemotherapy is standard of care for radically resected stage III colon cancer and an accepted option for high-risk stage II. A shorter duration of therapy, if equally efficacious, would be advantageous for patients and Health-Care Systems.. TOSCA ['Randomized trial investigating the role of FOLFOX-4 or XELOX (3 versus 6 months) regimen duration and bevacizumab as adjuvant therapy for patients with stage II/III colon cancer] is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III radically resected colon cancer to receive 3 months (arm 3 m) versus 6 months (arm 6 m) of FOLFOX4/XELOX. Primary end-point was relapse-free survival. We present here safety and compliance data.. From June 2007 to March 2013, 3759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX4 and 36% XELOX in either arm. Treatment completion rate without any modification was 35% versus 12% and with delays or dose reduction 52% versus 44% in arm 3 and 6 m. Treatment was permanently discontinued in 8% (arm 3 m) and 33% (arm 6 m). In arm 6 m, 50% of patients discontinuing treatment did so after completing 80% of planned program. Grade 3+ toxicities were higher in arm 6 m than that in 3 m. Grade 2+ neuropathy was 31.2% versus 8.8% (P < 0.0001) while grade 3+ was 8.4 versus 1.3 (P < 0.0001), in arm 3 and 6 m. Seven deaths within 30 days from last treatment administration in arm 6 m and three deaths in arm 3 m were observed (0.3% versus 0.1%, P = 0.34).. TOSCA is the first trial comparing 3 versus 6 months of adjuvant chemotherapy completing accrual within the international initiative of treatment duration evaluation (International Duration Evaluation of Adjuvant, IDEA). High compliance to treatment in control arm will allow a correct assessment of potential differences between the two treatment durations.. NCT00646607.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Patient Compliance

Leucovorin is commonly used as folate supplement in 5-fluorouracil-based chemotherapy, but needs to be converted to active 5,10-methylenetetrahydrofolate (methyleneTHF) intracellularly. This provides for interindividual differences. MethyleneTHF has recently been developed into the stable, distributable drug, Modufolin®. The aim was to compare the concentration of folate metabolites in tumor, mucosa, and plasma of patients with colon cancer after administration of Modufolin® or Isovorin® (levo-leucovorin).. Thirty-two patients scheduled for colon resection were randomized to receive Modufolin® or Isovorin® at dosage of 60 or 200 mg/m². The study drug was given as one i.v. bolus injection after anesthesia. Plasma was collected for pharmacokinetic (PK) analysis before, during, and after surgery. Tissue biopsies were collected at surgery. Folate metabolites were analyzed by LC-MS/MS.. MethyleneTHF and THF concentrations were significantly higher in mucosa (p < 0.01, both dosages) and tumors (p < 0.01, 200 mg/m²) after Modufolin® as compared to Isovorin® administration. The results correlated with PK observations. The Modufolin® to Isovorin® C(max) ratio for methyleneTHF was 113 at 200 mg/m² and 52 at 60 mg/m²; the AUC(last) ratios were 17 and 9, respectively. The THF plasma concentrations were also higher after Modufolin® administration (C(max) ratio 23, AUC(last) ratio 13 at 200 mg/m²; C(max) ratio 15, AUC(last) ratio 11 at 60 mg/m²).. Modufolin® administration resulted in significantly higher methyleneTHF levels than Isovorin® and may potentially increase the efficacy of 5-fluorouracil-based chemotherapy. The results encourage further evaluation of Modufolin® as a substitute to Isovorin® including the potential clinical benefits.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Biotransformation; Colonic Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Injections, Intravenous; Intestinal Mucosa; Levoleucovorin; Male; Middle Aged; Perioperative Period; Prodrugs; Single-Blind Method; Tetrahydrofolates; Tissue Distribution

Although colon cancer (CC) with microsatellite instability (MSI) has a more favorable prognosis than microsatellite stable (MSS) CC, the impact varies according to clinicopathological parameters. We studied how MSI status affects prognosis in a trial-based cohort of stage II and III CC patients treated with 5-fluorouracil (5-FU)/leucovorin or FOLFIRI.. Tissue specimens of 1254 patients were tested for 10 different loci and were classified as MSI-high (MSI-H) when three or more loci were unstable and MSS otherwise. Study end points were overall survival (OS) and relapse-free survival (RFS).. In stage II, RFS and OS were better for patients with MSI-H than with MSS CC [hazard ratio (HR) 0.26, 95% CI 0.10-0.65, P = 0.004 and 0.16, 95% CI 0.04-0.64, P = 0.01). In stage III, RFS was slightly better for patients with MSI-H CC (HR 0.67, 95% CI 0.46-0.99, P = 0.04), but the difference was not statistically significant for OS (HR 0.70, 95% CI 0.44-1.09, P = 0.11). Outcomes for patients with MSI-H CC were not different between the two treatment arms. RFS was better for patients with MSI-H than with MSS CC in the right and left colon, whereas for OS this was significant only in the right colon. For patients with KRAS- and BRAF-mutated CC, but not for double wild-type patients, RFS and OS were significantly better when the tumors were also MSI-H. An interaction test was statistically significant for KRAS and MSI status (P = 0.005), but not for BRAF status (P = 0.14).. Our results confirm that for patients with stage II CC but less so for those with stage III MSI-H is strongly prognostic for RFS and OS. In the presence of 5-FU treatment, stage II patients with MSI-H tumors maintain their survival advantage in comparison with MSS patients and adding irinotecan has no added benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT00026273.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Microsatellite Repeats; Neoplasm Recurrence, Local

Adjuvant FOLFOX is a widely accepted standard therapy for resected colon cancer. The incidence of grade 3-4 peripheral sensory neuropathy (PSN) was 12.4 and 5.7 % in the MOSAIC and Eastern MASCOT trials, while that of grade 3-4 allergic reactions (AR) was 2.9 and 3.1 %, respectively. The JFMC41-1001-C2 trial (JOIN trial) investigated the tolerability of modified FOLFOX6 (mFOLFOX6) in Japanese colon cancer patients.. Twelve cycles of mFOLFOX6 were given to patients with the same eligibility criteria as in the MOSAIC study: stage II or III curatively resected colon cancer, performance status of 0-1, aged 20 years or older, starting mFOLFOX6 within 7 weeks of surgery, and adequate organ function. The primary endpoints were the incidence of PSN persisting for ≥8 days that interfered with daily activities and the incidence of grade 3-4 AR. The target sample size was 800.. From November 2010 to March 2012, 882 patients were enrolled at 198 institutions. Safety was analyzed in 828 patients with finalized data out of 848 patients receiving mFOLFOX6. The incidence of PSN persisting ≥8 days was 3.3 % [95 % confidence interval (CI) 2.2-4.7], while that of grade 3-4 AR was 1.7 % (95 % CI 0.9-2.8). The treatment completion rate was 67.0 %. The median total dosage of oxaliplatin was 811.1 mg/m(2). The overall incidence of grade 3-4 PSN was 5.8 %. Interstitial pneumonitis occurred in one patient. There were no treatment-related deaths.. Adjuvant mFOLFOX6 is tolerable for Japanese patients with colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Young Adult

In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery.. PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial.. NCT01675999 (ClinicalTrials.gov).

Topics: Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds

Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation.. Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy.. Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001).. Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Calcium Compounds; Chronic Disease; Colonic Neoplasms; Double-Blind Method; Fluorouracil; Humans; Leucovorin; Magnesium Compounds; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases

To report the final efficacy findings and biomarker analysis from the NO16968 trial comparing bolus fluorouracil/folinic acid (FU/FA) with capecitabine plus oxaliplatin (XELOX) in resected stage III colon cancer.. After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks, or bolus FU/FA, as the Mayo Clinic or Roswell Park regimens, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS).. The intention-to-treat population comprised 1,886 patients (XELOX, n = 944; FU/FA, n = 942). Seven-year DFS rates were 63% and 56% in the XELOX and FU/FA groups, respectively (hazard ratio [HR], 0.80; 95% CI, 0.69 to 0.93; P = .004). Seven-year OS rates were 73% and 67% in the XELOX and FU/FA groups, respectively (HR, 0.83; 95% CI, 0.70 to 0.99; P = .04). A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. Four hundred ninety-eight patients consented to the biomarker analysis: 242 in the XELOX group and 256 in the FU/FA group. Low tumor expression of dihydropyrimidine dehydrogenase may be predictive for XELOX efficacy; in the XELOX group, for high versus low dihydropyrimidine dehydrogenase expression levels, DFS HR was 2.45 (95% CI, 1.55 to 3.86; P < .001), and OS HR was 2.75 (95% CI, 1.65 to 4.59; P < .001). In the FU/FA group, no statistically significant associations were observed between any tumor biomarker and outcomes.. XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. XELOX should be considered a standard adjuvant treatment option in patients with stage III disease. Tumoral dihydropyrimidine dehydrogenase expression is a promising predictive, and potentially, highly clinically relevant, biomarker for XELOX efficacy requiring further prospective evaluation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Proportional Hazards Models; Treatment Outcome

While adjuvant chemotherapy is preferable for high-risk colon cancer, treatment duration is controversial. Oral uracil and tegafur (UFT)/leucovorin (LV) is widely used as a standard adjuvant chemotherapy for colon cancer in Japan. We conducted a phase III trial to investigate the optimal duration of adjuvant chemotherapy for stage IIB/III colon cancer.. Patients with curatively resected stage IIB/III colon cancer were eligible for enrollment in this trial. Patients were registered within 6 weeks after surgery and were randomly assigned to receive UFT/LV for 28 of 35 days for 6 months in the control group or for 5 consecutive days per week for 18 months in the study group. The primary end point was the disease-free survival (DFS), and the secondary end points were overall survival (OS) and safety.. A total of 1071 patients were registered from 233 centers. A statistically significant difference in DFS was not observed between the study group and the control group; the 5-year DFS was 69% in the study group and 69% in the control group. The 5-year OS was 85% in the study group and 85% in the control group.. Eighteen-month treatment with UFT/LV did not improve DFS or OS compared with 6-month UFT/LV treatment in patients with stage IIB/III colon cancer. The important finding from this study is that not 18 months but 6 months of treatment is enough for postoperative UFT/LV for stage IIB/III colon cancer.. UMIN-CTR C000000245.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Tegafur; Time Factors; Uracil

Adjuvant treatment is still controversially discussed for elderly colon cancer (CC) patients. Our aim was to investigate the benefit of adjuvant treatment for younger (<70 years) and elderly (≥70 years) patients.. The long-term outcome of patients (n=855) enrolled in a randomized controlled trial comparing adjuvant chemotherapy with 5-FU alone, 5-FU plus folinic acid (FA), and 5-FU plus interferon-alpha (IFNa) was compared in younger (<70 years) and elderly (≥70 years) patients using a quotient of each patient's survival time and his expected residual life expectancy (QSL) and a multivariate Cox proportional hazards model.. Eight-year overall survival (OS) rates were 58.3% and 57.4% for younger (n=653) and elderly (n=202) patients, respectively. In elderly patients, 8-year OS rates were 51.4%, 61.8%, and 56.3, and median QSL scores were 0.338, 0.371, and 0.343 for 5-FU (n=59), 5-FU plus FA (n=76), and 5-FU plus IFNa (n=67), respectively. In elderly patients treatment with 5-FU plus FA decreased the risk for an event by 1.5-fold compared to 5-FU (HR=0.657, 95%CI=0.495-0.870, p=0.004) and 5-FU plus INFa (HR=0.685, 95%CI=0.515-0.912, p=0.009).. Our analysis clearly demonstrates for the first time an additional benefit of FA for adjuvant treatment of elderly CC patients. We conclude that this regimen is very safe and effective for adjuvant treatment of elderly patients.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Prospective Studies; Survival Rate; Young Adult

The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) study has demonstrated 3-year disease-free survival (DFS) and 6-year overall survival (OS) benefit of adjuvant oxaliplatin in stage II to III resected colon cancer. This update presents 10-year OS and OS and DFS by mismatch repair (MMR) status and BRAF mutation.. Survival actualization after 10-year follow-up was performed in 2,246 patients with resected stage II to III colon cancer. We assessed MMR status and BRAF mutation in 1,008 formalin-fixed paraffin-embedded specimens.. After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX4) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population, 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR and 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation.. The OS benefit of oxaliplatin-based adjuvant chemotherapy, increasing over time and with the disease severity, was confirmed at 10 years in patients with stage II to III colon cancer. These updated results support the use of FOLFOX in patients with stage III disease, including those with dMMR or BRAF mutation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Female; Fluorouracil; Follow-Up Studies; Glutamic Acid; Humans; Infusions, Intravenous; Injections, Intravenous; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Odds Ratio; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins B-raf; Treatment Outcome; Valine

Cumulative neurotoxicity is a prominent toxicity of oxaliplatin-based therapy. Intravenous calcium and magnesium have been extensively used to reduce oxaliplatin-induced neurotoxicity. This trial was designed to definitively test whether calcium/magnesium decreases oxaliplatin-related neurotoxicity.. In all, 353 patients with colon cancer undergoing adjuvant therapy with FOLFOX (fluorouracil, leucovorin, and oxaliplatin) were randomly assigned to intravenous calcium/magnesium before and after oxaliplatin, a placebo before and after, or calcium/magnesium before and placebo after. The primary end point was cumulative neurotoxicity measured by the sensory scale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20 tool.. There were no statistically significant neuropathy differences among the study arms as measured by the primary end point or additional measures of neuropathy, including clinician-determined measurement of the time to grade 2 neuropathy by using the National Cancer Institute Common Terminology Criteria for Adverse Events scale or an oxaliplatin-specific neuropathy scale. In addition, calcium/magnesium did not substantially decrease oxaliplatin-induced acute neuropathy.. This study does not support using calcium/magnesium to protect against oxaliplatin-induced neurotoxicity.

Topics: Administration, Intravenous; Aged; Antineoplastic Combined Chemotherapy Protocols; Calcium; Cold Temperature; Colonic Neoplasms; Double-Blind Method; Female; Fluorouracil; Humans; Leucovorin; Magnesium; Male; Middle Aged; Muscle Cramp; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Sensation Disorders

Two arms with FOLFIRI, with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG (North Central Cancer Treatment Group) N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab.. After resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation status was retrospectively determined in a central lab. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity.. One hundred and six patients received FOLFIRI and 40 received FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range, 0.1-7.0 years). The addition of cetuximab showed a trend toward improved DFS (hazard ratio [HR], 0.53; 95% CI, 0.26-1.1; P = .09) and OS (HR, 0.45; 95% CI, 0.17-1.16; P = .10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 nonhematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%; P = .02). Adjuvant FOLFIRI resulted in a 3-year DFS less than that expected for FOLFOX.. In this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with a nonsignificant trend toward improved DFS and OS. Nevertheless, considering the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Rate; Treatment Outcome

We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive.. The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models.. KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001).. KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033-43. ©2014 AACR.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Codon; Colonic Neoplasms; Disease-Free Survival; DNA Mutational Analysis; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mutation; Neoplasm Staging; Organoplatinum Compounds; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Young Adult

The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil-tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses.. Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated.. A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group.. Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Risk Factors; Tegafur; Uracil

The CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).. We analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.. Of the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.. Patients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; CpG Islands; Disease-Free Survival; DNA Methylation; DNA Mismatch Repair; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Phenotype; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Young Adult

Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS).. For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23.. Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone.. The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted.. Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Drug Eruptions; Exons; Female; Fluorouracil; Humans; Infusions, Intravenous; Intention to Treat Analysis; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins

S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV).. Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years.. A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups.. Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer.. NCT00660894.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxonic Acid; Tegafur; Uracil; Young Adult

The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial.. We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model.. KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051).. KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors.. This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Exons; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; Middle Aged; Mutation; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins B-raf

Colon cancers deficient in mismatch repair (MMR) may exhibit diminished expression of the DNA repair gene, MRE11, as a consequence of contraction of a T11 mononucleotide tract. This study investigated MRE11 status and its association with prognosis, survival and drug response in patients with stage III colon cancer.. Cancer and Leukemia Group B 89803 (Alliance) randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly adjuvant bolus 5-fluorouracil/leucovorin (FU/LV) or irinotecan+FU/LV (IFL), with 8 year follow-up. Tumors from these patients were analyzed to determine stability of a T11 tract in the MRE11 gene. The primary endpoint was overall survival (OS), and a secondary endpoint was disease-free survival (DFS). Non-proportional hazards were addressed using time-dependent covariates in Cox analyses.. Of 625 tumor cases examined, 70 (11.2%) exhibited contraction at the T11 tract in one or both MRE11 alleles and were thus predicted to be deficient in MRE11 (dMRE11). In pooled treatment analyses, dMRE11 patients showed initially reduced DFS and OS but improved long-term DFS and OS compared with patients with an intact MRE11 T11 tract. In the subgroup of dMRE11 patients treated with IFL, an unexplained early increase in mortality but better long-term DFS than IFL-treated pMRE11 patients was observed.. Analysis of this relatively small number of patients and events showed that the dMRE11 marker predicts better prognosis independent of treatment in the long-term. In subgroup analyses, dMRE11 patients treated with irinotecan exhibited unexplained short-term mortality. MRE11 status is readily assayed and may therefore prove to be a useful prognostic marker, provided that the results reported here for a relatively small number of patients can be generalized in independent analyses of larger numbers of samples.. ClinicalTrials.gov NCT00003835.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease-Free Survival; DNA-Binding Proteins; Female; Fluorouracil; Follow-Up Studies; Genetic Association Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; MRE11 Homologue Protein; Polymorphism, Single Nucleotide; Prognosis; Treatment Outcome; Young Adult

Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data.. We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided.. In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48).. In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Genetic Predisposition to Disease; Humans; Leucovorin; Logistic Models; Male; Middle Aged; Nausea; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Prospective Studies; Severity of Illness Index; Thrombocytopenia; Valine; Vomiting

By using data from North Central Cancer Treatment Group Phase III Trial N0147, a randomized adjuvant trial of patients with stage III colon cancer, we assessed the relationship between smoking and cancer outcomes, disease-free survival (DFS), and time to recurrence (TTR), accounting for heterogeneity by patient and tumor characteristics. PATIENTS AND METHODS Before random assignment to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or FOLFOX plus cetuximab, 1,968 participants completed a questionnaire on smoking history and other risk factors. Cox models assessed the association between smoking history and the primary trial outcome of DFS (ie, time to recurrence or death), as well as TTR, adjusting for other clinical and patient factors. The median follow-up was 3.5 years among patients who did not experience events.. Compared with never-smokers, ever smokers experienced significantly shorter DFS (3-year DFS proportion: 70% v 74%; hazard ratio [HR], 1.21; 95% CI, 1.02 to 1.42). This association persisted after multivariate adjustment (HR, 1.23; 95% CI, 1.02 to 1.49). There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer. Smoking was more strongly associated with poorer DFS in those with KRAS mutated versus KRAS wild-type colon cancer (HR, 1.50 [95% CI, 1.12 to 2.00] v HR, 1.09 [95% CI, 0.85 to 1.39]), although interaction by KRAS mutation status was not statistically significant (P = .07). Associations were comparable in analyses of TTR.. Overall, smoking was significantly associated with shorter DFS and TTR in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Odds Ratio; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Risk Factors; Smoking; Surveys and Questionnaires; Treatment Outcome

To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS) compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively resectable stage III colon cancer.. Patients (n=1601) were randomised to receive either the Mayo Clinic regimen or one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espaňol para el Tratamiento Digestivos (TTD), the data from which were combined to provide the HD-FU arm for final analysis.. Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42months, RFS (hazard ratio [HR]=0.997) and OS (HR=0.96) (primary end-point) were not statistically different between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus 5-FU regimen.. Infusional HD-FU does not improve RFS and OS in curatively resected stage III colon cancer patients compared to the Mayo Clinic regimen, but is less toxic.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Female; Fluorouracil; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Staging; Treatment Outcome; Young Adult

The method of combined neoadjuvant treatment of resectable cancer recti, consisting of preoperative radiaton therapy, using big-fractionized intensive irradiation on the endolymphatic chemotherapy background together with fluorouracil with following surgical intervention (main group), in terms up to 72 h, was elaborated in the clinic. The patients, to whom the chemotherapy and radiation therapy were conducted, were included into control groups. Postoperative complications have had occurred in 8 (12.5%) patients of the main group and in 10 (15.87%) and 13 (14.29%)--in control groups. The five-year survival indices in the main group have constituted (73.5 +/- 6.3)%, and in control groups--(64.6 +/- 5.8) and (64.4 +/- 6.8)%. The local recurrence rate in the main group have constituted (6.2 +/- 3.0)%, and of the remote metastatizing--(15.6 +/- 4.5)%.

Topics: Antimetabolites, Antineoplastic; Chemoradiotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Recurrence, Local

To compare long-term outcomes between men and women in a large cohort of clinical trial participants with early-stage colon cancer, specifically by examining whether the prognostic effect of sex varies based on age, stage of disease, and type of adjuvant therapy received.. A pooled analysis of individual patient data from 33,345 patients with colon cancer enrolled in 24 phase III studies of various adjuvant systemic therapies was conducted. Chemotherapy consisted of (1) fluorouracil (5-FU), (2) 5-FU variations, (3) 5-FU plus oxaliplatin, (4) 5-FU plus irinotecan, or (5) oral fluoropyrimidine-based regimens. The primary endpoint was disease-free survival; secondary endpoints included overall survival and time to recurrence. Stratified Cox models were used to assess the effect of sex on outcomes. Multivariate models were used to assess adjusted effects and to explore the interaction among sex and other factors.. A total of 18,244 (55%) men and 15,101 (45%) women were included. In the entire cohort, the median age was 61 years; 91% (24,868) were white; 31% (10,347) and 69% (22,964) had stage I/II and III disease, respectively. Overall, men had inferior prognoses when compared with women for time to recurrence (hazard ratio [HR] 1.05 [95% CI, 1.01-1.09]) and other endpoints after adjusting for age, stage, and treatment. Sex was not a predictive factor of treatment efficacy (P for interaction between sex and treatment when adjusting for age and stage were .40, .67, and .77 for disease-free survival, overall survival, and time to recurrence, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older patients when adjusting for stage and treatment (HR 1.08 in age ≤ 65 years vs. HR 1.18 in age > 65 years; interaction P = .016 for disease-free survival). The stage of disease and type of adjuvant regimen did not modify the prognostic value of sex.. Sex is a modest independent prognostic marker for patients with early-stage colon cancer, particularly in older patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Sex Factors; Survival Rate; Young Adult

The association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.. Resected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAF(V600E) (exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.. dMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAF(V600E) or KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (P(interaction) = .009) and lymph node category (N1 v N2; P(interaction) = .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAF(V600E) (HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (P(interaction) = .037).. The prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer.. We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided.. Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16).. Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Class I Phosphatidylinositol 3-Kinases; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Phosphatidylinositol 3-Kinases; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins

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

The National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time.. Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.. Of 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).. Bevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds

This multicenter randomized trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer.. Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5-FU/FA (Mayo Clinic regimen). The primary end point was disease-free survival (DFS).. The intent-to-treat population received capecitabine (n = 1004) or 5-FU/FA (n = 983). With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] and overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01); the 95% CI upper limits were significantly less than the predefined noninferiority margins of 1.20 (P < 0.0001) and 1.14 (P < 0.001), respectively. This pattern was maintained in all subgroups, including patients aged ≥ 70 years. Preplanned multivariate analyses showed that capecitabine had statistically significant beneficial effects on DFS (P = 0.021) and OS (P = 0.020) versus 5-FU/FA. A post hoc analysis suggested that the occurrence of hand-foot syndrome may be associated with better outcomes in capecitabine recipients.. Oral capecitabine is an effective alternative to bolus 5-FU/FA as adjuvant treatment of patients with stage III colon cancer with efficacy benefits maintained at 5 years and in older patients.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Pharmacological; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Hand-Foot Syndrome; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Pharmacokinetics; Pilot Projects; Prognosis; Treatment Outcome; Young Adult

Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer.. We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status.. Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46).. BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Staging; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf

High-level microsatellite instability (MSI-H) has been reported as a prognostic marker in colon cancer. We here analysed the prognostic significance of MSI and mutations of the Beta2-Microglobulin (B2M) gene, which occur in about 30% of MSI-H colon cancer, in the cohort of the prospective FOGT-4 (Forschungsruppe Onkologie Gastrointestinale Tumoren, FOGT) trial.. Microsatellite instability status was determined using standard protocols (NCI/ICG-HNPCC panel and CAT25) in 223 colon cancer lesions. Beta2-Microglobulin mutation status was evaluated by exon-wise sequencing in all MSI-H lesions.. Patients with MSI-H (n=34) colon cancer presented with a significantly lower risk of relapse after 12 months of follow-up compared with MSS (n=189) colon cancer patients (5 year time to relapse: MSI-H 0.82 vs MSS 0.66, P=0.03). No significant difference in overall survival was detected. Beta2-Microglobulin mutations were identified in 10 (29.4%) out of 34 MSI-H colon cancers and were associated with a complete absence of disease relapse or tumour-related death events (P=0.09).. The risk of late disease relapse was significantly lower in patients with MSI-H compared with MSS colon cancer. Moreover, B2M mutations may contribute to the favourable outcome of MSI-H colon cancer patients and should therefore be evaluated as a potential prognostic marker in future clinical trials.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; beta 2-Microglobulin; Biomarkers, Tumor; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Proportional Hazards Models; Prospective Studies; Treatment Outcome

The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis.. Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated.. Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively.. Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Oxonic Acid; Tegafur; Uracil

Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer.. To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer.. A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses.. Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity.. Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.. Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival.. clinicaltrials.gov Identifier: NCT00079274.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Organoplatinum Compounds; Oxaliplatin; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Treatment Outcome; Young Adult

Major concerns surround combining chemotherapy with bevacizumab in patients with colon cancer presenting with an asymptomatic intact primary tumor (IPT) and synchronous yet unresectable metastatic disease. Surgical resection of asymptomatic IPT is controversial.. Eligibility for this prospective, multicenter phase II trial included Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, asymptomatic IPT, and unresectable metastases. All received infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) combined with bevacizumab. The primary end point was major morbidity events, defined as surgical resection because of symptoms at or death related to the IPT. A 25% major morbidity rate was considered acceptable. Secondary end points included overall survival (OS) and minor morbidity related to IPT requiring hospitalization, transfusion, or nonsurgical intervention.. Ninety patients registered between March 2006 and June 2009: 86 were eligible with follow-up, median age was 58 years, and 52% were female. Median follow-up was 20.7 months. There were 12 patients (14%) with major morbidity related to IPT: 10 required surgery (eight, obstruction; one, perforation; and one, abdominal pain), and two patients died. The 24-month cumulative incidence of major morbidity was 16.3% (95% CI, 7.6% to 25.1%). Eleven IPTs were resected without a morbidity event: eight for attempted cure and three for other reasons. Two patients had minor morbidity events only: one hospitalization and one nonsurgical intervention. Median OS was 19.9 months (95% CI, 15.0 to 27.2 months).. This trial met its primary end point. Combining mFOLFOX6 with bevacizumab did not result in an unacceptable rate of obstruction, perforation, bleeding, or death related to IPT. Survival was not compromised. These patients can be spared initial noncurative resection of their asymptomatic IPT.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Female; Fluorouracil; Gastrointestinal Hemorrhage; Humans; Intestinal Obstruction; Intestinal Perforation; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds

The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.. Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.. MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.. Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Chemotherapy, Adjuvant; Chromosomes, Human, Pair 18; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Immunohistochemistry; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Loss of Heterozygosity; Male; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); ras Proteins; Research Design; Smad4 Protein

Bevacizumab improves the efficacy of oxaliplatin-based chemotherapy in metastatic colorectal cancer. Our aim was to assess the use of bevacizumab in combination with oxaliplatin-based chemotherapy in the adjuvant treatment of patients with resected stage III or high-risk stage II colon carcinoma.. Patients from 330 centres in 34 countries were enrolled into this phase 3, open-label randomised trial. Patients with curatively resected stage III or high-risk stage II colon carcinoma were randomly assigned (1:1:1) to receive FOLFOX4 (oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 1; leucovorin 200 mg/m(2) plus fluorouracil 400 mg/m(2) bolus plus 600 mg/m(2) 22-h continuous infusion on day 2) every 2 weeks for 12 cycles; bevacizumab 5 mg/kg plus FOLFOX4 (every 2 weeks for 12 cycles) followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks); or bevacizumab 7·5 mg/kg plus XELOX (oxaliplatin 130 mg/m(2) on day 1 every 2 weeks plus oral capecitabine 1000 mg/m(2) twice daily on days 1-15) every 3 weeks for eight cycles followed by bevacizumab monotherapy 7·5 mg/kg every 3 weeks (eight cycles over 24 weeks). Block randomisation was done with a central interactive computerised system, stratified by geographic region and disease stage. Surgery with curative intent occurred 4-8 weeks before randomisation. The primary endpoint was disease-free survival, analysed for all randomised patients with stage III disease. This study is registered with ClinicalTrials.gov, number NCT00112918.. Of the total intention-to-treat population (n=3451), 2867 patients had stage III disease, of whom 955 were randomly assigned to receive FOLFOX4, 960 to receive bevacizumab-FOLFOX4, and 952 to receive bevacizumab-XELOX. After a median follow-up of 48 months (range 0-66 months), 237 patients (25%) in the FOLFOX4 group, 280 (29%) in the bevacizumab-FOLFOX4 group, and 253 (27%) in the bevacizumab-XELOX group had relapsed, developed a new colon cancer, or died. The disease-free survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·17 (95% CI 0·98-1·39; p=0·07), and for bevacizumab-XELOX versus FOLFOX4 was 1·07 (0·90-1·28; p=0·44). After a minimum follow-up of 60 months, the overall survival hazard ratio for bevacizumab-FOLFOX4 versus FOLFOX4 was 1·27 (1·03-1·57; p=0·02), and for bevacizumab-XELOX versus FOLFOX4 was 1·15 (0·93-1·42; p=0·21). The 573 patients with high-risk stage II cancer were included in the safety analysis. The most common grade 3-5 adverse events were neutropenia (FOLFOX4: 477 [42%] of 1126 patients, bevacizumab-FOLFOX4: 416 [36%] of 1145 patients, and bevacizumab-XELOX: 74 [7%] of 1135 patients), diarrhoea (110 [10%], 135 [12%], and 181 [16%], respectively), and hypertension (12 [1%], 122 [11%], and 116 [10%], respectively). Serious adverse events were more common in the bevacizumab groups (bevacizumab-FOLFOX4: 297 [26%]; bevacizumab-XELOX: 284 [25%]) than in the FOLFOX4 group (226 [20%]). Treatment-related deaths were reported in one patient receiving FOLFOX4, two receiving bevacizumab-FOLFOX4, and five receiving bevacizumab-XELOX.. Bevacizumab does not prolong disease-free survival when added to adjuvant chemotherapy in resected stage III colon cancer. Overall survival data suggest a potential detrimental effect with bevacizumab plus oxaliplatin-based adjuvant therapy in these patients. On the basis of these and other data, we do not recommend the use of bevacizumab in the adjuvant treatment of patients with curatively resected stage III colon cancer.. Genentech, Roche, and Chugai.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Young Adult

A regimen consisting of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) is widely used in France in the first-line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non-inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX-6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX-6 for 6 months. The primary endpoint was overall response rate (ORR) in the per-protocol (PP) population; however, progression-free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX-6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX-6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non-inferiority margin of 15%. In the intent-to-treat population, median progression-free survival was 8.8 months with XELOX and 9.3 months with FOLFOX-6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX-6 patients. We conclude that XELOX is non-inferior in terms of efficacy to FOLFOX-6 in the first-line treatment of MCRC, but has a different toxicity profile.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Treatment Outcome; Young Adult

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and efficacy of adding bevacizumab to modified FOLFOX6 (mFOLFOX6; ie, infusional/bolus fluorouracil, leucovorin, and oxaliplatin) for the adjuvant treatment of patients with stages II to III colon cancer.. Patients received mFOLFOX6 every 2 weeks for 26 weeks alone or modified as FOLFOX6 + bevacizumab (5 mg/kg every 2 weeks for 52 weeks [ie, experimental group]). The primary end point was disease-free survival (DFS).. Among 2,672 analyzed patients, demographic factors were well balanced by treatment. With a median follow-up of 35.6 months, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.89; 95% CI, 0.76 to 1.04; P = .15). The point estimates for 3-year DFS for the overall population were 77.4% and 75.5% for the experimental and control arms, respectively. For patients with stages II and III diseases, these same estimates were 87.4% and 84.7%, respectively, for stage II and 74.2% and 72.4%, respectively, for stage III. Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 15-month landmark (time-by-treatment interaction P value < .0001). Bevacizumab had a strong effect before the landmark (HR, 0.61; 95% CI, 0.48 to 0.78; P < .001) but no significant effect after (HR, 1.22; 95% CI, 0.98 to 1.52; P = .076).. Bevacizumab for 1 year with mFOLFOX6 does not significantly prolong DFS in stages II and III colon cancer. However, a significant but transient effect during bevacizumab exposure was observed in the experimental arm. We postulate that this observation reflects a biologic effect during bevacizumab exposure. Given the lack of improvement in DFS, the use of bevacizumab cannot be recommended for use in the adjuvant treatment of patients with colon cancer.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds

To determine whether irinotecan plus oxaliplatin (mIROX) is superior to irinotecan plus infusional 5-fluorouracil, leucovorin (FUFIRI) as first-line therapy of patients with metastatic colorectal cancer (mCRC).. A phase III, randomised, open-label multicentre study compared standard treatment with FUFIRI (irinotecan 80 mg/m(2), 5-fluorouracil 2000 mg/m(2), folinic acid 500 mg/m(2) weekly times 6) to mIROX using an identical schedule of irinotecan plus oxaliplatin 85 mg/m(2) applied on days 1, 15 and 29 of a 7-week cycle. The primary end-point was progression-free survival (PFS).. A total of 479 eligible patients were randomly assigned. Progression-free survival was 7.2 months in the mIROX arm and 8.2 months in the FUFIRI arm [hazard ratio=1.14; 95% confidence interval (CI) 0.94-1.37; P=0.178]. Comparable results were also obtained for overall survival time with 19 months in the mIROX-arm and 22 months in the FUFIRI-arm (hazard ratio=1.08, P=0.276). Both regimens induced an identical objective response rate (ORR) of 41%, but disease control rate (ORR plus stable disease) was significantly greater in the FUFIRI group (81% versus 68%, P=0.001). Most frequent grades 1-4 side-effects of mIROX and FUFIRI treatment were nausea (80% versus 73%) and delayed diarrhoea (79% versus 68%). Grades 3-4 toxicities were generally below 10%, except for diarrhoea which was more frequent in the mIROX-arm compared to the FUFIRI-arm (19% versus 30%, P=0.006). mIROX failed to show superior activity compared to high-dose 5-FU/folinic acid plus irinotecan. Due to better tolerability the combination of high-dose 5-FU/folinic acid and irinotecan remains a standard of care in first-line treatment of metastatic colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Young Adult

Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer.. The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m2 intravenously (i.v.), LV 200 mg/m2 and 5FU 450 mg/m2 bolus (Arm A) versus LV 200 mg/m2 and 5FU 500 mg/m2 i.v. bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years.. The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms.. Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity.. Australian New Zealand Clinical Trials Registry: ACTRN12610000148077.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Greece; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Treatment Outcome; Young Adult

This multicenter, randomized trial compared capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil (FU) and folinic acid (FA) as adjuvant therapy for patients with stage III colon cancer.. Patients who had undergone curative resection were randomly assigned to XELOX (oxaliplatin 130 mg/m(2) on day 1 plus capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks for 24 weeks) or a standard bolus FU/FA adjuvant regimen (Mayo Clinic for 24 weeks or Roswell Park for 32 weeks). The primary study end point was disease-free survival (DFS).. The intention-to-treat population comprised 1,886 patients; 944 patients were randomly assigned to XELOX and 942 to FU/FA (Mayo Clinic, n = 664; Roswell Park, n = 278). After 57 months of follow-up for the primary analysis, 295 patients (31.3%) in the XELOX group had relapsed, developed a new primary colon cancer, or died compared with 353 patients (37.5%) in the FU/FA group (hazard ratio [HR] for DFS, 0.80; 95% CI, 0.69 to 0.93; P = .0045). The 3-year DFS rate was 70.9% with XELOX and 66.5% with FU/FA. The HR for overall survival (OS) for XELOX compared to FU/FA was 0.87 (95% CI, 0.72 to 1.05; P = .1486). The 5-year OS for XELOX and FU/FA were 77.6% and 74.2%, respectively. Follow-up is ongoing. Preplanned multivariate and subgroup analyses supported the robustness of these findings.. The addition of oxaliplatin to capecitabine improves DFS in patients with stage III colon cancer. XELOX is an additional adjuvant treatment option for these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models

The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets.. Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets.. In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients.. Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Survival Rate

The objective of this study is to conduct a pooled analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) colon trials involving surgery and surgery plus 5-fluorouracil and leucovorin (5-FU/LV) to compare survival and establish a baseline from which to evaluate future studies.. All patients enrolled in NSABP adjuvant trials C-01 through C-05 with stage II and III disease who were treated with surgery or with surgery plus 5-FU/LV were examined for overall survival (OS), disease-free survival (DFS), and recurrence-free interval (RFI). Time-to-event by treatment group was examined using adjusted Kaplan-Meier estimates and multivariable Cox regression analysis.. There were 2,966 eligible patients: 693 (23%) surgery and 2,273 (77%) surgery plus 5-FU/LV; 1,255 (42%) stage II and 1,711 (58%) stage III. Age > or =60 years [hazard ratio (HR) = 1.36, P < 0.0001], male gender (HR = 1.20, P = 0.0012), and more nodes positive or fewer nodes examined (P < 0.0001) were associated with worse survival. At 5 years, the adjusted OS was 0.62 [confidence interval (CI) = 0.60-0.63] in the surgery group and 0.76 (CI = 0.74-0.78) in the surgery plus 5-FU/LV group. Treatment with 5-FU/LV was associated with improved outcome compared with surgery: OS (HR = 0.62, P < 0.0001), DFS (HR = 0.66, P < 0.0001) and RFI (HR = 0.64, P < 0.0001). Improved OS with adjuvant treatment was seen in both stage II (HR = 0.58, 95% CI = 0.48-0.71) and stage III disease (HR = 0.65, 95% CI = 0.55-0.75).. This analysis demonstrates that treatment of colon cancer patients with 5-FU/LV following surgery provides benefit over surgery alone and can provide anticipated survival outcomes with which to compare modern adjuvant trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Surgical Procedures, Operative; Survival Rate; Time Factors; Treatment Outcome

Antitumor immune response and chemotherapy-induced immunomodulation in colon cancer patients represented the rationale to design new strategies, like GOLFIG chemoimmunotherapy (gemcitabine, oxaliplatin, 5-fluorouracil/folinic acid, granulocyte macrophage colony-stimulating factor, and aldesleukine), that resulted a safe and very active regimen. Antitumor activity and immunity feedback to GOLFIG were strictly correlated with the best outcome observed in patients with autoimmunity signs, increase of central memory T cells, and decrease of regulatory T cells (Treg) in the peripheral blood. We thus investigated a potential correlation between the Treg tumor infiltration at diagnosis and the clinical outcome in a current randomized phase 3 trial aimed to compare the GOLFIG regimen with the standard FOLFOX chemotherapy (GOLFIG-2). An immunohistochemistry study was carried out to quantify the infiltration of Treg/FoxP3+ T lymphocytes in tumor samples of 57 patients enrolled in the GOLFIG-2 trial. Treg tumor infiltration scores were correlated with overall survival, treatment-relative survival, and progression-free survival (PFS). Higher Treg tumor infiltration scores were associated with a better prognosis in the whole series (Treg high score vs. low score: overall survival=mean 43.2 mo vs. 28.6 mo, P=0.0005) and a better outcome after treatment (Treg high score vs. low score: PFS=mean 15.8 mo vs. 8.8 mo, P=0.0009; treatment-relative survival=mean 23.1 mo vs. 18.2 mo, P=0.004). PFS was significantly longer in GOLFIG high versus all other subgroups (mean 18.1 mo vs. 9.9 mo, P=0.01). Our results suggest that a higher FoxP3+ T-lymphocyte tumor infiltration score is a favorable prognostic factor in colon cancer patients undergoing chemo or chemoimmunotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Disease Progression; Female; Fluorouracil; Forkhead Transcription Factors; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunohistochemistry; Immunotherapy; Leucovorin; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Recombinant Proteins; Survival Analysis; T-Lymphocytes, Regulatory

To assess the efficacy and safety of bevacizumab plus irinotecan-based regimen for the first line treatment in metastatic colorectal cancer (mCRC) patients, and to investigate the correlation between serum tumor markers including CEA and CA19-9 and response as well as prognosis.. From May 2007 to July 2008, 67 previously untreated mCRC patients received treatment of IFL (n = 25), IFL plus Bevacizumab (n = 20) or FOLFIRI (n = 22). The treatment continued until disease progression or unacceptable toxicity. The data were retrospectively analyzed.. All patients were evaluable for response, survival and toxicity analysis. The objective response rate of IFL, IFL plus Bevacizumab or FOLFIRI regimen groups was 16.0% (4/25), 35.0% (7/20) and 18.2% (4/22), respectively (χ(2) = 6.026, P = 0.049). The median progression-free survival (PFS) of IFL plus bevacizumab group was 7.5 months, significantly improved as compared with 3.7 months in the IFL group and 4 months in FOLFIRI group (χ(2) = 11.97, P = 0.003). Of all 67 cases, the one-year survival rate was 47.0%, two-year survival rate was 27.0%, and the median overall survival (OS) was 13.0 months, with no significant difference among the three treatment groups (χ(2) = 3.42, P = 0.18). The serum CEA and CA19-9 levels were decreased after treatment, but with no significant difference among the three groups (P > 0.05). The common toxicity profiles of IFL and FOLFIRI regimens were diarrhea and neutropenia, while the toxicity related to bevacizumab was consistent with that documented in previous literature, such as hypertension, hemorrhage, cardiac toxicity and delayed wound healing.. The addition of bevacizumab to irinotecan-based regimen significantly improves the response rate and PFS in first-line treatment for patients with mCRC and its toxicity is well tolerated.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; CA-19-9 Antigen; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Hypertension; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Rectal Neoplasms; Remission Induction; Retrospective Studies; Survival Rate; Young Adult

Oxaliplatin combined with either fluorouracil/leucovorin (OXAFAFU) or capecitabine (OXXEL) has a demonstrated activity in metastatic colorectal cancer patients. We aimed at comparing these two regimens in terms of response rate (RR), safety, progression-free survival (PFS), and quality of life (QoL) of patients.. A total of 322 patients with metastatic colorectal cancer were randomized to receive biweekly: oxaliplatin 100 mg/m(2) i.v. on day 1, capecitabine 1,000 mg/m(2) orally twice daily from day 1 to day 11 (OXXEL); or oxaliplatin 85 mg/m(2) i.v. on day 1; 6S-leucovorin 250 mg/m(2) i.v. and fluorouracil 850 mg/m(2) i.v. on day 2 (OXAFAFU).. Eleven complete and 42 partial responses were registered with OXXEL (RR = 34%); six complete and 48 partial responses were obtained with OXAFAFU (RR = 33%) (P = 0.999). Severe adverse events were less frequent (32 vs. 43%) with OXXEL, which also reduced the occurrence of severe neutropenia (10 vs. 27%) and febrile neutropenia (6 vs. 13%), but produced more gastric side effects (8 vs. 3%) and diarrhea (13 vs. 8%). QoL did not differ across the two arms. Median PFS was 6.6 months in the OXXEL, and 6.5 months in the OXAFAFU arm (HR = 1.12, P = 0.354). Median overall survival was 16.0 and 17.1 months (HR = 1.01, P = 0.883).. OXXEL and OXAFAFU regimens were equally active in metastatic colorectal cancer. The choice should be based on patient preference and on pharmacoeconomic evaluations.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Colorectal Neoplasms; Deoxycytidine; Disease Progression; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Rectal Neoplasms; Survival Analysis; Time Factors

This multicenter adjuvant phase III trial evaluated the addition of irinotecan to LV5FU2 in colon cancer patients at high risk of relapse.. A total of 400 patients with histologically proven primary colon cancer with postoperative N1 detected by occlusion/perforation or N2 were randomised to: A-LV5FU2 [leucovorin 200 mg/m(2), 2-h infusion, 5-fluorouracil (5-FU) 400 mg/m(2) bolus, 600 mg/m(2) 22-h continuous infusion, days 1 and 2] or B-LV5FU2 + IRI (irinotecan 180 mg/m(2) 90-min infusion day 1 + LV5FU2) fortnightly for 12 cycles. Primary end point was disease-free survival (DFS).. Median follow-up was 63 months. Significantly more T4 tumours and 15 or more positive lymph nodes were observed in arm B. 5-FU relative dose intensity (RDI) was >0.80 for 94% and 77% in arms A and B, respectively (P < 0.001). Irinotecan RDI was >0.80 for 70% patients. There were more grades 3 and 4 neutropenia in arm B (4% versus 28%, P < 0.001). The 3-year DFS was 60% [95% confidence interval (CI) 53% to 66%] and 51% (95% CI 44% to 58) in arms A and B, respectively. No difference was observed [hazard ratio (HR) = 1.12, 95% CI 0.85-1.47, P = 0.42] even when adjusted for prognostic factors (adjusted HR = 0.98, 95% CI 0.74-1.31, P = 0.92). The 5-year overall survival (OS) was 67% (95% CI 59% to 73%) and 61% (95% CI 53% to 67%) in arms A and B, respectively.. Adjuvant LV5FU2 + IRI compared with LV5FU2 alone in patients at high risk of relapse showed no improvement in DFS and OS.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Recurrence; Risk Assessment

Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) -based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers.. Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype.. Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117).. Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Prognosis; Prospective Studies; Survival Analysis; Young Adult

to evaluate the therapeutic efficacy of oxaliplatin and to analyze the pharmacokinetics of both ultrafiltrable (free) and protein-bound platinum in patients with metastatic colon cancer.. 60 patients with stage IV colon carcinoma received 4-6 (mean 4.5) cycles of oxaliplatin based combination chemotherapy. Response rate, progression-free survival (PFS) and toxicity were evaluated. The pharmacokinetics of oxaliplatin was evaluated in 8 patients who were given 85 mg/sqm or 130 mg/sqm using an infusion time of 2-4 h. Pharmacokinetic analysis was performed on blood, plasma and plasma ultrafiltrable by ICP-MS (Inductively Coupled Plasma Mass Spectrometry).. Overall response rate (complete and partial) occurred in 33 (55%) patients. The median time of progression was 9.3 months. Cumulative neurotoxicity, vomiting and diarrhea, myelosuppression appeared in 32.3%, 21.3%, and 39.4% patients, respectively. The mean Cmax and AUC 0-24 of oxaliplatin increased in a dose-related manner. The pharmacokinetics of platinum after oxaliplatin administration was triphasic characterized by a short initial distribution phase and a long terminal elimination phase.The clearance of ultrafiltrable platinum was relatively high and the clearance of platinum from plasma and blood cells was relatively low, which is probably a reflection of the covalent binding of platinum to these matrices.. Oxaliplatin is active and well tolerated in patients with advanced colon cancer. With a relatively low interpatient variability, it is eliminated triphasically and the mean Cmax and AUC 0-24 increases in a dose-related manner. These results provide a scientific basis for the safe and effective use of oxaliplatin in the clinic.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colonic Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Mass Spectrometry; Metabolic Clearance Rate; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Protein Binding; Time Factors; Treatment Outcome

The National Surgical Adjuvant Breast and Bowel Project C-08 trial was designed to investigate the safety and effectiveness of adding bevacizumab to modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for the adjuvant treatment of patients with stage II or III colon cancer. We present safety information in advance of the planned analysis of efficacy.. Among 2,710 randomly assigned patients, demographic factors were balanced. Patients received modified FOLFOX6 every 2 weeks x 12 or modified FOLFOX6 plus bevacizumab (5 mg/kg every 2 weeks x 26, experimental group).. Overall rates of grade 4 or 5 toxicities were nearly identical in the FOLFOX6 and FOLFOX6 plus bevacizumab arms (15.2% and 15.0%, respectively). Six-month mortality rates were 0.96% and 0.90% for the control and experimental groups, respectively. Grade 3+ toxicities that occurred more often in the experimental arm versus control arm included hypertension (12% v 1.8%, respectively), wound complications (abdominal incisional hernia or infusion port dehiscence/inflammation; 1.7% v 0.3%, respectively), pain (11.1% v 6.3%, respectively), and proteinuria (2.7% v 0.8%, respectively). Grade 2+ neuropathy was increased in the experimental arm versus the control arm (grade 2, 33% v 29%, respectively; grade 3, 16% v 14%, respectively; and grade 4, < 1% each). In the experimental arm versus control arm, significantly less thrombocytopenia (1.4% v 3.4%, respectively) and fewer allergic reactions (3.1% v 4.7%, respectively) were observed. Advanced age was associated with a significantly greater rate of grade 4 and 5 toxicities regardless of treatment.. Bevacizumab with modified FOLFOX6 is well tolerated in the surgical adjuvant setting in these patients. No significant increase in GI perforation, hemorrhage, arterial or venous thrombotic events, or death with the addition of bevacizumab to modified FOLFOX6 has been observed. Follow-up for potential delayed adverse effects and efficacy is ongoing.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Nervous System Diseases; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Pain; Treatment Outcome

PURPOSE The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. PATIENTS AND METHODS After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m(2) as a 2-hour infusion, followed by FU; as a 400 mg/m(2) bolus and then a 600 mg/m(2) continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m(2) as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. CONCLUSION Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging

PURPOSE Three-year disease-free survival (DFS) was significantly improved in patients who had undergone resection with curative intent for stage II or III colon cancer who received bolus plus continuous-infusion fluorouracil plus leucovorin (LV5FU2) with the addition of oxaliplatin (FOLFOX4). Final results of the study, including 6-year overall survival (OS) and 5-year updated DFS, are reported. PATIENTS AND METHODS A total of 2,246 patients were randomly assigned to receive LV5FU2 or FOLFOX4 for 6 months. The primary end point was DFS. Secondary end points were OS and safety. Results Five-year DFS rates were 73.3% and 67.4% in the FOLFOX4 and LV5FU2 groups, respectively (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.93; P = .003). Six-year OS rates were 78.5% and 76.0% in the FOLFOX4 and LV5FU2 groups, respectively (HR = 0.84; 95% CI, 0.71 to 1.00; P = .046); corresponding 6-year OS rates for patients with stage III disease were 72.9% and 68.7%, respectively (HR = 0.80; 95% CI, 0.65 to 0.97; P = .023). No difference in OS was seen in the stage II population. The incidence of second noncolorectal cancers was 5.5% and 6.1% in the FOLFOX4 and LV5FU2 groups, respectively. Among patients receiving oxaliplatin, the frequency of grade 3 peripheral sensory neuropathy was 1.3% 12 months after treatment and 0.7% at 48 months. CONCLUSION Adding oxaliplatin to LV5FU2 significantly improved 5-year DFS and 6-year OS in the adjuvant treatment of stage II or III colon cancer and should be considered after surgery for patients with stage III disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

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

Recent clinical studies on patients with malignancies, who were treated with UHF and LMWHs raised the possibility, that these agents may possess an inhibitory effect on tumor progression. Further studies supported that this effect is independent from the anticoagulant and antithrombotic action. In this retrospective study oncological patients with an increased risk for thromboembolism were choosen, who received prophylactic treatment with an LMWH (nadroparin) at least for 6 months. Comparing with the control group, in some subgroups (T3 and T4, as well as M1) the LMWH-treated patients showed a significantly increased survival.

Topics: Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Colonic Neoplasms; Cyclophosphamide; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Nadroparin; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Pilot Projects; Retrospective Studies; Survival Analysis; Time Factors

GOLFIG chemoimmunotherapy regimen proved to be a safe and very active chemoimmunotherapy regimen in advanced colon cancer patients. We have thus investigated the immunobiological feedback to the treatment and its possible correlation with the clinical outcome of these patients.. This clinical and immunologic study involved 46 patients, 27 males and 19 females, enrolled in the GOLFIG-1 phase II trial who received gemcitabine (1,000 mg/m(2) on days 1 and 15), oxaliplatin (85 mg/m(2) on days 2 and 16), levofolinic acid (100 mg/m(2) on days 1, 2, 15, and 16), and 5-fluorouracil (400 mg/m(2) as a bolus, and 800 mg/m(2) as a 24-hour infusion on days 1, 2, 15, and 16) followed by s.c. granulocyte macrophage colony-stimulating factor (100 mug, on days 3-7) and interleukin 2 (0.5 x 10(6) IU twice a day on days 8-14 and 17-29).. The regimen was confirmed to be safe and very active in pretreated patients with metastatic colorectal cancer. A subgroup analysis of these patients revealed a prolonged time to progression and survival in six patients who developed late signs of autoimmunity. A multivariate analysis validated the occurrence of autoimmunity signs as an independent predictor of favorable outcome. A parallel immunologic study detected in the peripheral blood mononuclear cells of these patients a progressive increase in lymphocyte and eosinophil counts, amplification in central memory, a marked depletion of immunosuppressive regulatory T cells, and activation of colon cancer-specific cytotoxic T cells.. Our results suggest that immunity feedback to GOLFIG regimen and its antitumor activity are tightly correlated.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Injections, Subcutaneous; Interleukin-2; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Recombinant Proteins; Treatment Outcome

To evaluate the efficacy and safety of an adjuvant chemotherapy regimen: XELOX (Capecitabine puls Oxaliplatin) used after curative resection for stage III colorectal cancer.. From Jan. 1998 to Jan. 2004, 256 cases with stage III colorectal cancer randomized received de Gramont, modified FOLFOX4 (mFOLFOX4) and XELOX regimens. The 3-year disease-free survival (DFS) and overall survival (OS) were compared within the three groups and relative prognosis factors within mFOLFOX4 and XELOX groups. Therapeutic adverse events were recorded and analyzed with Kaplan-Meier test.. 98, 87 and 71 cases were respectively enrolled in the de Gramont, mFOLFOX4 and XELOX groups, mFOLFOX4 and XELOX had superior efficacy compared with de Gramont regimen. The two former could significantly improve 3-year DFS (79.7% vs. 66.2%, P = 0.015; 81.5% vs. 66.2%, P = 0.004) and medium survival time (40.2 mon vs. 37.8 mon, P = 0.024; 41.4 mon vs. 37.8 mon, P = 0.014). Meanwhile they could respectively decrease the ratio of recurrence risk by 18.0% (P = 0.024) and 21.0% (P = 0.003). The relative benefit of mFOLFOX4 versus XELOX didn't differ for 3-year DFS [hazard ratio (HR): 0.84, 95% confidence interval (CI): 0.79-1.12, P = 0.13] and OS (HR: 0.87, 95% CI: 0.84-1.06, P = 0.54). In the analysis of DFS in relative prognosis factors, XELOX had a better trend of survival advantage. mFOLFOX4 had higher adverse events within these regimens, especially in grade 3 or 4 neutropenia and peripheral neurologic adverse events.. XELOX maintains its efficacy and safety ratio in advanced colorectal cancer. Patients have good tolerance and compliance. The regiment is deserves to be applied in clinical treatment. Oxaliplatin;

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Proportional Hazards Models; Rectal Neoplasms; Retrospective Studies; Survival Rate; Young Adult

PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer.. Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively.. The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23).. The trial failed to demonstrate non-inferiority of raltitrexed.. Free drugs and financial support from AstraZeneca.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quinazolines; Survival Analysis; Thiophenes; Treatment Outcome; Young Adult

Irinotecan (CPT-11), a specific inhibitor of topoisomerase I, has been proven to be effective in the treatment of refractory or metastatic colorectal cancer. Furthermore, several first line phase III trials of the combination therapy (FOLFIRI) using CPT-11 and fuorouracil/leucovorin (5-Fu/LV) were reported to have significant improvement in treatment result. Therefore, we designed a multicenter clinical study to observe the overall survival (OS), time to death (TTD), time to progression (TTP), efficacy and safety of FOLFIRI regimen for patients with refractory or metastatic colorectal cancer after first line chemotherapy failure.. Patients with metastatic or refractory colorectal cancer after first line oxaliplatin-based chemotherapy failure were enrolled into this prospective, one arm and open-labeled multicenter study. Irinotecan 180 mg/m2 was administered biweekly on D1, LV 200 mg/m2 by intravenous infusion in 2 hours before bolus intravenous injection of 5-Fu 400 mg/m2, then followed immediately by intravenous infusion of 5-Fu 2.4 g/m2 in 46 hours. OS, TTD, TTP, response rate (RR) and adverse events were assessed according to RSCIST criteria and NCIC-CTG CTCAE (3.0).. Sixty-six patients were valuable for safety assessment and and 61 for efficacy. There was no CR patient in this series. Ten patients had PR, 35 SD (57.4% ) and 16 PD (26.2%) with a response rate of 16.4% (10/61). The median TTP was 5.0 months (1-12 months), median TTD 9.9 months (5-27 months)and median OS 18.2 months (7-33 months). The adverse events including nausea,vomiting, anorexia,diarrhea, leucopenia and cholinergic syndrome were frequent, but usually in I - II degree. The rate of III/IV degree diarrhea and leucopenia was 7.6% and 22.7%, respectively.. The regimen of irinotecan plus fuorouracil/leucovorin (FOLFIRI) is effective and well-tolerated as a second-line chemotherapy and may prolong the overall survival for the patient with refractory or metastatic colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neutropenia; Prospective Studies; Rectal Neoplasms; Remission Induction; Survival Rate; Vomiting; Young Adult

The dose limiting toxicity of oxaliplatin (l-HOP) is neurotoxicity, which is characterized by an acute neuropathy and a clinically distinct chronic neuropathy. This randomized study evaluated if prolonged l-HOP infusion over the conventional l-HOP schedule was useful in reducing acute and possibly chronic l-HOP induced neurotoxicity in colon and gastric cancer patients receiving l-HOP-based regimen as adjuvant chemotherapy.. Sixty-four patients were randomly assigned to group A (26 colon and 6 gastric cancer) and to group B (23 colon and 9 gastric cancer). Chemotherapy in both groups consisted of l-HOP 85 mg/m(2) i.v. only on day 1, with leucovorin 100 mg/m(2) i.v. as a 2-h infusion followed by bolus 5-fluorouracil (5-FU) 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day, repeated for two consecutive days every 2 weeks for a maximum of 12 cycles. Patients in group A received l-HOP as a continuous 6-h i.v. infusion, and patients in group B received l-HOP as the conventional 2-h i.v. infusion.. The percentage of patients presenting with grade >/=2 neurotoxicity was statistically lower in group A than in group B (28.1% vs. 59.3%: P = 0.02). There was a statistically lower percentage of cycles with grade >/=2 neurotoxicity in group A (6.1%) than in group B (18.5%) (P < 0.001).. This study suggests that l-HOP as a continuous 6-h infusion is useful in preventing and reducing acute l-HOP induced neurotoxicity in patients with colon and gastric cancer receiving FOLFOX-4 regimen as adjuvant treatment.

Topics: Acute Disease; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neurotoxicity Syndromes; Organoplatinum Compounds; Stomach Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

The standard adjuvant treatment for stage III colon cancer in Europe is the 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX-4) regimen, given for 6 months. Cetuximab, a monoclonal antibody directed against the EGF receptor, appears to be effective and safe when combined with oxaliplatin-based regimens, including FOLFOX-4, in patients with metastatic colorectal cancer. PETACC-8, a randomized, multicenter, European Phase III trial, is comparing the efficacy of cetuximab plus FOLFOX-4 with that of FOLFOX-4 alone in patients with stage III colon cancer. The study began in December 2005 and approximately 2000 patients are to be enrolled in nine European countries. The primary end point is disease-free survival time, analyzed after a minimum follow-up of 3 years per patient. Secondary end points include overall survival, treatment compliance, safety and pharmacogenomic parameters.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease-Free Survival; Europe; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Survival Analysis; Treatment Outcome

Adjuvant chemotherapy is recommended for stage III colon cancer. The aim of this study was to identify important prognostic factors among patients with colon cancer receiving adjuvant 5-FU-based treatment.. Data sets of 855 colon cancer patients treated between 1992 and 1999 within a multicenter adjuvant trial comparing 5-FU modulation with folinic acid or interfereron-alpha were examined. Backward elimination in a proportional hazards model was used to identify prognostically relevant clinical and pathological factors.. Tumor recurrence (p<0.001), duration of adjuvant treatment (p<0.001), tumor substage (p=0.004), age (p=0.005), grading (p=0.016), treatment-related toxicity (p=0.021), and treatment (p=0.031) were identified in descending order of importance as prognostic factors for overall survival.. Adjuvant 5-FU-based treatment should be performed for at least 6months with a stepwise adjustment of 5-FU doses until toxicity >WHO II. Substages should be reported separately and used for stratification in future trials due to their broad variation in outcome. In the future, this may result in adjuvant treatment of stage III colon cancer adjusted for the risk of substages.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Follow-Up Studies; Germany; Humans; Immunologic Factors; Incidence; Interferon-alpha; Leucovorin; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Time Factors; Vitamin B Complex

To report the results of a planned safety analysis from a phase III trial comparing capecitabine plus oxaliplatin (XELOX) with bolus fluorouracil/leucovorin (FU/LV) as adjuvant therapy for stage III colon cancer.. Patients with stage III colon carcinoma were randomly assigned to receive either XELOX (intravenous oxaliplatin plus oral capecitabine; 3-week cycle for eight cycles) or standard intravenous bolus FU/LV administered as the Mayo Clinic (Mayo; Rochester, MN) or Roswell Park (RP; Buffalo, NY) regimen for a similar length of time. A total of 1,886 patients were randomly assigned.. The safety population comprised 1,864 patients, of whom 938 received XELOX and 926 received FU/LV. Most treatment-related adverse events (AEs) occurred at similar rates in both treatment arms. However, patients receiving XELOX experienced less all-grade diarrhea, alopecia, and more neurosensory toxicity, vomiting, and hand-foot syndrome than those patients receiving FU/LV. Compared with Mayo, XELOX showed fewer grade 3/4 hematologic AE and more grade 3/4 gastrointestinal AE. Compared with RP, XELOX showed less grade 3/4 gastrointestinal AE and more grade 3/4 hematologic AE. As expected grade 3/4 neurosensory toxicity and grade 3 hand-foot syndrome were higher with XELOX. Treatment-related mortality within 28 days from the last study dose was 0.6% in the XELOX group and 0.6% in the FU/LV group.. XELOX has a manageable tolerability profile in the adjuvant setting. Efficacy data will be available within the next 24 months.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Research Design; Safety; Treatment Outcome

We compared health-related quality of life (HRQL), symptoms, and convenience of care (COC) in patients with stage II/III carcinoma of the colon who received either oral uracil/ftorafur (UFT) plus leucovorin (LV) or standard intravenous (IV) fluorouracil (FU) plus LV as adjuvant chemotherapy.. We measured HRQL with the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) questionnaire, Short Form-36 Vitality Scale (SF-36), and a Quality of Life Rating Scale (QLRS) at baseline, once during chemotherapy, and at 1 year. We used the Symptom Distress Scale (SDS) and treatment-specific Symptom Checklist (SCL) to assess symptoms and a modified Burden of Care form to assess COC at baseline, on day 1 of each treatment cycle, and at 1 year. Repeated measures analyses controlling for demographic variables and baseline scores were used for statistical comparisons.. The study accrued 1,608 patients, 803 to the FU arm and 805 to the UFT arm. There were no differences between the arms in overall FACT-C scores, FACT-C scores within the subscales of colon-specific, physical, emotional, social, and functional health, or QLRS scores. Patients taking UFT reported substantially higher COC. Statistically significant but small differences were observed for SF-36, favoring FU, and for SDS and SCL, both favoring UFT.. Patients perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Health Status; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Quality of Life; Tegafur; Uracil

The MOSAIC trial demonstrated that oxaliplatin/5-fluorouracil/leucovorin (FU/LV) (FOLFOX4) as adjuvant treatment of TNM stage II and III colon cancer significantly improves disease-free survival compared with 5-FU/LV alone. For stage III patients the 4-year disease-free survival (DFS) was 69% in the FOLFOX4 arm vs 61% in the LV5FU2 arm, P = .002). The cost-effectiveness of FOLFOX4 in stage III patients was evaluated from a US Medicare perspective.. By using individual patient-level data from the MOSAIC trial (median follow-up: 44.2 months), DFS and overall survival (OS) were estimated up to 4 years from randomization. DFS was extrapolated from 4 to 5 years by fitting a Weibull model and subsequent survival was estimated from life tables. OS beyond 4 years was predicted from the extrapolated DFS estimates and observed survival after recurrence. Costs were calculated from trial data and external estimates of resources to manage recurrence.. Patients on FOLFOX4 were predicted to gain 2.00 (95% confidence interval [CI]: 0.63, 3.37) years of DFS over those on 5-FU/LV. The predicted life expectancy of stage III patients on FOLFOX4 and 5-FU/LV was 17.61 and 16.26 years, respectively. Mean total lifetime disease-related costs were $56,300 with oxaliplatin and $39,300 with 5-FU/LV. Compared with 5-FU/LV, FOLFOX4 was estimated to cost $20,600 per life-year gained and $22,800 per quality-adjusted life-year (QALY) gained, discounting costs and outcomes at 3% per annum.. FOLFOX4 is likely to be cost-effective compared with 5-FU/LV in the adjuvant treatment of stage III colon cancer. The incremental cost-effectiveness ratio compares favorably with other funded interventions in oncology.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; United States

The randomized, multicenter, phase III protocol C-07 compared the efficacy of adjuvant bolus fluorouracil and leucovorin (FULV) versus FULV with oxaliplatin (FLOX) in stage II or III colon cancer. Definitive analysis revealed an increase in 4-year disease-free survival from 67.0% to 73.2% in favor of FLOX. This study compares neurotoxicity between the treatments.. Neurotoxicity was recorded for all patients using standard adverse event reporting. Patients at select institutions completed a neurotoxicity questionnaire through 18 months of follow-up.. A total of 2,492 patients enrolled onto C-07 and 400 patients enrolled onto the patient-reported substudy. Mean patient-reported neurotoxicity was higher with oxaliplatin throughout the 18 months of study (P < .0001). During therapy, patients receiving oxaliplatin experienced significantly more hand/foot toxicity (eg, "quite a bit" of cold-induced hand/foot pain 26% FLOX v 2.6% FULV) and overall weakness (eg, moderate weakness in 27.4% FLOX v 16.2% FULV). At 18 months, hand neuropathy had diminished, but patients who received oxaliplatin experienced continued foot discomfort (eg, moderate foot numbness and tingling for 22.1% FLOX v 4.6% FULV). Observer-reported neurotoxicity was low grade and primarily neurosensory rather than neuromotor. Sixty-eight percent in the FLOX group v 8% in the FULV group had neurotoxicity at their first on-treatment assessment. Time to resolution was significantly longer for those receiving oxaliplatin, and continued beyond 2 years for more than 10% in the oxaliplatin group.. Oxaliplatin causes significant neurotoxicity. It is experienced primarily in the hands during therapy and in the feet during follow-up. In a minority of patients the neurotoxicity is long lasting.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases

This phase III clinical trial evaluated the impact on disease-free survival (DFS) of adding oxaliplatin to bolus weekly fluorouracil (FU) combined with leucovorin as surgical adjuvant therapy for stage II and III colon cancer.. Patients who had undergone a potentially curative resection were randomly assigned to either FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8-week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX).. A total of 2,407 patients (96.6%) of the 2,492 patients randomly assigned were eligible. Median follow-up for patients still alive is 42.5 months. The hazard ratio (FLOX v FULV) is 0.80 (95% CI, 0.69 to 0.93), a 20% risk reduction in favor of FLOX (P < .004). The 3- and 4-year disease-free survival (DFS) rates were 71.8% and 67.0% for FULV and 76.1% and 73.2% for FLOX, respectively. Grade 3 neurosensory toxicity was noted in 8.2% of patients receiving FLOX and in 0.7% of those receiving FULV (P < .001). Hospitalization for diarrhea associated with bowel wall thickening occurred in 5.5% of the patients receiving FLOX and in 3.0% of the patients receiving FULV (P < .01). A total of 1.2% of patients died as a result of any cause within 60 days of receiving chemotherapy, with no significant difference between regimens.. The addition of oxaliplatin to weekly FULV significantly improved DFS in patients with stage II and III colon cancer. FLOX can be recommended as an effective option in clinical practice.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.. Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.. Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P=0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P=0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P=0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (log(e)) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P<0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P=0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P<0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.. This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Neoplasm Metastasis; Odds Ratio; Rectal Neoplasms; Survival Analysis; Tissue Inhibitor of Metalloproteinase-1; Treatment Outcome

Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer.. A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS).. Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm.. The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Treatment Outcome

This randomized, 2 x 2 factorial study compared a semimonthly regimen (fluorouracil [FU] and leucovorin [LV] semi-monthly is LV5FU2) with a monthly regimen of FU and LV (mFU/LV) as well as 24 weeks versus 36 weeks of each regimen as adjuvant treatment of stage II and III colon cancer.. LV5FU2 was administered semimonthly for 2 days as racemate (dl) or levogyre (l-; 200 or 100 mg/m(2)) as a 2-hour infusion, followed by 400 mg/m(2) FU bolus and a 600-mg/m(2) FU 22-hour continuous infusion. FU and LV were administered monthly (mFU/LV) for 5 days as dl- or l-LV 15-minute infusion, followed by a 400 mg/m(2) FU 15-minute infusion. The primary end point was disease-free survival (DFS).. Between September 1996 and November 1999, 905 patients with stage II (43%) and III (57%) colon cancer were enrolled. The median follow-up was 6 years. There was no statistically significant difference between mFU/LV and LV5FU2 in terms of DFS (150 v 148 events; hazard ratio [HR],1.01; 95% CI, 0.806 to 1.269; P = .94) and overall survival (OS; 104 v 103 events; HR,1.02; 95% CI, 0.77 to 1.34; P = .91). No statistical difference was observed between 24 or 36 weeks of chemotherapy. Median survival from metastatic relapse was 24 months. The survival of patients with metastatic relapse (n = 243) was significantly longer for patients with a longer time from random assignment to relapse (< 1, 1 to 2, >or= 2 years; log-rank test for trend P, .0497).. DFS and OS were not statistically different between treatment groups and treatment durations. These data confirm the value of LV5FU2 as control arm in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer and Pan-European Trials in Adjuvant Colon Cancer studies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Neoplasm Recurrence, Local; Prognosis; Survival Rate

The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern.. Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS).. Evidence of OXLIPN was disclosed in 16 of the 25 patients (64%). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9 +/- 5.8 (range 7-28). All longitudinal comparisons concerning the motor conduction parameters failed to reach significance. By contrast, comparisons of the median changes at baseline and each of the follow-up studies revealed significant decrease in all sensory action potentials examined.. Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colonic Neoplasms; Electrophysiology; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Motor Neurons; Neoplasm Metastasis; Neurons, Afferent; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Severity of Illness Index

Cases of severe gastrointestinal toxicity were monitored prospectively during NSABP C-07, a randomized clinical trial of adjuvant therapy for patients with stage II/III colon cancer.. Patients were treated with weekly bolus 5-fluorouracil (5-FU) and leucovorin (FL; "Roswell Park Regimen") or the same regimen plus oxaliplatin (FLOX).. Of 1857 patients, 79 (4.3%) developed a syndrome of bowel wall injury (BWI, small or large) characterized by hospitalization for the management of severe diarrhea or dehydration and radiographic or endoscopic evidence of bowel wall thickening or ulceration. Fifty-one (64.6%) of these adverse events occurred in patients treated with FLOX and 28 (35.4%) in those treated with FL (P < .01). Enteric sepsis (ES), characterized by grade 3 or greater diarrhea and grade 4 neutropenia with or without proven bacteremia occurred in 22 patients treated with FLOX, versus 8 in those treated with FL (P = .01). Patients >60 years were at higher risk for BWI after treatment with FLOX (6.7%) versus treatment with FL (2.9%, P < .01). Female patients had a higher incidence of BWI with FLOX (9.1%) than with FL (3.9%, P < .01). Severe gastrointestinal toxicity usually occurred during the third or fourth week on the first cycle of therapy, required hospitalization, and was managed with fluids, antidiarrheals, and antibiotics. There were 5 deaths (0.3%) due to enteropathy, 2 related to ES and 3 related to both BWI and ES. Seventy-one percent of patients resumed treatment with FL after recovery.. Patients treated with adjuvant FL should be closely monitored for diarrhea and aggressively managed, especially if oxaliplatin has been added to the regimen. Society.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Diseases; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Sex Factors

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging

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

Oral capecitabine (Xeloda) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings pound3653). Societal costs, including patient travel/time costs, were reduced by >75% with capecitabine vs 5-FU/LV (cost savings pound1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Drug Costs; Fluorouracil; Health Care Costs; Health Resources; Humans; Injections, Intravenous; Leucovorin; Neoplasm Staging; Quality of Life; Remission Induction; Sensitivity and Specificity; Survival Rate; Time Factors; Treatment Outcome; United Kingdom

The primary aim of this study was to compare the relative efficacy of oral uracil and tegafur (UFT) plus leucovorin (LV) with the efficacy of weekly intravenous fluorouracil (FU) plus LV in prolonging disease-free survival (DFS) and overall survival (OS) after primary surgery for colon carcinoma.. Between February 1997 and March 1999, 1,608 patients with stage II and III carcinoma of the colon were randomly assigned to receive either oral UFT+LV or intravenous FU+LV.. Of the total patients, 47% had stage II colon cancer, and 53% had stage III colon cancer. Median follow-up time was 62.3 months. The estimated hazard ratio (HR) for OS of patients who received UFT+LV versus that of patients who received FU+LV was 1.014 (95% CI, 0.825 to 1.246). The estimated HR for DFS was 1.004 (95% CI, 0.847 to 1.190). Cox proportional hazards model analyses with regard to age (< 60 v > or = 60 years), stage, or number of involved nodes (none v one to three v > or = four nodes) revealed no interaction with OS or DFS. Toxicity was similar in the two groups. In the UFT+LV arm, 38.2% of patients experienced any grade 3 or 4 toxic event compared with 37.8% of patients in the FU+LV arm. Primary quality-of-life end points did not differ between the two regimens, although convenience of care analysis favored UFT+LV.. UFT+LV achieved similar DFS and OS when compared with an intravenous, weekly, bolus FU+LV regimen. The two regimens were equitoxic and generally well tolerated.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Quality of Life; Tegafur; Uracil

Infusional fluorouracil (5-FU) and leucovorin (LV) with oxaliplatin is one of the current standard regimens for the treatment of patients with metastatic colorectal cancer. Weekly bolus 5-FU with high-dose LV (Roswell Park Memorial Institute Regimen: RPMI) is the most commonly used regimen in Japan. The objectives of this study were to determine the recommended dose (RD) of RPMI combined with oxaliplatin and to evaluate the toxicity and efficacy at the RD.. The subjects were 18 patients with metastatic colorectal cancer. Oxaliplatin (85 mg/m2) was given intravenously over 2 h on days 1 and 15 with l-LV (250 mg/m2) given intravenously over 2 h and 5-FU as an intravenous bolus on days 1, 8, and 15. This treatment was repeated every 4 weeks. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2).. A total of 14 patients received level 1, and 4 received level 2. Three of the patients had dose-limiting toxicity (DLT) in cycle 1 of level 2 (grade 3 thrombocytopenia, grade 4 neutropenia and grade 2 neutropenia in one patient each), requiring that treatment was delayed for longer than 7 days. None of the 14 patients given level 1 had DLT or grade 3 or 4 gastrointestinal toxicity. Sensory neuropathy occurred in all patients. Objective response rates were 61% in the 18 patients studied and 64% at level 1. The median time to progression was 171 days, and the median overall survival time was 603 days in the 18 patients studied.. Oxaliplatin (85 mg/m2) with weekly bolus 5-FU (400 mg/m2) and high-dose l-LV (250 mg/m2) is recommended for further phase III studies in patients with metastatic colorectal cancer.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Rectal Neoplasms; Remission Induction; Survival Rate

Levamisole combined with 5-fluorouracil (5-FU) was previously shown to significantly reduce tumor relapses and improve patient survival when given postoperatively in patients with resected stage III colon cancer. Laboratory investigations subsequently documented a direct dose-dependent enhancement of 5-FU cytotoxicity with increasing concentrations of levamisole against human cancer cell lines. A clinical trial was designed to test the value of levamisole given at its maximum tolerated dose in combination with 5-FU-based chemotherapy.. Eight hundred seventy-eight patients who had undergone complete surgical resection of high-risk stage II/III colon cancer were stratified by known prognostic factors and randomized to receive 1 of 2 treatment regimens: standard-dose levamisole combined with 5-FU and leucovorin; or high-dose levamisole combined with the same chemotherapy. Serum neopterin was monitored in a cohort of patients to evaluate immune function.. Severe vomiting and neurologic side effects required reduction in the dose of levamisole that could be safely administered on the high-dose levamisole regimen. There were no significant differences in disease-free survival, overall survival, or levels of serum neopterin between the treatment regimens.. It was not possible to improve the efficacy of surgical adjuvant chemotherapy for patients with high-risk colon cancer by giving levamisole at its maximum tolerated dose in combination with 5-FU and leucovorin. High rates of severe gastrointestinal and neurologic side effects were observed with the high-dose levamisole regimen.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neopterin

Similar epidemiologic characteristics suggest a common etiology for colon cancer (CC) and diverticular disease of the colon (DD). The relationship between the 2 diseases is still unclear, and the impact of DD in patients diagnosed with CC on disease-free survival (DFS) and overall survival (OS) is unknown. National Surgical Adjuvant Breast and Bowel Project (NASBP) protocol C-06 is a clinical trial comparing oral uracil/tegafur/leucovorin with 5-fluorouracil/leucovorin in patients with resected stage II/III carcinoma of the colon.. The NASBP enrolled 1,608 patients who had undergone potentially curative resection for stage II/III colon cancer from 256 medical sites between February 14, 1997, and March 31, 1999.. Pathology reports from 1561 eligible patients retrospectively reviewed for the presence of DD revealed that 160 (10.2%) had this disease. The median ages of patients with CC and DD and without DD were 67 and 61 years, respectively (P < 0.05). The majority of patients were white, and Hispanic patients were better represented in the group with DD (P < 0.05). Colon cancer was located in the rectosigmoid in 46.88% of patients with DD and in 31.92% of patients without DD (P < 0.05). A baseline diagnosis of DD made no significant contribution to DFS or OS without adjustment for confoundin factors (P = 0.2 and P = 0.32, respectively) or adjusted for Dukes classification and age (P = 0.49 and P = 0.68, respectively).. The prevalence of DD in patients diagnosed and treated for CC was 10.2%. Patients with CC with and without DD differed from each other with respect to age, tumor location, and ethnicity. There was no negative impact of having DD on DFS and OS in patients treated for stage II/III CC.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Cohort Studies; Colonic Neoplasms; Diverticulum, Colon; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Tegafur

There is an argument on whether or not glutamine-supplemented parenteral nutrition is beneficial to chemotherapy in gastrointestinal neoplasm patients. The aim of this study was to prospectively evaluate the effect of parenteral nutrition with alanyl-glutamine dipeptide on gastrointestinal neoplasm patients receiving chemotherapy.. This study was a prospective, randomized double-blind clinical trial. Seventy-two patients were randomly divided into study group and control group (each group had 36 patients). The side effects during chemotherapy were observed. Serum albumin, serum pre-albumin, IgG, IgA, IgM, C3, C4 level were measured before chemotherapy and on day 4 and day 8 after chemotherapy. Nitrogen balance was also calculated simultaneously.. (1) Less side effects during chemotherapy in study group were revealed compared to those in control group (P<0.05). (2) Serum albumin and pre-albumin levels were both decreased in the two groups on day 4 after chemotherapy, and were markedly decreased in control group on day 8 after chemotherapy (P<0.05). (3) IgG, IgM, IgA levels were all decreased compared with the test results before chemotherapy on day 4 after chemotherapy in two groups, and were significantly decreased in control group on day 8 after chemotherapy (P<0.05). C3 and C4 levels were higher in study group compared with control group on day 8 after chemotherapy (P<0.05). (4) Nitrogen balance in study group was better than that in control group (P<0.05) on day 8 after chemotherapy.. Alanyl-glutamine dipeptide is beneficial to chemotherapy in gastrointestinal neoplasm patients. It could reduce the side effects of chemotherapy, which helps to improve the nutritional status, the immune function and the survival quality of patients during chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Complement C3; Complement C4; Dipeptides; Double-Blind Method; Female; Fluorouracil; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Leucovorin; Male; Middle Aged; Nitrogen; Parenteral Nutrition; Prealbumin; Prospective Studies; Rectal Neoplasms; Serum Albumin; Stomach Neoplasms; Young Adult

To evaluate the efficacy and safety of modified FOLFIRI regimen in advanced colorectal cancer (CRC) patients refractory to fluoropyrimidine and oxaliplatin.. The modified FOLFIRI regimen consisted of intravenous infusion of irinotecan 180 mg/m2 d1 + LV 200 mg/m2 dl + 5-Fu 400 mg/m2 bolus dl plus 46-hour intravenous infusion of 5-Fu 2.4 g/m2, every 2 weeks as one cycle. The main selection criterion for this study was the advanced CRC refractory to fluoropyrimidine and oxaliplatin.. Of the 80 evaluable patients for efficacy: 10 (12.5%) had a partial response, 51 (63.7%) stable disease, and 19 (23.8%) progressive disease. The median time to progression was 96 days. Safety analysis was based on the data of 83 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia (24.1%), nausea/vomiting (8.4%), and diarrhea (2.4%).. Modified FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Pyrimidines; Rectal Neoplasms; Remission Induction; Treatment Failure

The orally bioavailable matrix metalloproteinase inhibitor MMI270 reduces tumour growth metastasis in preclinical models. We assessed the feasibility and pharmacokinetic interactions of combining MMI270 with 5-fluorouracil (5-FU) and folinic acid (FA). Entered into the study were 33 patients with advanced colorectal cancer. They received FA 200 mg/m2 over 2 h followed by 5-FU 400 mg/m2 over 15 min and 5-FU 600 mg/m2 over 22 h on days 1 and 2 of a 14-day cycle. MMI270 commenced with the second cycle at either 50 mg once daily, 150 mg three times daily or 300 mg twice daily. No dose-limiting toxicity was observed at any MMI270 dose level. Ten patients (61%) experienced joint symptoms independent of MMI270 dose, leading to interruption, modification, or discontinuation of treatment in seven patients (23%). MMI270 did not alter 5-FU pharmacokinetics. Six patients had a partial response and seven had stable disease. 5-FU/FA with MMI270 at a dose of 300 mg twice daily is well tolerated. MMI270 has no significant effect on 5-FU pharmacokinetics.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Hydroxamic Acids; Leucovorin; Male; Metalloendopeptidases; Middle Aged; Protease Inhibitors; Pyrazines; Rectal Neoplasms; Sulfonamides

Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. The impact of continuous 5-FU with and without leucovorin on survival and tumor recurrence was analyzed in this study compared with the effects of bolus 5-FU/leucovorin.. Patients with a curatively resected UICC stage III colon cancer were stratified according to T, N and G category and randomly assigned to receive one of the three adjuvant treatment schemes: 5-FU 450 mg/m2 and leucovorin 100 mg/m2 x 5 days every 4 weeks; six cycles, arm A; 24-h infusion of high-dose 5-FU/leucovorin 2,600 mg/m2 and 500 mg/m2, two cycles of six applications, arm B; 24-h infusion of high-dose 5-FU 2,600 mg/m2, two cycles of six applications, arm C.. One hundred and forty-five patients enrolled into this study were eligible. To date, 28 patients have died; 9 on arm A, 11 on arm B, and 8 on arm C (P was nonsignificant). After a median follow-up time of 45 months, there was no statistical difference in survival and tumor recurrence between the three treatment arms. Adjuvant treatment in all arms was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities.. There is no statistical difference in efficacy and toxicity in patients receiving either high-dose 5-FU with or without leucovorin or the standard 5-FU bolus regime after a curative resection of a stage III colon cancer.

Topics: Adenocarcinoma; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Postoperative Period; Retrospective Studies; Treatment Outcome

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Survival Rate

Modest toxicity and possibly enhanced activity makes continuous-infusion fluorouracil (FU) an attractive alternative to FU plus leucovorin (FU/LV) for the adjuvant treatment of colorectal cancer. Intergroup trial 0153 (Southwest Oncology Group trial 9415) was developed to compare the efficacy of continuous-infusion FU (CIFU) plus levamisole to FU/LV plus levamisole in the adjuvant treatment of high-risk Dukes' B2 and C1 or C2 colon cancer.. After surgery, patients were randomly assigned to CIFU 250 mg/m(2)/d for 56 days every 9 weeks for three cycles or FU 425 mg/m(2) and LV 20 mg/m(2) daily for 5 days every 28 to 35 days for six cycles. All patients received levamisole 50 mg tid for 3 days every other week. The primary end point was overall survival (OS).. The study closed in December 1999 after an interim analysis demonstrated little likelihood of CIFU showing superiority to FU/LV within the stipulated hazard ratio. A total of 1,135 patients were registered. At least one grade 4 toxicity occurred in 39% of patients receiving FU/LV and 5% of patients receiving CIFU. However, almost twice as many patients receiving CIFU discontinued therapy early compared with those receiving FU/LV. The 5-year OS is 70% (95% CI, 66% to 74%) for FU/LV and 69% (95% CI, 64% to 73%) for CIFU. The corresponding 5-year disease-free survival (DFS) is 61% (95% CI, 56% to 65%) and 63% (95% CI, 59% to 68%), respectively. For all patients, 5-year OS is 83%, 74%, and 55%; 5-year DFS is 78%, 67%, and 47% for N0, N1, and N2-3, respectively.. CIFU had less severe toxicity but did not improve DFS or OS in comparison with bolus FU/LV.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Levamisole; Male; Middle Aged

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

The purpose of this trial was to examine the efficacy of the addition of levamisole (LEV) or interferon alfa (IFN) to an adjuvant chemotherapy with 5-fluorouracil (5-FU) in patients with stage III colon cancer. According to a 2 x 2 factorial study design, 598 patients were randomly assigned to one of four adjuvant treatment arms. Patients in arm one received 5-FU weekly for 1 year, patients in arm two 5-FU plus LEV, in arm three 5-FU plus IFN and patients in arm four 5-FU, LEV and IFN. The relative risk of relapse and the relative risk of death were significantly higher for patients treated with LEV compared with those without LEV treatment (HR 1.452, 95% CI 1.135-1.856, P=0.0028; HR 1.506, 95% CI 1.150-1.973, P=0.0027, respectively). No significant impact on survival was observed for therapy with IFN in the univariate analysis. The addition of LEV to adjuvant 5-FU significantly worsened the prognosis of patients with stage III colon cancer. Interferon alfa had no significant influence on survival when combined with adjuvant 5-FU, but increased the toxicity of therapy substantially.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Survival Analysis

Seventy-two patients suffering from a metastatic colorectal cancer received, as first line treatment, a combination chronotherapy with 5-FU and folinic acid (infused from 10 pm to 10 am with a peak at 4 am, respectively at doses of 700 and 300 mg/m2 per day) and carboplatin (infused at the dose of 40 mg/m2 per day from 10 am to 10 pm with a peak at 4 pm). The courses of four days were repeated every two weeks. A major tumoral response was observed in 60% cases (68% in those not previously treated with adjuvant chemotherapy). The median times to progression and overall survival established at 11 and 27 months. The clinical (grades 3-4 in maximum 5% cases) and hematological (grades 3-4 in maximum 10-29% cases) toxicities were quite limited. Our observations suggest the interest to incorporate carboplatin in the combined infusional treatment of colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chronobiology Phenomena; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Survival Analysis

Thirty-seven patients operated from a Dukes B2-C colon cancer were randomised to receive as adjuvant infusional chemotherapy, nine 5 FU and folinic acid courses with or without carboplatin, as standard (de Gramont; 2 days every 2 weeks) or chronomodulated administration (4 days every 2 weeks). The overall tolerance was judged excellent with less than 7% courses with dose-adaptations. The two carboplatin arms presented an enhanced haematological toxicity, while some more cutaneous toxicity was observed in the chronomodulated arm with the three drugs.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chronobiology Phenomena; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

A randomized controlled trial was started in Japan to evaluate whether laparoscopic surgery is the optimal treatment for colorectal cancer. Patients with T3 or deeper carcinoma in the colorectum without transverse and descending colons are pre-operatively randomized to either open or laparoscopic colorectal resection. Surgeons in 24 specialized institutions will recruit 818 patients. The primary end-point is overall survival. Secondary end-points are relapse-free survival, short-term clinical outcome, adverse events, the proportion of conversion from laparoscopic surgery to open surgery, and the proportion of completion of laparoscopic surgery.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Endpoint Determination; Fluorouracil; Humans; Laparoscopy; Leucovorin; Lymph Node Excision; Middle Aged; Rectal Neoplasms; Sigmoid Neoplasms; Survival Rate; Treatment Outcome

The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer.. Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha.. A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively.. Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Interferon-alpha; Leucovorin; Levamisole; Male; Middle Aged; Patient Compliance; Survival Rate

Hemolytic anemia has been noted during treatment with a variety of chemotherapeutic agents. We observed mild compensated hemolytic anemia in a patient receiving capecitabine during a randomized, controlled trial of adjuvant therapy. In order to investigate the hypothesis that hemolysis is the underlying cause of the hyperbilirubinemia sometimes observed during capecitabine treatment, we evaluated factors associated with hemolysis in ten patients. Factors were also analyzed in ten patients receiving 5-fluorourocil/leucovorin (5-FU/LV).. Twenty chemotherapy-naïve patients undergoing surgery for Dukes' C colon cancer were included in the phase III, 'X-ACT' trial, and randomized to receive 24-week adjuvant treatment with either oral capecitabine (eight cycles of 1,250 mg/m2 twice daily for 14 days, followed by a 7-day rest period) (n=10) or 5-FU/LV administered according to the Mayo Clinic regimen (six cycles of LV 20 mg/m2 followed by 5-FU 425 mg/m2, administered as an i.v. bolus on days 1-5 every 28 days) (n=10). Ten patients randomized in each treatment arm were evaluated. Hemolytic parameters evaluated included bilirubin, lactate dehydrogenase, haptoglobin, and reticulocytes.. Seven patients receiving capecitabine and three patients receiving 5-FU/LV experienced grade 1/2 elevations of bilirubin during the 24-week treatment period. In most cases, hyperbilirubinemia was associated with concomitant alterations in other hemolytic parameters. Five episodes of grade 1 compensated hemolytic anemia were reported in four capecitabine-treated patients, all of which were associated with hyperbilirubinemia.. Adjuvant treatment with capecitabine or 5-FU/LV in a small sample of patients with Dukes' C colon cancer was associated with alterations in hemolytic parameters. These alterations, in particular hyperbilirubinemia, were associated in some patients with low-grade compensated hemolytic anemia. All changes were clinically insignificant, fully reversible, and may represent a fluoropyrimidine class effect. Further studies are indicated to evaluate the incidence and implications of this effect.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Hemolysis; Humans; Hyperbilirubinemia; Injections, Intravenous; Leucovorin; Middle Aged

Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy.. We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 males and 13 females with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement.. The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMCs) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25T-reg+). A cytofluorimetric study of the PBMCs of five HLA-A(*)02.01+ patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes.. The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.

Topics: Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colonic Neoplasms; Colorectal Neoplasms; Cytotoxicity, Immunologic; Deoxycytidine; Disease Progression; Female; Flow Cytometry; Fluorouracil; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Infusions, Intravenous; Interleukin-2; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; T-Lymphocytes, Regulatory; Thymidylate Synthase; 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

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Middle Aged; Survival Analysis; Treatment Outcome

In 1990, fluorouracil (FU) plus levamisole for 1 year became standard adjuvant treatment for patients with high-risk stages II and III colon cancer. Intergroup (INT) 0089 assessed the relative contributions of leucovorin and levamisole in such patients.. From 1988 to 1992, 3,794 patients were randomly assigned. Experimental treatment consisted of one of three chemotherapy regimens: the low-dose leucovorin plus FU (Mayo Clinic; LDLV) regimen, the high-dose leucovorin plus FU (Roswell Park; HDLV) regimen, and the low-dose leucovorin plus levamisole plus FU (LDLV plus LEV) regimen, each administered for 30 to 32 weeks. The control arm was levamisole plus FU (LEV) for 1 year.. After a median follow-up of 10 years, of 3,561 eligible patients, 1,691 (47%) have died and 1,330 (37%) have experienced disease recurrence; 137 (10%) of those experiencing recurrence are still alive. A total of 481 patients (13%) died without evidence of recurrence, and 1,723 (48%) are alive and disease free. Although there were toxicity differences among the four arms, none was statistically superior in disease-free or overall survival.. The 6- to 8-month regimens of LDLV and HDLV without levamisole used in this trial, rather than the previous standard regimen of 12 months of LEV, have become widely used. INT-0089 has long-term follow-up of the largest clinical trial of patients with high-risk colon cancer, documenting not only the durability of the treatment effects, but also the natural history of patients with high-risk colon cancer, and analyses of treatment based on age, race, and comorbid conditions such as obesity, diabetes, and second primary cancers.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adult; Aged; Agranulocytosis; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Patient Compliance; Risk Factors; Survival Analysis; Treatment Outcome; Vitamin B Complex

The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.. Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination. Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent.. The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Topics: Adult; Aged; Amidines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Indans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pseudomyxoma Peritonei; Rectal Neoplasms; Treatment Outcome

5-fluorouracil-based adjuvant chemotherapy after surgical resection of colon cancer is standard treatment. However, the choice of best delivery route--that is, systemic (i.e., intravenous or oral) or regional (i.e., intraportal, intraperitoneal, or hepatic arterial infusion)--has been controversial. In a randomized clinical trial of patients with colon cancer, we compared the benefits of chemotherapy delivered by these routes individually or in combination.. From April 2, 1992, through April 30, 1998, 1084 eligible patients with Dukes' stage B or C colon carcinoma were randomly assigned: 369 patients to the IP regimen (continuous portal vein infusion of 5-fluorouracil at 500 mg/m2 of body surface daily and heparin at 5000 IU daily for 7 consecutive days, beginning on the day of surgery), 358 patients to the SY regimen (six 28-day courses of systemic leucovorin at 100 mg/m2 daily on days 1 through 5 followed by systemic bolus 5-fluorouracil at 370 mg/m2 daily on days 1 through 5, with treatment initiated 15-35 days after surgery), and 357 patients to the IP+SY regimen (the IP regimen followed by the SY regimen, with the same scheduling). Primary survival was analyzed with the log-rank statistic and a Cox multivariable regression model. All statistical tests were two sided.. At a median follow-up time of 99 months, 389 events (recurrences, second malignancies, or deaths) had occurred, and 361 patients died. Sites of first recurrences were similar among the three arms. At 5 years, overall and event-free survival rates were similar among those on the IP (74% and 68%, respectively), SY (78% and 71%), and IP+SY (73% and 67%) regimens. When compared with the group on the SY regimen, the risk for death associated with the IP regimen (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 0.82 to 1.36) was similar to that associated with the IP+SY regimen (HR = 1.12, 95% CI = 0.78 to 1.45) (P =.69), as were the risks for first event (HR = 1.07, 95% CI = 0.84 to 1.37 and HR = 1.10, 95% CI = 0.86 to 1.41, respectively) (P=.74).. Overall and event-free survival rates were similar in all three arms. The combined regimen was no better than either single regimen alone.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Italy; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Portal Vein; Prognosis; Research Design; Risk Factors; Survival Analysis; Treatment Outcome

The aim of this study was to evaluate the efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (l-LV) given at the same dose intensity and administered monthly (given weekly for 3 weeks followed by a week of rest; arm A) or every 2 months (given weekly for 6 weeks followed by 2 weeks rest; arm B) to patients with advanced colorectal carcinoma. The dose of 5-FU was 500 mg/body or 750 mg/body, with an average dose of 432.8 mg/m2. A total of 7 institutions participated in this multi-center study and were randomly divided into 2 groups of arms A and B. Thirty-three patients were entered into arm A and 21 into B. The overall response rate was significantly (p = 0.007) greater in arm B (23.5%) than in arm A (0%). The most frequently observed toxicity was diarrhea, which was observed in 6.5% of arm A and in 33.3% of arm B, marking a significant difference (p = 0.034). These data suggest that a monthly 5-FU/l-LV regimen might be less toxic than a 2-months regimen and less effective at the dose given as above. Further study is needed to evaluate the efficacy of a monthly regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Case-Control Studies; Colonic Neoplasms; Diarrhea; Drug Administration Schedule; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Rectal Neoplasms; Remission Induction; Survival Rate

The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting.. We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival.. A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent).. Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Survival Analysis

5-Fluorouracil (5-FU) is a common anticancer agent used in the treatment of solid tumours, with a reported variability in the pharmacokinetic profile and inter-patient differences in efficacy and toxicity. Since 5-FU is intracellularly metabolised to active cytotoxic fluoronucleotides, some authors suggested it would be useful to determine the plasma levels of its main metabolites 5-fluoro-5,6-dihydrouracil (5-FUH2), 5-fluorouridine (5-FUrd) and 5-fluoro-2'-deoxyuridine (5-FdUrd), in order to better characterise population pharmacokinetics-pharmacodynamics (PK-PD) of this drug. We developed and validated an HPLC method to simultaneously determine plasma concentrations of 5-FU and the three main metabolites, and we analysed the plasma concentration-time curves of the first dose of 18 colon cancer patients treated with folinic acid and 5-FU 400 mg m(-2) by intra-venous bolus injection as adjuvant chemotherapy. Non-compartmental PK analysis has been applied to 5-FU and 5-FUH2 concentrations, estimating the following parameters (median values): Cmax 55.44 and 6.23 microg ml(-1), respectively, AUC(0-2 h) 11.59 and 5.94 hx microg ml(-1), CLTB 30.64 and 51.81 lh(-1) m(-2), 5-FUH2/5-FU AUC ratio 0.47 (range 0.29-1.12). We verified the patient covariables which could influence the inter-patient variability in the area under the time-concentration curves, and we observed that age, sex, weight, body surface area, cycle of therapy, toxicity development and 5-FUrd or 5-FdUrd detectability did not have statistical influence on 5-FUH2/5-FU AUC ratio. In eight subjects, we compared the PK data of the first and the fifth day of dose administration, and we found stable 5-FU values, but the 5-FUH2 disposition decreased with lower AUC(0-2 h) (7.90 hx microg ml(-1) versus 5.99 hx microg ml(-1)) and, particularly, Cmax (8.38 microg ml(-1) versus 5.50 microg ml(-1)) at day 5. This fact, evident in almost every patient, could suggest a possible reduction in the catabolic pathway of 5-FU leading to 5-FUH2, with a possible increase of the therapeutic pathway. For this reason, we tried to detect 5-FUrd and 5-FdUrd and, in fact, in our patients these metabolites were detected only in few samples, but most of them at day 5. In conclusion, our study confirms the relevance of pharmacokinetic analysis of 5-FU main metabolites and especially 5-FUH2, to better understand the metabolism and to improve the therapeutic efficacy.

Topics: Adult; Aged; Area Under Curve; Chromatography, High Pressure Liquid; Colonic Neoplasms; Drug Administration Schedule; Drug Evaluation; Female; Floxuridine; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Kinetics; Leucovorin; Male; Middle Aged; Uridine

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Neoplasm Staging; Treatment Outcome

To define the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with stage II and III colon carcinoma.. We retrospectively analyzed the prognostic value of TS, Ki-67, and p53 in 706 patients with Dukes' B (291 patients) or Dukes' C (415 patients) colon carcinoma who were treated with either surgery alone (275 patients) or surgery plus fluorouracil (FU)-leucovorin chemotherapy (431 patients) in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols C01-C04. All three markers were assayed using immunohistochemical techniques.. Using 5 years of follow-up data, our retrospective analysis demonstrated an association between TS intensity (relapse-free survival [RFS]: risk ratio [RR] = 1.46, P =.01; overall survival [OS]: RR = 1.54, P =.002), Ki-67 (RFS: RR = 0.76, P =.05; OS: RR = 0.62, P =.001), and p53 (RFS: RR = 1.49, P =.01; OS: RR = 1.21, P =.18) for RFS and OS. High TS intensity levels and positive p53 staining were associated with a worse outcome. Tumors containing a high percentage of Ki-67-positive cells enjoyed an improved outcome compared with those patients whose tumors contained relatively few positive cells. An interaction with treatment was not identified for any of the markers.. This retrospective investigation demonstrated that TS, Ki-67, and p53 staining each had significant prognostic value for patients with Dukes' B and C colon carcinoma. However, none of the markers could be used to clearly discern groups of individuals who would be predicted to derive greater or lesser benefit from the use of adjuvant chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Immunoenzyme Techniques; Ki-67 Antigen; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Thymidylate Synthase; Tumor Suppressor Protein p53

Adjuvant postoperative treatment with 5-fluorouracil (5-FU) and leucovorin in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrences and improves survival. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in a long-term follow-up study in comparison with the effects of 5-FU plus levamisole in the prospective multicenter trial adjCCA-01.. Patients with a curatively resected stage III (International Union Against Cancer) colon cancer were stratified according to tumor, node and grading category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m2 body surface area intravenously in the first chemotherapy course, then 450 mg/m2 x 5 days, plus leucovorin 100 mg/m2, 12 cycles (arm A), or 5-FU plus levamisole (Moertel scheme; arm B).. Six hundred and eighty (96.9%) of 702 patients enrolled into this study were eligible. To date, 261 patients have died, 117 on arm A and 144 on arm B (P = 0.007). After a median follow-up time of 82 months, the 5-FU plus leucovorin combination significantly improved disease-free survival [79.8 months in arm A versus 69.3 months in arm B (P = 0.012)] and significantly increased median overall survival (88.9 months in arm A versus 78.6 months in arm B; P = 0.003). Adjuvant treatment with 5-FU plus levamisole as well as 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities.. After curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated. This long-term follow-up study demonstrates that adjuvant treatment with 5-FU plus leucovorin given for 12 cycles is significantly more effective than 5-FU plus levamisole (Moertel scheme) in reducing tumor relapse and improving survival.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis

Obesity is a risk factor for the development of colon carcinoma. The influence of body mass index (BMI) on long-term outcomes and treatment-related toxicity in patients with colon carcinoma has not been well characterized.. This cohort study was conducted within a large, randomized adjuvant chemotherapy trial of 3759 men and women with high-risk, Stage II and Stage III colon carcinoma who were treated between 1988 and 1992 throughout the United States. With a median follow-up of 9.4 years, the authors examined the influence of BMI on disease recurrence, overall survival, and treatment-related toxicity.. Compared with women of normal weight (BMI, 21.0-24.9 kg/m(2)), obese women with colon carcinoma (BMI > or = 30.0 kg/m(2)) experienced significantly worse overall mortality (hazard ratio [HR], 1.34; 95% confidence interval [95% CI], 1.07-1.67) and a nonsignificant increase in the risk of disease recurrence (HR, 1.24; 95% CI, 0.98-1.59). The influence of BMI among women was not related to any differences in chemotherapy dose-intensity across categories of BMI. In contrast, BMI was not related significantly to long-term outcomes among male patients in this cohort. Among all study participants, obese patients had significantly lower rates of Grade 3-4 leukopenia and lower rates of any Grade > or = 3 toxicity compared with patients of normal weight.. Among women with Stage II-III colon carcinoma, obesity was associated with a significant increase in overall mortality as well as a borderline significant increase in disease recurrence. Nonetheless, obesity was not associated with any increase in chemotherapy-related toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Body Weight; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity; Risk Factors; Survival Rate; Treatment Outcome; United States

This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer.. LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion.. A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001).. Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chi-Square Distribution; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Prognosis; Proportional Hazards Models; Survival Analysis; Treatment Outcome

To compare, in terms of compliance, toxicity, quality of life (QOL) and efficacy, intravenous 5-fluorouracil plus folinic acid with oral tegafur-uracil plus folinic acid as postoperative adjuvant chemotherapy after curative resection in patients with Dukes' stage B2 and C2 colon cancer. Among all patients with adenocarcinoma of the colon operated on between July 1997 and June 1999, 122 with Dukes' stage B2 or C2 colon cancer were enrolled in this study. Fifty-three patients were treated with intravenous 5-fluorouracil plus folinic acid (5-FU group) and 69 with oral tegafur-uracil plus folinic acid (UFT group). Compliance, toxicity, QOL and efficacy were evaluated. Compared with the 5-FU group, patients in the UFT group experienced a lower incidence of grade 1 toxicity. The incidences of grade 2-4 toxicity were similar in the two treatment groups. However, severe toxicity (grade 3 or 4) was rare in both groups. A steady and significant increase of the QOL score, both during and after therapy, was evident in both groups suggesting that chemotherapy is quite tolerable and does not deteriorate the patients' QOL. At the median follow-up duration of 28 months, the survival rate and disease free survival rate for the UFT and 5-FU groups were 94.9% vs. 92.5% and 87.5% vs. 84.1%, respectively (p > 0.05). These data suggest that oral tegafur-uracil modulated with oral folinic acid as an adjuvant chemotherapy in patients with Dukes' stage B2 and C2 colon cancer may be a good alternative to infusional 5- fluorouracil.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Male; Middle Aged; Tegafur

To determine whether the addition of leucovorin to the combination 5-fluorouracil plus levamisole prolongs disease-free survival and overall survival in patients with radically resected colon cancer (Dukes' B(2-3) and C).. Patients (1703) were accrued between March 1992 and February 1995 in a large-scale clinical trial within five Italian cooperative groups. After stratification for center, patients were randomized as follows: arm A, 5-fluorouracil [450 mg/m(2) intravenous (i.v.) bolus on days 1-5] and levamisole (150 mg orally for 3 days, every 14 days for 6 months) versus arm B, 6-S-leucovorin (100 mg/m(2) i.v. bolus on days 1-5) followed by 5-fluorouracil (370 mg/m(2) i.v. bolus on days 1-5), plus levamisole (as arm A), every 4 weeks for six cycles.. After a median follow-up of 6.4 years no significant difference was seen for either disease-free survival (58% versus 60%, not significant) or 5-year overall survival (68% versus 71%, not significant), respectively. Gastrointestinal toxicity (World Health Organization grade 3/4) was more frequent in arm B (8% versus 18%, not significant).. In this trial the schedules used showed no statistically significant differences in terms of disease-free survival or overall survival in the treatment 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; Levamisole; Male; Middle Aged; Treatment Outcome

To evaluate the efficacy and safety of irinotecan as second-line treatment in patients with advanced colorectal cancer (ACC) failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV) standard chemotherapy.. Irinotecan was randomly administered in two different schedules (once every 3 weeks, and every 10 days) in patients failing prior 5-FU plus LV. Patients were randomized to two treatment groups: group A received irinotecan 350 mg/m2 every 21 days and group B received irinotecan 175 mg/m2 days 1 and 10 every 21 days.. Group A comprised 60 patients: 34 male/26 female, median age 64 years (range 48-70 years), and median Karnofsky performance status (PS) 90. Their metastatic sites included liver (n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8), "other" (n=2), and local recurrence (n=12). Group B comprised 60 patients: 36 male/24 female, median age 62 years (46-70 years), and median PS 90. Their metastatic sites included liver (n=49), lymph nodes (n=29), lung (n=17), abdomen (n=16), pelvis (n=11), "other" (n=2), and local recurrence (n=13). Group A showed the following responses: complete response (CR) 2, partial response (PR) 12, stable disease (SD) 21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor growth control 58%. Group B showed the following responses: CR 1, PR 14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities included acute cholinergic syndrome (group A 53%, group B 19%; P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%) and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A 30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%, group B 28%; P<0.03), with febrile neutropenia seen in only four patients in group A, anemia grade more than 2 (group A 28%, group B 12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%; P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%; P<0.2).. . The present study indicates that, in patients with ACC who have relapsed after 5-FU plus LV, the administration of irinotecan fractionated into two doses every 21 days yields a similar efficacy to, but a much lower incidence of toxicity than, the same total dose of irinotecan administered once every 21 days.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Disease Progression; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Irinotecan; Karnofsky Performance Status; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Rectal Neoplasms; Topoisomerase I Inhibitors

Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer.. Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m(2) with i.v. leucovorin 20 mg/m(2) on days 1-5, repeated every 28 days (n = 974).. Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or > or = 65 years old.. Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer

Topics: Administration, Oral; Adult; Age Factors; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Peripheral Nervous System Diseases; Safety

Active specific immunotherapy, using vaccines with autologous tumour cells and BCG, significantly reduces the rate of tumour recurrence in stage II colon cancer patients, while no clinical benefit has yet been observed in stage III patients. Adjuvant treatment with 5-Fluorouracil/Leucovorin is now considered standard therapy for stage III colon carcinoma and results in an absolute survival benefit of approximately 10%. Yet, the 5-year overall survival rate of stage III colon cancer patients is only 40-50%. Combining chemotherapy and immunotherapy might improve prognosis for stage III patients, especially when considering that active specific immunotherapy and chemotherapy have shown synergistic effects in pre-clinical tumour models. We performed a phase II study with 56 patients, using the combination of active specific immunotherapy and chemotherapy as an adjuvant therapy in stage III colon cancer patients to assess the influence of 5-Fluorouracil/Leucovorin on anti-tumour immunity induced by autologous tumour cell vaccinations. Anti-tumour immunity was measured before and after chemotherapy by means of delayed type hypersensitivity reactions, taken 48 h after the third and the fourth vaccination. We also investigated the toxicity of this combined immuno-chemotherapy treatment. Delayed type hypersensitivity reactions before chemotherapy had a median size of 20.3 mm, while after chemotherapy delayed type hypersensitivity size was 18.4 mm (P=0.01), indicating that chemotherapy hardly affected anti-tumour immunity. The severity of ulcers at the BCG vaccination sites was comparable to previous studies. In 30% of the patients grade III or grade IV chemotherapy related toxicity was seen; this is comparable to what is normally observed after adjuvant chemotherapy alone. This study shows that the active specific immunotherapy-induced anti-tumour immune response is only minimally impaired by consecutive chemotherapy and that the combined treatment of stage III colon cancer patients with active specific immunotherapy and 5-Fluorouracil/Leucovorin does not cause unexpected toxicity.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Hypersensitivity, Delayed; Immunotherapy, Active; Leucovorin; Male; Middle Aged; Neoplasm Staging

The purpose of the present study was to investigate the association between performance status (PS) and mean dose of irinotecan (CPT-11) in patients with recurrent advanced colorectal cancer relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients who had completed their last chemotherapy course with 5-fluorouracil and leucovorin for at least 6 weeks and progressed were included. Based on PS, we administered a starting dose of 250 mg/m(2) in patients with a PS 70-80 (group A), and 350 mg/m(2) for those with a PS > 80 (group B). Of a total of 90 treated patients, all were evaluable, 18 had a partial response (PR) (20%), 39 stable disease (43%), and 15 progressed (37%). No significant difference was noticed between patients with PS > or = 90 or < or = 80 (p = 0.925), or between those who received a mean dose of CPT-11 > or = 300 or < or = 300 (p = 0.602), for response, survival and time to progression. Toxicity was increased in group B as expected, with significant differences for acute cholinergic syndrome (p = 0.02), diarrhea after the first 24 h (p = 0.03) and severe diarrhea (p = 0.03). According to these results, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m(2) every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation.

Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Camptothecin; Colonic Neoplasms; Cost-Benefit Analysis; Drug Costs; Drug Resistance, Neoplasm; Female; Fluorouracil; Health Status; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; 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

Adjuvant postoperative treatment with fluorouracil (5-FU) and levamisole in curatively resected stage III colon cancer significantly reduces the risk of cancer recurrence and improves survival. Biochemical modulation of 5-FU with leucovorin has resulted in increased remission rates in metastatic colorectal cancer, thus reflecting an increased tumor-cell kill. The impact of 5-FU plus leucovorin on survival and tumor recurrence was analyzed in comparison with the effects of 5-FU plus levamisole in the prospective multicentric trial adjCCA-01.. Patients with a curatively resected International Union Against Cancer stage III colon cancer were stratified according to T, N, and G category and randomly assigned to receive one of the two adjuvant treatment schemes: 5-FU 400 mg/m(2) body-surface area intravenously in the first chemotherapy course, then 450 mg/m(2) x 5 days; 12 cycles, plus leucovorin 100 mg/m(2) (arm A), or 5-FU plus levamisole (Moertel scheme; arm B).. Six hundred eighty (96.9%) of 702 patients enrolled onto this study were eligible. After a median follow-up time of 46.5 months, the 5-FU plus leucovorin combination significantly improved disease-free survival (P =.037) and significantly decreased overall mortality (P =.0089) in comparison with 5-FU plus levamisole. In a multivariate proportional hazards model, adjuvant chemotherapy emerged as a significant prognostic factor for survival (P =.0059) and disease-free survival (P =.03). Adjuvant treatment with 5-FU plus levamisole as well as with 5-FU plus leucovorin was generally well tolerated; only a minority of patients experienced grade 3 and 4 toxicities.. After a curative resection of a stage III colon cancer, adjuvant treatment with 5-FU plus leucovorin is generally well tolerated and significantly more effective than 5-FU plus levamisole in reducing tumor relapse and improving survival.

Topics: Adjuvants, Immunologic; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome

The International Multicenter Pooled Analysis of Colon Cancer Trials (IMPACT) investigators have now completed two large systematic reviews of adjuvant therapy trials in colon cancer. The IMPACT 1 study pooled data from three separate trials each comparing the efficacy of 5-fluorouracil (5-FU)/leucovorin with observation alone as adjuvant treatment for 1,526 patients with Dukes' B or C colon cancer. The results showed that treatment with 5-FU/leucovorin significantly reduced mortality by 22% (P = .029) and events such as relapse, second tumor, or death by 35% (P < .0001) after 3 years of follow-up. The side effects associated with 5-FU/leucovorin were clinically acceptable. The IMPACT 1 study also showed a clear benefit of adjuvant treatment for patients with Dukes' C colon cancer, but not for stage-B patients. After up to 10 years of follow-up, 5-FU/leucovorin significantly reduced mortality by 30% for patients with Dukes' C disease (P = .003), but only reduced mortality by 8% in patients with Dukes' B colon cancer (P = .658). The aim of the IMPACT 2 study was to determine whether 5-FU/leucovorin is an effective adjuvant treatment for patients with Dukes' B2 colon cancer. Results were pooled from five separate trials that randomized 1,016 patients. After a median of 5.75 years of follow-up, B2 patients receiving 5-FU/leucovorin did not have a significant increase in overall survival or event-free survival. At 5 years, the hazard ratio for overall survival was 0.86 (90% confidence interval, 0.68 to 1.07) and for event-free survival was 0.83 (90% confidence interval, 0.72 to 1.07). 5-Fluorouracil/leucovorin was not recommended as a standard adjuvant treatment for all patients with Dukes' B2 colon cancer.

Topics: Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Neoplasm Staging; Survival Analysis

The aim of this randomized open-label study was to compare a bimonthly with a monthly regimen of 5-fluorouracil (5-FU) and leucovorin for the adjuvant treatment of colon and high-rectum adenocarcinoma. The bimonthly regimen was administered for 2 consecutive days every 14 days as d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 as a 2-hour infusion followed by 5-FU bolus of 400 mg/m2 and a 600 mg/m2 5-FU 22-hour continuous infusion (LVSFU2). In the monthly regimen, d,L-leucovorin 200 mg/m2 or L-leucovorin 100 mg/m2 15-minute infusion followed by a 400 mg/m2 15 minute 5-FU bolus was administered for 5 consecutive days every 28 days (FUFOL). Nine hundred five patients with recently resected stage B2 or C colon or high-rectum adenocarcinoma (inferior pole of the tumor subperitoneal) were recruited into the study. Patients were randomized in a 2 x 2 factorial design to receive either LV5FU2 or FUFOL for 24 or 36 weeks. Characteristics of the patients in the two different treatment groups were similar at baseline. Compliance was good. Mean 5-FU dose intensities were 930 mg/ m2/wk and 463 mg/m2/wk for LVSFU2 and FUFOL, respectively. The incidence of maximal grade III-IV toxicities for LVSFU2 and FUFOL was neutropenia 6% and 16% (P < .001), diarrhea 4% and 10% (P < .001), and mucositis 2% and 7% (P < .001), respectively. Maximum grade III-IV toxicities in the LV5FU2 treatment group were significantly lower than in the FUFOL group (10% v 26%; P < .001). Although patients in the LV5FU2 group received twice the dose of 5-FU compared with those in the FUFOL group, LV5FU2 was shown to be less toxic. Efficacy data will be available in 2001.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

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

We investigated the dose-related effect of the 5-fluorouracil (5-FU)/leucovorin regimen on survival in 139 colon cancer patients with Dukes' B2 and C2 stage disease. Chemotherapy consisted of 400 mg/m(2) of 5-FU and 20 mg/m(2) of leucovorin injected daily for 5 days in every 4 weeks for a maximum of 12 cycles. The total dose of 5-FU administered per body surface area had a significant effect on the 5-year disease-free survival and 5-year overall survival in stage B2 and C2 colon cancer patients (P=0.0018, P=0.0011). Analysis with reference to the median DSDI demonstrated that there was a significant difference in 5-year survival in Dukes' C2 (P=0.0016), but survival was not affected by the dose intensity. Multivariate analysis demonstrated that only the total dose of 5-FU administered per surface area affected the 5-year disease-free survival and 5-year overall survival (P=0.0016, P=0.0007, respectively). It can be concluded that the total dose of 5-FU administered is important in planned dosage schedule of adjuvant chemotherapy in colon cancer.

Topics: Adult; Aged; Antineoplastic Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Recurrence; Survival Analysis

To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination.. Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m(2) followed by a 400-mg/m(2) 5-FU bolus injection, then a 600-mg/m(2) continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m(2) on day 1) and oxaliplatin (85 mg/m(2) on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2) every 3 weeks.. In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred.. The every-3-weeks OC combination is safe and active in advanced 5-FU-resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Survival Rate; Treatment Outcome

5-fluorouracil (5-FU) clearly behaves as two different drugs according to the schedules for its administration. A weekly, 8-h 5-FU continuous infusion (CI) regimen may produce a dual effect, because it elicits both a high plasma 5-FU level and also a durable exposure to 5-FU, which may have the advantage of inhibiting both DNA synthesis and RNA activities. The plasma 5-FU level, however, cannot be monitored in most hospitals, so we initiated a pragmatic clinical trial with this weekly 8-h 5-FU Cl regimen and adjusted the drug's dose according to the detected toxicity.. The initial dose of 5-FU was 1200 mg/m2 and this was escalated by 200 mg/m2 weekly, provided that no evidence of significant (grade 2 or greater) toxicity became apparent. Twenty-six patients entered the study from June 1998 to March 1999.. The median dose of 5-FU delivered was 1600 mg/m2. The major symptoms precluding dose escalation were nausea and vomiting. Seven patients demonstrated a partial response (26.9%), 11 patients revealed stable disease (42.3%) and eight exhibited progressive disease (30.8%).. This weekly 8-h CI 5-FU protocol with the adjustment of dose according to toxicity was not able to achieve the same 5-FU dose and response rate as in previous studies with pharmacokinetic monitoring of 5-FU levels. However, with the concurrent administration of intensive anti-emetic premedication, it is still possible to achieve adequate plasma 5-FU levels by adjusting the 5-FU dose according to elicited toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Nausea; Rectal Neoplasms; Vomiting, Anticipatory

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

It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-alpha and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer.. To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer.. From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients).. A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received > or =80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths.. The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prognosis; Recombinant Proteins; Survival Analysis; Treatment Outcome

Biochemical modulation of 5-Fluorouracil activity with Leucovorin has been well documented in colorectal cancer. Several studies have shown increased efficacy of 5-fluorouracil in combination with alpha interferon. We therefore initiated a phase II trial of dual modulation of 5-fluorouracil with leucovorin and alpha interferon to evaluate outcomes in patients with metastatic carcinoma of the colon.. Patients with metastatic colon carcinoma with expected survival > 4 months and performance status of ECOG < or = 2 were treated weekly with Leucovorin 400 mg i.v. followed by 5-FU 600 mg/m2 i.v. bolus. Alpha interferon 3-9 million units was administered subcutaneously every Monday, Wednesday and Friday. Patients were analyzed for toxicity, tumor response and survival.. Sixteen patients with a median age of 66 years were treated. Three patients were not evaluable for response but were evaluable for toxicity. Grades 3 and 4 toxicities were neutropenia, diarrhea, mucositis, nausea and vomiting, fatigue, fever, asthenia and elevated hepatic enzymes. One patient died from complications associated with diverticulitis and neutropenia. Objective response rate was 23% (95% confidence interval 4-46%) and median survival was 11.5 months (95% confidence interval 6.3-19 months). Thirty-eight percent of the patients were alive at one year and 19% at two years.. The combination of 5-fluorouracil, leucovorin and alpha interferon as administered in this phase II study did not result in enhanced response rate or survival. However this regimen was associated with considerable toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Colonic Neoplasms; Combined Modality Therapy; Diverticulitis; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Immunologic Factors; Interferon-alpha; Leucovorin; Life Tables; Male; Middle Aged; Neutropenia; Survival Analysis; Treatment Failure

Standard adjuvant chemotherapy for colorectal cancer consists of fluorouracil with folinic acid or levamisole. The large QUASAR randomised trial aimed to investigate (in a two x two design) whether use of a higher dose of folinic acid or addition of levamisole to fluorouracil and folinic acid improved survival.. Patients with colorectal cancer, without evident residual disease, were randomly assigned fluorouracil (370 mg/m2) with high-dose (175 mg) or low-dose (25 mg) L-folinic acid and either active or placebo levamisole. The fluorouracil and folinic acid could be given either as six 5-day courses with 4 weeks between the start of the courses or as 30 once-weekly doses. Levamisole (50 mg) or placebo was given three times daily for 3 days repeated every 2 weeks for 12 courses. The primary endpoint was mortality from any cause. Analyses were by intention to treat.. Between 1994 and 1997, 4,927 patients were enrolled. 1,776 had recurrences and 1,576 died. Survival was similar with high-dose and low-dose folinic acid (70.1% vs 71.0% at 3 years; p=0-43), as were 3-year recurrence rates (36.0% vs 35.8%; p=0.94). Survival was worse with levamisole than with placebo (69.4% vs 71.5% at 3 years; p=0.06), and there were more recurrences with the active drug (37.0% vs 34.9% at 3 years; p=0.16).. The inclusion of levamisole in chemotherapy regimens for colorectal cancer does not delay recurrence or improve survival. Higher-dose folinic acid produced no extra benefit in these regimens over that from low-dose folinic acid. Trials of chemotherapy versus no chemotherapy will show whether these four treatments are equally effective or equally ineffective.

Topics: Adjuvants, Immunologic; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Levamisole; Neoplasm Recurrence, Local; Radiotherapy, Adjuvant; Rectal Neoplasms; Survival Analysis

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Levamisole; Neoplasm Staging

To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients.. Fifty-two patients with advanced colorectal carcinoma previously treated with one (25 cases) or two or more lines of chemotherapy, including irinotecan (26 cases), and/or modulated 5-FU (40 cases) entered this study. Starting doses of L-OHP, TOM, and 5-FU were 85, 2.5 and 750 mg/m2, respectively.. Seven dose levels were tested. Neutropenia was the main dose limiting toxicity of the dose escalation (8 of 13 cases). The recommended doses were 130 mg/m2 of L-OHP, and 3.0 mg/m2 of TOM on day 1, followed by 250 mg/m2 of LFA, and 1050 mg/m2 of 5-FU on day 2, every two weeks. Severe diarrhoea and stomatitis were rarely reported. Most patients complained of mild peripheral sensitive aeurotoxicity, which was related to the cumulative dose of L-OHP. Twelve patients were considered as having a major responses (one complete), and an additional eight patients showed a minor response; the median time to treatment failure was twenty-four weeks.. With this regimen it is possible to give full doses of all three cytotoxic drugs every two weeks. Its activity and its manageable toxicity profile deserve further evaluation in pretreated advanced colorectal cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Rectal Neoplasms; Thiophenes; Treatment Outcome

To assess the effect of the addition of leucovorin to the combination of 5-fluorouracil (5-FU)-levamisole on recurrence risk and overall survival in patients after a resection with curative intent of a Dukes' C colon cancer.. Five hundred patients with Dukes' C colon cancer were randomly assigned to adjuvant treatment for one year with 5-fluorouracil (450 mg/m2 i.v. weekly) and levamisole (150 mg p.o. every two weeks), the C-group or with leucovorin (20 mg/m2 i.v.), 5-fluorouracil and levamisole, the L-group. The median follow-up for patients still alive is 36 months. Four patients were ineligible because of advanced disease at the time of randomisation.. Sixty percent of the patients have completed all courses of chemotherapy. Of the remaining 40% of the patients who did not complete one-year treatment with chemotherapy, 46% discontinued because of toxic and/or emotional reasons. They were equally divided over both treatment arms. The addition of leucovorin increased toxicity (especially mucositis and conjunctivitis) without a significant increase in treatment withdrawal. Five-year disease-free interval (C-group: 49%, L-group: 46%; log-rank test, P = 0.86) and overall survival (C-group: 55%, L-group: 59%, log-rank test: P = 0.96) were very similar in both treatment arms.. The addition of low dose leucovorin to the combination of 5-fluorouracil and levamisole in a 12-month adjuvant therapy for curatively resected Dukes' C colon cancer patients does not improve disease-free interval nor overall survival. The addition of leucovorin to the combination of 5-FU levamisole increases toxicity. Therefore leucovorin 5-FU levamisole is not recommended in a 12 months adjuvant regime of Dukes' C colon cancer.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Middle Aged; Treatment Outcome

We assessed the hypothesis that a compromised p53 function could account for the non response of colon cancer patients with low thymidylate synthase (TS) expression receiving a bolus 5-fluorouracil (5-FU) leucovorin (LV) combination.. The study population consisted of 41 patients with unresectable metastatic colon cancer, homogeneously, treated with bolus 5-FU and LV.. Twenty-seven patients (66%) showed high levels of TS expression. The difference in the proportion of objective responses between patients with low (CR + PR: 7 of 14, 50%) and high (CR + PR: 0 of 27) TS levels was statistically significant (P = 0.0001, chi-square test). p53 nuclear over-expression was found in 27 of 41 patients (66%). No differences were observed in p53 overexpression in patients with high (66%) or low (66%) TS expression. p53 status was not found to be associated with response even in patients with low TS expression.. p53 status measured by immunohistochemistry does not seem to be useful to identify unresponsive patients with low TS expression.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colonic Neoplasms; Female; Fluorouracil; Genes, p53; Humans; Immunohistochemistry; Leucovorin; Male; Middle Aged; Predictive Value of Tests; Thymidylate Synthase; Tumor Suppressor Protein p53

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (fluorouracil [5-FU] plus leucovorin and 5-FU plus levamisole) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus leucovorin may offer a small disease-free survival and overall survival advantage. Evidence that UFT (uracil and tegafur) plus oral leucovorin is associated with significant antitumor activity and has an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU plus leucovorin vs UFT plus leucovorin. Preliminary analysis of the toxicity findings among 1,530 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Tegafur; Treatment Outcome; Uracil

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

Although the benefit from adjuvant chemotherapy has been clearly established in patients with Dukes' C colon cancer, such benefit has been questioned in patients with Dukes' B disease. To determine whether patients with Dukes' B disease benefit from adjuvant chemotherapy and to evaluate the magnitude of the benefit, compared with that observed in Dukes' C patients, we examined the relative efficacy of adjuvant chemotherapy according to Dukes' stage in four sequential National Surgical Adjuvant Breast and Bowel Project trials (C-01, C-02, C-03, and C-04) that compared different adjuvant chemotherapy regimens with each other or with no adjuvant treatment.. The four trials included Dukes' B and C patients and were conducted between 1977 and 1990. The eligibility criteria and follow-up requirements were similar for all four trials. Protocol C-01 compared adjuvant semustine, vincristine, and fluorouracil (5-FU) (MOF regimen) with operation alone. Protocol C-02 compared the perioperative administration of a portal venous infusion of 5-FU with operation alone. Protocol C-03 compared adjuvant 5-FU and leucovorin (LV) with adjuvant MOF. Protocol C-04 compared adjuvant 5-FU and LV with 5-FU and levamisole (LEV) and with the combination of 5-FU, LV, and LEV.. Forty-one percent of the patients included in these four trials had resected Dukes' B tumors. In all four studies, the overall, disease-free, and recurrence-free survival improvement noted for all patients was evident in both Dukes' B and Dukes' C patients. When the relative efficacy of chemotherapy was examined, there was always an observed reduction in mortality, recurrence, or disease-free survival event, irrespective of Dukes' stage, and in most instances, the reduction was as great or greater for Dukes' B patients as for Dukes' C patients. When data from all four trials were examined in a combined analysis, the mortality reduction was 30% for Dukes' B patients versus 18% for Dukes' C patients. The mortality reduction in Dukes' B patients occurred irrespective of the presence or absence of adverse prognostic factors.. Patients with Dukes' B colon cancer benefit from adjuvant chemotherapy and should be presented with this treatment option. Regardless of the presence or absence of other clinical prognostic factors, Dukes' B patients seem to benefit from chemotherapy administration.

Topics: Adenocarcinoma; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Randomized Controlled Trials as Topic; Semustine; Survival Analysis; Vincristine

Systemic palliative chemotherapy is usually regarded as ineffective in disseminated colorectal cancer, and the risk of toxic adverse effects is often considered a contraindication, as many patients are old and cannot be offered curative treatment. Randomized trials during the last decade have shown, however, that an effect on both survival and quality of life can be expected. Only casuistic reports of total remission have been published but a partial tumour response can be expected in 20-50% of patients. Toxicity is related to palliative chemotherapy and accelerated with old age (> 70 years). When disseminated colorectal cancer is diagnosed the possibility of palliative chemotherapy should be conferred with an oncologist.

Topics: Age Factors; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Meta-Analysis as Topic; Palliative Care; Quality of Life; Randomized Controlled Trials as Topic; Rectal Neoplasms

Adjuvant chemotherapy has been shown to alter the natural history of resected colon cancer. Two regimens (5-fluorouracil [5-FU] plus calcium folinate and 5-FU plus levamisole [Ergamisol]) have been found to prolong disease-free survival and overall survival in affected patients. Previous comparisons of these two regimens indicate that 5-FU plus calcium folinate may offer a small disease-free survival and overall survival advantage. The demonstration that UFT (uracil and tegafur) plus oral calcium folinate (Orzel) offers significant antitumor activity and an acceptable toxicity profile makes this a logical formulation for the adjuvant treatment of colon cancer. The National Surgical Adjuvant Breast and Bowel Project Protocol C-06 is a randomized comparison of the relative efficacies of 5-FU/calcium folinate vs UFT plus oral calcium folinate. Preliminary analysis of toxicity findings among 473 evaluable patients indicates that both regimens are well tolerated and have similar toxicity profiles. If, in the final survival analysis, UFT plus oral calcium folinate treatment yields the same or better disease-free survival and/or overall survival as the 5-FU/calcium folinate treatment and the toxicity profiles remain similar, it is likely that UFT plus oral calcium folinate will be accepted as a new standard for adjuvant treatment of colon cancer.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Survival Rate; Tegafur; Treatment Outcome; Uracil

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

To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV).. Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months.. A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P =.04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P =.07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P =.67) or overall survival (74% v 73%; P =.99). There was no interaction between Dukes' stage and the effect of treatment.. In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local

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

This study had two major goals: (1) to assess the effectiveness of a regimen of fluorouracil (5-FU) plus levamisole plus leucovorin as postoperative surgical adjuvant therapy for patients with high-risk colon cancer, and (2) to evaluate 6 months versus 12 months of chemotherapy.. Patients with poor-prognosis stage II or III colon cancer were randomly assigned to receive adjuvant chemotherapy with either intensive-course 5-FU and leucovorin combined with levamisole, or a standard regimen of 5-FU plus levamisole. Patients were also randomly assigned to receive either 12 months or 6 months of chemotherapy, which resulted in four treatment groups.. Eight hundred ninety-one of 915 patients entered (97.4%) were eligible. The median follow-up duration is 5.1 years for patients still alive. There was a difference among the four treatment groups with respect to patient survival, and a significant duration-by-regimen interaction was observed. Specifically, standard 5-FU plus levamisole was inferior to 5-FU plus leucovorin plus levamisole when treatment was given for 6 months (5-year survival rate, 60% v 70%; P < .01).. There was no significant improvement in patient survival when chemotherapy was given for 12 months compared with 6 months. When chemotherapy was given for 6 months, standard 5-FU plus levamisole was associated with inferior patient survival compared with intensive-course 5-FU plus leucovorin plus levamisole. These data suggest that 5-FU plus levamisole for 6 months should not be used in clinical practice, whereas 6 months of treatment with 5-FU plus leucovorin plus levamisole is effective.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Staging; Prospective Studies

UFT [Taiho Pharmaceutical Co. Ltd., Tokyo, Japan; (BMS-200604), Bristol-Myers Squibb, Princeton, NJ], a fluorouracil prodrug, is an oral 4:1 molar concentration of uracil plus tegafur. This study examined the dose-limiting toxic effects and maximum tolerated dose of UFT plus leucovorin administered for 28 consecutive days followed by a 7-day rest period. A course of therapy was repeated every 35 days. UFT dose levels examined were 200 mg/m2/day, with planned escalations to 250, 300, 350, and 400 mg/m2/day; the leucovorin dose remained at 150 mg/day. Three patients were initially enrolled at each UFT dose level. The total daily doses of both UFT and leucovorin were divided into three doses administered every 8 hr. Diarrhea became the dose-limiting toxicity at 400 mg/m2/day UFT, with grade 3 diarrhea noted in 2 of the 3 patients receiving that dose. To further define a phase II UFT starting dose, 3 additional patients were entered at the 350 mg/m2 level; 3 of the 6 patients treated at this level developed grade 3 nonhematological toxic effects. No partial or complete responses were observed. The recommended phase II UFT starting dose is 300 mg/m2/day plus 150 mg/day leucovorin. Since neutropenia, significant mucositis, and "hand-foot syndrome" were not observed with UFT plus leucovorin, the toxicity profile of this regimen appears favorable compared with that of intravenous regimens of fluorouracil plus leucovorin. This phase I trial of UFT served as the basis for a phase II trial, current phase III trials, and a national adjuvant therapy trial of UFT for high-risk colon cancer patients.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Female; Humans; Leucovorin; Male; Middle Aged; Tegafur; Uracil

A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial.. Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined.. A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase.. Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms; Survival Analysis

Adjuvant chemotherapy with fluorouracil (FU) and levamisole or FU/leucovorin (LV) has been established as effective adjuvant treatment for patients with stage III colon cancer. Among several other promising treatment strategies in resected colon cancer, intraperitoneal anti-cancer drug administration with its appealing rationale of counteracting microscopic residual disease on peritoneal surfaces and occult metachronous liver metastases by achieving high intraportal drug concentrations has not yet undergone sufficient clinical evaluation. To determine whether a combination of this locoregional therapeutic concept with systemic intravenous administration of FU/LV would yield better results than conventional adjuvant chemoimmunotherapy with FU/levamisole, the present randomized study was initiated. A total of 241 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned to 'standard therapy' with FU and levamisole, given for a duration of 6 months, or to an investigational arm, consisting of LV 200 mg m(-2) plus FU 350 mg m(-2), both administered intravenously (days 1-4) and intraperitoneally (days 1 and 3) every 4 weeks for a total of six courses. In patients with stage II disease, no significant difference was noted between the two arms after a median follow-up time of 4 years (range 2.5-6 years). Among 196 eligible patients with stage III disease, however, a comparative analysis of the two treatment groups suggested both an improvement in disease-free survival (P = 0.0014) and a survival advantage (P = 0.0005), with an estimated 43% reduction in mortality rate (95% confidence interval 26-70%) in favour of the investigational arm. In agreement with its theoretical rationale, combined intraperitoneal and intravenous FU/LV was particularly effective in reducing locoregional tumour recurrences with or without liver or other organ site involvement (9 vs 25 patients in the FU/levamisole arm; P = 0.005). Treatment-associated side-effects were infrequent and generally mild in both arms, although a lower rate of severe (WHO grade 3) adverse reactions was noted in patients receiving locoregional plus intravenous chemotherapy (3% vs 12%; P = 0.01). The results of this trial suggest that combined intraperitoneal plus systemic intravenous chemotherapy with FU/LV is a promising adjuvant treatment strategy in patients with surgically resected stage III colon carcinoma.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Adult; Aged; Antimetabolites, Antineoplastic; Colonic Neoplasms; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Intraperitoneal; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Survival Rate; Treatment Outcome

In 1989, the authors began a randomized trial to determine whether 5-fluorouracil and high dose folinic acid (HD-FUFA) would increase the event free and overall survival of patients with resectable Dukes B and C (AJCC/UICC Stage II and Stage III) colon carcinoma, and to assess the toxicity of the treatment and its impact on selected health-related quality-of-life indicators. Early results were published as a part of an international multicenter pooled analysis (IMPACT) in 1995. The purpose of this report is to update the survival data for patients enrolled in the trial and describe their reported perceptions of their own health and quality of life.. The trial involved multiple treatment centers, with a centralized randomization between surgery alone and surgery with chemotherapy. The HD-FUFA regimen employed consisted of 5-fluorouracil (370 mg/m2) plus folinic acid (200 mg/m2) administered daily for 5 days every 4 weeks for 6 cycles. Patients' perceptions of their own health status were obtained by means of 3 self-administered questionnaires, which were completed by patients at the time of discharge from the treatment center and at 6 and 24 months after randomization.. Overall, 888 patients with resected Dukes B2 and C colon carcinoma were enrolled in the trial. HD-FUFA significantly reduced mortality by 25% (95% confidence interval, 5-41%; P=0.02) and events by 31% (95% confidence interval, 14-45%; P < or = 0.001). Compliance with treatment was good; more than 80% of patients completed the planned therapy. Toxicity was mild, and oral mucositis was the main side effect. None of the health-related quality-of-life parameters investigated (emotional status, worry about the future, changes in social life, impact of the disease, follow-up, and global quality of life) seemed to be affected by the treatment to which patients were allocated. A positive trend in the evolution of patients' psychologic status was observed.. Long term results of this SITAC study confirm that HD-FUFA is a well-tolerated, effective 6-month adjuvant regimen for patients with colon carcinoma that has no detrimental effect on their quality of life.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Quality of Life

Patients with colorectal carcinoma progressing after a 5-fluorouracil (5-FU)-containing regimen were eligible. One treatment cycle consisted of repeated administrations of 5-FU combined to folinic acid for six times and to oxaliplatin for three times over 50 days. 5-FU was given at the dose of 2.6 g/m2 as a continuous infusion over 24 h on days 1, 8, 22, 29 and 43 preceded by i.v. folinic acid (FA) at a dose of 500 mg/m2 over 1 h. Oxaliplatin was given 1 h after 5-FU at the dose of 130 mg/m2 over a 2 h infusion on days 1, 22 and 43. A total of 37 patients were treated according to this schedule. The rates of objective responses after the first and second treatment cycles were 28 and 17%, respectively, with rates of tumor growth control, i.e. including the stabilizations, of 55 and 28%. The median duration of response was 10 months and the median duration of stabilizations was 6 months. The median survival time from initiation of oxaliplatin-containing therapy is 10 months (2-28+). The median survival time from the diagnosis of metastatic disease is 24 months (2-40+). The main toxicities were leucopenia, diarrhea, fatigue and paresthesias. The combination of 5-FU/FA/oxaliplatin was well tolerated and appears as a meaningful therapy after failure of a previous 5-FU-containing treatment.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Survival Analysis; Time Factors

We have used a relatively new trial methodology, the group sequential design, to prospectively evaluate two dose levels of bolus/infusional 5-fluorouracil (5-FU) and folinic acid in 192 consecutive-patients with advanced colorectal carcinoma. On day 1, all patients received 200 mg m(-2) of folinic acid infusion over 2 h. Cohort A (n = 102 patients) received 500 mg m(-2) 5-FU by i.v. 15-min infusion followed by an infusion of 500 mg m(-2) 5-FU over 22 h. Treatment was repeated on day 2 and further cycles given 2-weekly. After sequential analysis excluded a response rate of over 40%, cohort B (n = 90 patients) received an increased dose of 600 mg m(-2) 5-FU bolus and infusion. Patients had received no prior 5-FU therapy and the two cohorts had similar demographic features. In 179 evaluable patients, the overall response rate was 18% (95% CI 12-24%) with CR of 6% and PR of 12%, with no difference between the two cohorts. Overall median survival was 34 weeks (95% CI 30-39) with no significant difference between cohorts (median survival 32 and 37 weeks in cohort A and B respectively; P = 0.27). On multivariate analysis, poor performance status, elevated initial WBC and alkaline phosphatase and low serum albumin were associated with reduced survival (P < 0.05), and initial raised WBC showed an association with reduced likelihood of response (P = 0.002). Overall toxicity was low with CTC grade 3 mucositis, diarrhoea, nausea or vomiting in < or = 6% of patients and no treatment-related deaths. Significant (grade 3 or above) leucopenia was more common in cohort B than in cohort A (9% and 1% respectively); there were more dose reductions, and the median administered dose intensity was lower in cohort B than in cohort A (89% and 97% respectively; P = 0.006). In this group of relatively unselected patients, we have confirmed a relatively low objective response rate and median survival of 7.8 months with this regimen. There was no significant difference in outcome between the two dose levels but the higher dose of 5-FU was associated with more dose reductions and greater toxicity.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Cohort Studies; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Middle Aged; Prospective Studies; Rectal Neoplasms; Survival Rate; Treatment Outcome

Data from 12 metastatic colorectal cancer patients who were submitted to a pilot study with a multistep subcutaneous (sc) low dose recombinant interleukin-2 (rIL-2), 5-fluorouracil (5-FU) and leucovorin (LV) administration were compared with those from 13 historical controls who were comparable for the major prognostic indices. All 12 patients in the pilot study were subjected initially to six to eight courses of 5-FU-LV by endovenous (ev) bolus consistent with the Machover schedule alternating with 6 weeks of rIL-2 cycles. At the progression of metastatic disease, the patients were given 500 mg/m2 per day of 5-FU by continuous infusion (ci) for 5 days every 4 weeks and in case of further progression, 2,600 mg/m2 of 5-FU by 24-h ci once a week for 6 weeks. The control patients were treated with 5-FU-LV by the Machover schedule until progression and then observed. As yet, two patients in the pilot study and three control patients are currently alive. In the pilot study, the patients' response rate (CR + PR) and overall response rate (CR + PR + SD) were much higher than in the controls (50 vs 23% and 92 vs 54%, respectively). Time duration of response and survival from primary surgery were more prolonged in the pilot study than in the historical control, although not significantly (10.5 vs 6 and 41.5 vs 29 months, respectively). Time from starting therapy to progression and survival from relapse were significantly in favour of the pilot study (11.5 vs 4 and 31 vs 13.5 months; P < 0.01 and P < 0.05 unpaired t-test, respectively). Low dose s.c. rIL-2 cycles were well tolerated and no interruption occurred. In the pilot study sporadic grade 3 toxicity (diarrhoea or leucopenia) was responsible for the reduction of 5-FU doses to 80% of the previous infusion, but no treatment was postponed. In conclusion, these preliminary data suggest the opportunity to initiate large prospective randomized trials using a multistep therapy with rIL-2, 5-FU ci at conventional and at high dose in metastatic colorectal cancer.

Topics: Aged; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Interleukin-2; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Pilot Projects; Rectal Neoplasms; Survival Rate

National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 showed a benefit from leucovorin (LV)-modulated 5-fluorouracil (5-FU) adjuvant therapy (5-FU + LV) in patients with Dukes' stage B or C carcinoma of the colon. Preclinical and clinical phase I/II data suggested that interferon alfa-2a (IFN) enhanced the efficacy of 5-FU therapy. Accordingly, in NSABP protocol C-05, the addition of recombinant IFN to 5-FU + LV adjuvant therapy was evaluated.. Data are presented for 2176 patients with Dukes' stage B or C cancer entered onto protocol C-05 during the period from October 1991 through February 1994. Individuals with an Eastern Cooperative Oncology Group performance status of 0-2 (ranges from fully active to ambulatory and capable of self-care but unable to work), a life expectancy of at least 10 years, and curative resection were stratified by sex, disease stage, and number of involved lymph nodes and were randomly assigned to receive either 5-FU + LV or 5-FU + LV + IFN; the mean time on the study as of June 30, 1997, was 54 months. All statistical tests were two-sided.. There was no statistically significant difference in either disease-free survival (5-FU + LV, 69%; 5-FU + LV + IFN, 70%) or overall survival (5-FU + LV, 80%; 5-FU + LV + IFN, 81%) at 4 years of follow-up. Toxic effects of grade 3 or higher were observed in 61.8% of subjects in the group treated with 5-FU + LV and in 72.1% of subjects in the group treated with 5-FU + LV + IFN; fewer patients in the latter group completed protocol-mandated 5-FU + LV therapy than in the former group (77.1% versus 88.5%).. The addition of IFN to 5-FU + LV adjuvant therapy confers no statistically significant benefit, but it does increase toxicity.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Staging; Recombinant Proteins; Survival Analysis; Treatment Outcome

The goal of this study was to determine the efficacy of intensive-course fluorouracil (5FU) plus low-dose leucovorin given for 6 months following potentially curative resection of colon cancer.. Three hundred seventeen patients with high-risk stage II or stage III colon cancer were randomly assigned 3 to 4 weeks following surgery to receive either (1) chemotherapy with six cycles of 5FU (425 mg/m2) plus leucovorin (20 mg/m2) by rapid intravenous injection daily for 5 consecutive days every 4 to 5 weeks, or (2) observation.. The median follow-up duration is 72 months for patients still alive. Patients who received postoperative 5FU plus leucovorin experienced significant improvement in time to relapse (P < .01) and survival (P = .02) compared with control patients treated with surgery alone. Stomatitis, diarrhea, and leukopenia were the predominant chemotherapy toxicities. There were no treatment-related deaths.. These results indicate that intensive-course 5FU plus low-dose leucovorin is effective in preventing tumor relapse and improving survival in patients with high-risk colon cancer. These benefits were seen with only six cycles of treatment, using low-dose leucovorin in combination with 5FU on a schedule convenient for outpatient administration.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Factors

The activity of 5-fluorouracil (5-FU) against colon cancer is enhanced by leucovorin and the combination of 5-FU and levamisole has activity in the adjuvant treatment of colonic malignancies. The combination of 5-FU with both leucovorin and levamisole may provide additional benefit in the treatment of colon cancer.. A phase I study to assess qualitative and quantitative toxicities of this three-drug combination and to determine a dose for further phase II testing was undertaken. The role of levamisole as an immunomodulator was also assessed.. A group of 38 patients with incurable metastatic malignancies received 119 cycles of treatment at eight dose levels. 5-FU (375 mg/m2 per day) and leucovorin (200 mg/m2 per day) were administered intravenously (days 1-5). Levamisole was administered orally (days 1-3 and 15-17) at doses from 30 to 470 mg/m2 per day. Patients received both 5FU/leucovorin and 5-FU/leucovorin/levamisole in random order for their initial two cycles. All subsequent treatments were with the three-drug combination. Toxicities included nausea, vomiting, stomatitis, thrombocytopenia and granulocytopenia. Diarrhea was the dose-limiting toxicity at 470 mg/m2 per day levamisole. The addition of levamisole resulted in more toxicity than 5-FU and leucovorin alone. No clinical responses were seen with this regimen. The addition of levamisole resulted in more immunomodulation than 5-FU and leucovorin alone as evidenced by release of neopterin from monocytes.. With this schedule and dose of 5-FU and leucovorin, the maximum tolerated dose of levamisole was 354 mg/m2. However, given the lack of response and the absence of dose-dependent immunomodulation, this may not be the appropriate dose for further phase 11 studies.

Topics: Adjuvants, Immunologic; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Levamisole; Male; Middle Aged; Stomatitis

Twenty-three patients with metastatic colorectal carcinoma were randomized as part of two multicenter Phase III trials to receive either 5-fluorouracil (5-FU)/interferon alpha-2A (INF-alpha) or 5-FU +/- leucovorin. The patients were evaluated regularly for response by CT of the abdomen when treatment began and then every six to eight weeks. incidentally, we found that four of 13 patients treated with 5-FU/INF-alpha and none of ten patients treated with 5-FU +/- leucovorin developed hepatic steatosis during treatment. The diagnoses were based on a decreased CT value of the liver parenchyma by the repeated CT, and histologically verified by liver biopsies. There was no relationship to cumulative 5-FU or INF-alpha dose. Based on posttreatment CT, the liver parenchyma changes were reversible after therapy was stopped. Recognition of this condition in patients receiving 5FU/INF-alpha is important to prevent a patient from being labeled as having progressive hepatic metastases.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Colonic Neoplasms; Fatty Liver; Female; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Liver; Male; Middle Aged; Radiography; Rectal Neoplasms

A phase II study to evaluate the response rate and toxicities of a trimetrexate, fluorouracil (5FU), and leucovorin regimen in patients with advanced incurable colorectal cancer.. Thirty-six patients with unresectable or metastatic colorectal cancer who had not been treated for advanced disease received the following chemotherapy regimen weekly for six courses every 8 weeks: trimetrexate 110 mg/m2 intravenously (I.V.) on day 1, leucovorin 200 mg/m2 I.V. on day 2 (24 hours later), 5FU 500 mg/m2 on day 2 immediately following leucovorin, and oral leucovorin 15 mg every 6 hours for seven doses starting 6 hours after 5FU. Patients were treated until progression or unacceptable toxicity.. Thirty patients were assessable for response, and all 36 were assessable for toxicity. Two patients (7%) achieved a complete response (CR) and 13 (43%) a partial response (PR), for an overall response (OR) rate of 50% (95% confidence interval [CI], 32% to 68%). Analysis by intent to treat demonstrated a 42% OR rate (95% CI, 26% to 58%). At final analysis, 16 patients were alive. The median survival duration for the entire cohort was 53.4 weeks. Gastrointestinal toxicity was most common, with 21 patients (58%) having grade 3/4 diarrhea and 12 patients (34%) grade 3/4 nausea. Hematologic toxicity was generally low grade, although two patients died of sepsis.. The combination of trimetrexate with 5FU and leucovorin is active in metastatic colorectal cancer. Gastrointestinal toxicity with this regimen is most prominent, but is manageable.

Topics: Adult; Aged; Aged, 80 and over; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Rectal Neoplasms; Trimetrexate

Oxaliplatin has shown in vivo cytotoxic activity against colorectal cell lines. Preliminary studies suggest potentiation of fluorouracil (5-FU). To assess this issue, we performed a phase II study in pretreated patients with advanced colorectal cancer (CRC) resistant to leucovorin and 5-FU. The regimen (FOLFOX2) consisted of oxaliplatin 100 mg/m2 as a 2-h infusion on day 1; leucovorin 500 mg/m2 as a 2-h infusion, followed by 5-FU 24-h infusion 1.5-2 g/m2 for two consecutive days every 2 weeks. The initial 5-FU dose was 1.5 g/m2 for two cycles and increased to 2 g/m2 in case of no toxicity > grade 2. 46 patients were treated, all with disease progression on leucovorin and 5-FU therapy for metastatic disease, or relapse less than 6 months after the end of adjuvant therapy. One complete response (CR) and 20 partial responses (PRs) were observed for an overall response rate of 46%. 22 patients had prior documented progression while receiving the same schedule of leucovorin and 5-FU as the one used in the FOLFOX2 regimen, and among them, 10 had PRs (45%). From the start of FOLFOX2, median progression-free survival was 7 months and median survival 17 months. WHO toxicity > or = grade 3 per patient was: peripheral neuropathy 9%, nausea 4%, diarrhoea 9%, mucositis 13%, neutropenia 39%, thrombocytopenia 11%, alopecia 9%, and allergy 2%. Overall, 21 patients (46%) experienced grade 3-4 toxicity. This combination of leucovorin, 5-FU and oxaliplatin achieves a high response rate in pretreated patients with CRC resistant to leucovorin and 5-FU. Limiting toxicities are neutropenia and peripheral neuropathy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Survival Rate; Treatment Outcome

A randomized comparative study of surgical adjuvant chemotherapy using dl-leucovorin (dl-LV) and 5-fluorouracil (5-FU) (FL-therapy) with CDDP, 5-FU, and dl-LV (PFL-therapy) was conducted. The following were the administration schedules: Arm A was 13 mg/m2 of CDDP, 300 mg/m2 of 5-FU, and 30 mg/body of dl-LV for 5 consecutive days and arm B was 300 mg/m2 of 5-FU and 30 mg/body of dl-LV for 5 consecutive days. Both regimens were followed by biweekly administration of the same dose of dl-LV and 5-FU in outpatients. Arm A was started at the 26th postoperative day and arm B at the 21st day on average. Some 26 cases composed of 11 cases of arm A and 15 cases of arm B completed the administration schedules. Only one case in arm A was complicated by local recurrence around 35 months after operation. Major toxicities were anorexia and neutropenia. Both toxicities were seen more in arm A than in arm B, showing complete recovery in all cases. These data suggest that PFL-therapy and FL-therapy seem to be possible and promising surgical adjuvant therapies for advanced colorectal carcinoma.

Topics: Adenocarcinoma; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Rectal Neoplasms; Survival Rate

Monoclonal antibody (mAb) A33 reacts with an antigen expressed by >95% of colon cancer and normal colon epithelial cells. An earlier Phase I trial of 131I-labeled mAb A33 (131I-mAb A33) demonstrated bone marrow suppression as the dose-limiting toxicity, and although modest antitumor effects were seen, no normal colon toxicity was observed. In this study, a nude mouse model was used to test whether combinations of low-dose 131I-mAb A33 (0.1 mCi) and chemotherapy [5-fluorouracil (5-FU) or 5-FU + leucovorin, doxorubicin, or carmustine] enhance the antitumor effects, compared to 131I-mAb A33 alone or either drug regimen alone. 5-FU was administered either at 30 mg/kg/day for 5 days or at 75 mg/kg/day on days 1 and 5. In assessing the reduction in tumor volumes over the first 28 days of the experiment, 5-FU treatment (with or without leucovorin) in combination with 131I-mAb A33 showed a statistically significant additive antitumor effect compared to 131I-mAb A33 alone or to chemotherapy alone. When long-term survival was used as an end point, 38% of the mice treated with 5-FU and 131I-mAb A33 were disease free at 276 days compared to none from any other group, suggesting a synergistic effect. These data indicate that Phase II clinical trials combining radiolabeled antibody therapy with 5-FU-based treatments are warranted.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Monoclonal; Antigens, Neoplasm; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Colon; Colonic Neoplasms; Doxorubicin; Female; Fluorouracil; Humans; Iodine Radioisotopes; Leucovorin; Membrane Glycoproteins; Mice; Mice, Nude; Neoplasm Transplantation; Radioimmunotherapy; Time Factors; Transplantation, Heterologous; Tumor Cells, Cultured

The present study compared the effects of sequential methotrexate and fluorouracil followed by leucovorin rescue (MFL), as an adjuvant chemotherapy versus a combination of tegafur (UFT) and mitomycin C (MMC), on patient survival and recurrence after surgery for colorectal carcinoma.. Between January 1990 and December 1995, a total of 46 patients with advanced colorectal cancer were treated postsurgically by adjuvant chemotherapy using MFL or UFT-MMC. Surgical treatment was performed according to standardized procedures for radical resection of colorectal cancer. The patients were stratified into two groups after surgery. The MFL regimen consisted of MTX (100 mg/m2) and 5-FU (600 mg/m2) at hour 24, followed by leucovorin rescue. The UFT-MMC regimen consisted of MMC (12 mg/m2) intraoperatively and MMC (6 mg/m2) ever other week after surgery for 2 months and oral UFT (375 mg/m2/day), a combination of tegafur and uracil in a molar ratio of 1:4, was continued for 3 years or longer depending on the patients tolerance.. The overall survival rates after surgery was significantly (P < 0.05) higher in the MFL than the UFT-MMC group. Recurrence rates were significantly lower in the MFL than the UFT-MMC Group, especially for liver recurrence. Disease-free survival was significantly (P < 0.05) higher in the MFL than the UFT-MMC group.. The present results demonstrated the superiority of MFL therapy for improving postsurgical survival in patients with advanced colorectal cancer, in particular for those patients with a high risk of recurrence following potential curative resection.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Mitomycin; Postoperative Period; Rectal Neoplasms; Survival Rate; Tegafur; Uracil

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

The purpose of this study was to test the hypothesis that 5-methyltetrahydrofolate (Me-THF), a source of reduced folates alternative to leucovorin, could effectively modulate 5-fluorouracil's (5-FU) cytotoxic activity in patients with advanced colon cancer. A total of 23 patients were enrolled in a phase 11 trial; they received 5-FU as a 30-min infusion at a dose of 370 mg/m2 following a rapid i.v. push of 200 mg/m2 Me-THF, both drugs being given for 5 consecutive days. Cycles were repeated every 4 weeks until disease progression. No patient achieved a complete response. In all, 4 patients showed a partial response (17.4%), 7 developed stable disease (30.4%), and the remaining 12 (52.2%) progressed. Toxicity was acceptable and never exceeded WHO grade III intensity. According to our experience, the MeTHF/5-FU combination does not appear to be an effective treatment for advanced colon cancer. Despite its low toxic profile, in our opinion its wider use should be discouraged.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cell Death; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Tetrahydrofolates

The prognosis for patients with cancer of the colon is dubious. An intendedly curative colon resection is performed in two-thirds of these patients, but half of them will subsequently die from metastatic disease. Randomized trials of adjuvant therapy with fluorouracil in combination with levamisole or leucovorin have shown significant benefit in terms of increased disease-free survival and overall survival. In 1990 adjuvant treatment was recommended as routine therapy in high risk patients in USA. A number of European countries are routinely treating high risk patients with Dukes' C coloncarcinoma. The recommendations are based on results from several cooperative trials reviewed in this article. Treatment related toxicity accelerates with increasing age but was acceptable in the reviewed trials. Adjuvant therapy is widely accepted as an important supplement to surgery in high risk patients. A Conference on the results and experiences now available should take place in the near future in order to establish a national consensus on adjuvant chemotherapy in Denmark. Patients with resected Dukes' C coloncarcinoma should receive adjuvant chemotherapy including 5-fluorouracil and leucovorin. Randomized trials are needed to establish the most effective regimens but "no-treatment" controls are no longer ethically acceptable.

Topics: Adjuvants, Immunologic; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Levamisole; Prognosis

To investigate if double modulation of fluorouracil (5-FU) with leucovorin (folinic acid [FA]) and interferon alfa-2b (IFN 2b) improves responses and survival in comparison to single modulation of 5-FU with FA.. One hundred six patients with histologically confirmed advanced colorectal cancer, measurable disease, and without previous chemotherapy were prospectively randomized into two groups. Patients in group A received 5-FU 450 mg/m2 as an intravenous bolus in the midinfusion of FA weekly. FA was given at a dose of 200 mg/m2 in 500 mL 0.9% normal saline solution in 2-hour infusion. Patients in group B received exactly the same regimen plus IFN 2b 5 million units subcutaneously three times weekly.. All patients were well balanced in both groups regarding age, sex, performance status, number, and site of metastasis. One hundred two patients were assessable. All patients have died. There was no difference in response between the two groups (7.8% v 9.8%). Median survival was 10.1 months in group A, and 7.2 months in group B (P = .00189). Median time to progression was 8.4 and 5.2 months, respectively (P = .00196). Overall, better performance status and older age had a positive impact on survival. Toxicity was the most important and catastrophic aspect of this study. Patients who received IFN 2b had significantly worse anemia, neutropenia, diarrhea, anorexia, weight loss, flu-like syndrome, and psychological reactions.. Based on this final analysis, the addition of IFN 2b to the combination of 5-FU and FA enhances toxicity and contributes to decreased survival.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Rectal Neoplasms

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Resistance, Neoplasm; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

The role of fluorouracil and folinic acid and adjuvant therapy for colon cancer is not clear. We undertook independently three randomised trials to find out the efficacy of fluorouracil and high-dose folinic acid after surgery for Dukes' B and C stage colon cancer. The three studies by the Gruppo Interdisciplinare Valutazione Interventi Oncologia (GIVIO), the National Cancer Institute Canada Clinical Trials Group (NCIC-CTG), and the Fondation Française de Cancerologie Digestive (FFCD) were pooled for combined analysis. Each trial was multicentre and used the same treatment regimen (fluorouracil 370-400 mg/m2 plus folinic acid 200 mg/m2 daily for 5 days, every 28 days for 6 cycles). A pooled analysis of the results was done on the basis of a previously agreed protocol when there were sufficient events to detect at least a 10% reduction in mortality with 80% power. 1526 patients with resected B (56%) and C (44%) carcinoma of the colon were enrolled and 1493 were confirmed as eligible. 736 were assigned to the treatment group and 757 to the control group. Fluorouracil/folinic acid significantly reduced mortality by 22% (95% CI 3-38; p = 0.029) and events by 35% (22-46; p < 0.0001), increasing 3-year event-free survival from 62% to 71% and overall survival from 78% to 83%. Compliance with treatment was good; more than 80% of patients completed the planned treatment. Side-effects were clinically acceptable with only 1 treatment-related death. The commonest side-effects were gastrointestinal, but severe toxic effects (WHO grade 4) occurred in fewer than 3% of cases. We conclude that fluorouracil plus high-dose folinic acid is a well-tolerated and effective 6-month adjuvant regimen for colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Survival Rate

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

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Methotrexate; Middle Aged; Rectal Neoplasms; Retrospective Studies

Patients who underwent potential curative surgery for colonic adenocarcinoma were enrolled in a prospectively randomised, controlled clinical trial of combined intraperitoneal (i.p.) plus systemic intravenous (i.v.) chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV). We investigated whether this adjuvant treatment approach, specifically addressing the risk of peritoneal and hepatic recurrence, could improve disease-free and overall survival. Between May 1988 and December 1990, 121 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned for observation (which was considered standard care until the NIH consensus conference) or adjuvant chemotherapy with LV (200 mg/m2) plus 5-FU (350 mg/m2), both given i.v. (days 1-4) and i.p. (days 1 and 3) every 4 weeks for a total of six courses. After a median follow-up time of 4.6 years, a comparative analysis between the two groups of patients suggested both an improvement in disease-free survival (75% versus 58%; P = 0.06) and a survival advantage (78% versus 63%; P = 0.05) in favour of adjuvant chemotherapy. The sites of recurrence were also different, i.e. local regional and intrahepatic tumour recurrences were observed in only 6/58 (10%) and 5/58 (9%) adjuvant treated patients as compared to 11/60 (18%) and 10/60 (17%) observed patients. The overall benefit of adjuvant therapy appeared to be greatest in patients with stage III colon cancer. Treatment-associated toxicity was infrequent and generally mild with only 5% experiencing severe (WHO grade 3) adverse reactions. Interim results of this adjuvant trial suggest that combined i.p. plus systemic i.v. chemotherapy with 5-FU and LV represents a potentially effective adjuvant regimen in stage II/III colon cancer.

Topics: Adenocarcinoma; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Therapy, Combination; Female; Fluorouracil; Humans; Infusions, Parenteral; Injections, Intravenous; Leucovorin; Male; Middle Aged; Prospective Studies; Survival Rate

Exogenous leucovorin is a source of reduced folate which enhances the inhibition of thymidylate synthase that results from 5-fluorouracil (5-FU) administration. Extracellular reduced folate concentrations of 1 microM have been reported to yield maximal enzyme inhibition in several cell lines treated with 5-FU in vitro. Clinical studies indicate that low doses of leucovorin have equivalent efficacy to higher doses in successfully modulating 5-FU in the treatment of colorectal cancer. Based on pharmacokinetics at higher doses, steady-state total plasma reduced folate concentrations of 1 microM would be expected from the administration of leucovorin 50 mg/m2 by 24 h infusion. This dose was admixed with 5-FU 2300 mg/m2 and administered by 24 h-infusion weekly to 38 patients with advanced colorectal cancer, of whom 32 are evaluable for response. Disease sites included liver (33 patients), lung (12 patients), and bone (4 patients). Toxicity was mild to moderate, except for grade 3 diarrhea in 5 patients, and chest pain in 2 patients. Among the 32 evaluable patients, there were 14 partial remissions for a total response rate of 44% (95% confidence interval 27-61%). The median duration of response was seven (range 1 to 20+) months, and median duration of survival 16 months. These results support the use of low doses of leucovorin to modulate weekly infusional 5-FU in colorectal cancer, and provide a basis for the integration of this regimen with other modulators of 5-FU.

Topics: Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Colonic Neoplasms; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

Based on experimental findings suggesting that 5-fluorouracil (FUra) may have different mechanisms of action depending on the schedule of administration, we generated the hypothesis that biochemical modulation of this fluoropyrimidine should be schedule specific. We thus tested the activity of a hybrid regimen consisting of two biweekly cycles of FUra bolus (600 mg/m2) modulated by pretreatment (24-h interval) with methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). Thirty-three consecutive patients with advanced measurable colorectal cancer and no prior therapy for metastatic disease entered the study from February 1992 to August 1993. They were treated with two biweekly cycles of FUra bolus (600 mg/m2) preceded by (24-h interval) methotrexate (200 mg/m2), alternating with a 3-week continuous infusion of FUra (200 mg/m2/day) modulated by low-dose (6S)leucovorin (20 mg/m2 bolus weekly). The median Eastern Cooperative Oncology Group performance status was 1; the liver was the only metastatic site in 17 patients. Treatment outcome was evaluated by computed tomographic scan in all patients, except for two. Three complete and 13 partial responses were obtained among these 33 patients (response rate, 48%; 95% confidence limits, 31-66%). Performance status (Eastern Cooperative Oncology Group) influenced clinical response. The combined complete response and partial response rate was 69%, 33%, and 25% in patients with an Eastern Cooperative Oncology Group performance status of 0, 1, and 2, respectively (chi2, 4.6, P = 0.032, two-tailed Mantel test for trend). After a median follow-up time of 26 months, 10 patients are still alive. The median progression-free survival and overall survival were 9.5 and 20.2 months, respectively. No toxic deaths or grade 4 toxicity occurred. The incidence of grade 3 toxicity per patient in any cycle was: mucositis 6%, diarrhea 3%, and vomiting 3% for the bolus part and 21%, 3%, and 6%, respectively, for the continuous infusion part of the regimen. Hand-foot syndrome occurred in 27% of the patients treated with the continuous infusion regimen.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Rectal Neoplasms

In advanced colorectal cancer the addition of folinic acid (FA) has been shown to lead to increased activity, at least in terms of response rate, in comparison with 5-fluorouracil (5FU) alone. Similarly, interferon-alpha (IFN) is able to potentiate 5FU, although high doses cause heavy toxicity. Given the different mechanisms of action of the two agents, the double modulation of 5FU deserves clinical evaluation. In a multicenter study (involving both primary care and referral institutions) 63 patients with advanced colorectal cancer, previously untreated with chemotherapy, received, in an outpatient setting, FA (200 mg/m2 i.v. bolus) + 5FU (400 mg/m2 i.v. in 15 min) for 5 consecutive days every 4 weeks + IFN 3 x 10(6) U on alternate days, starting 1 week before chemotherapy. During the 5 days of 5FU + FA, IFN was administered daily. The antitumour activity, the impact on response duration and survival and toxicity of the combination were evaluated according to WHO criteria. Of the 63 enrolled patients, 56 were evaluable: there were 2 complete responses (3%) and 13 partial responses (21%), giving an objective response rate of 24% (95% confidence interval 13-35%); no change was observed in 17 cases and progressive disease in 24. Median duration of response was 9 months and median survival (all patients) 13 months. Toxicity was acceptable, even though 4 patients presented reversible grade 4 side-effects (2 mucositis and 2 diarrhoea). With this schedule and these doses, addition of IFN did not lead to any increase in the activity of 5FU + FA. In colorectal cancer, further clinical studies with these drugs should be based on a deeper experimental knowledge of their mechanisms of interaction.

Topics: Adult; Aged; Colonic Neoplasms; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Rectal Neoplasms

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms

The purpose of this study was to evaluate the toxicity of immediate postoperative intraperitoneal (IP) floxuridine (FUdR) and leucovorin (LV) after resection of high risk colon cancer, and to determine the appropriate dose of intravenous fluorouracil (FU) plus levamisole during concurrent intraperitoneal therapy.. The authors conducted a tertiary referral Comprehensive Cancer Center Phase I Trial in patients with resected colon cancer at high risk for recurrence. After resection of all gross disease, intraperitoneal treatment was administered twice daily for 3 days every 2 weeks for three cycles (Days 1-3, 15-17, 29-31). Intravenous FU daily for 5 days was administered on days 29-33 concurrently with the third cycle of intraperitoneal therapy. Fluorouracil doses during the last cycle of intraperitoneal therapy were escalated; intraperitoneal FUdR and LV doses and weekly intravenous FU doses (starting on Day 58) were fixed.. Twenty-six patients with resected high risk colon cancer were treated. Three had Dukes' B2, 16 Dukes' C, and 7 Dukes' D (M1) resected tumors. Intraperitoneal therapy was well tolerated with no increase in operative morbidity and no operative mortality. Two patients had > or = Grade 3+ toxicity during IP therapy alone. There were no treatment related deaths. During concurrent intraperitoneal and intravenous chemotherapy, the maximum tolerated dose of FU was 300 mg/m2/day for 5 days. The recommended dose for Phase II or III trials is 200 mg/m2/day for 5 consecutive days. Pharmacokinetic analysis indicated that using the doses used in this trial, measurable systemic concentrations of FUdR and LV were obtained during IP therapy. This may have contributed to observed toxicity with intravenous FU doses of 300-400 mg/m2. With a median duration of follow-up of 18 months, four patients had recurrence of disease. No peritoneal recurrences have been noted to date.. Immediate postoperative IP FUdR and LV are well tolerated after resection of high risk colon cancer. The recommended dose of intravenous FU beginning on Day 29 (concurrent with the last dose of IP therapy) is 5FU 200 mg/m2 for 5 consecutive days. The remaining year of adjuvant fluorouracil and levamisole can be administered with standard dose attenuation. Although follow-up is short, the lack of recurrent peritoneal metastases is encouraging. Additional trials with this approach are warranted in patients with high risk colorectal cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Female; Floxuridine; Fluorouracil; Humans; Infusions, Parenteral; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Postoperative Period; Survival Analysis

To determine the time-dependence of fluorouracil (5FU)-induced thymidylate synthase (TS) inhibition in colon cancer patients, the effect of leucovorin (LV), and the relation to response.. A 5FU injection (500 mg/m2) was given to 47 patients with advanced colorectal cancer; tumor biopsy specimens were obtained 1 to 72 hours after laparotomy. Eleven patients received LV (2-hour infusion of 500 mg/m2) with 5FU midinfusion; biopsies were obtained after 45 hours. TS inhibition was evaluated by comparing the number of total and free 5-fluoro-2'-deoxy-uridine-5'- monophosphate (UMP) (FdUMP) binding sites and the total and residual catalytic activity of TS.. The total catalytic TS activity varied from 0 to 621 pmol/h/mg protein and the total number of FdUMP binding sites varied from 0 to 976 fmol/mg protein. The residual catalytic TS activity after 2, 23, and 45 hours was 41%, 65%, and 74% of the total catalytic activity; the number of free FdUMP binding sites was 12%, 27%, and 49% of the total number, respectively. LV enhanced TS inhibition after 45 hours; the residual catalytic activity decreased from 74% to 49%, and the number of free FdUMP binding sites from 49% to 24%. Eleven of 19 patients treated with hepatic arterial infusion of 5FU had a partial response (PR). In the nonresponding patients, total TS activity was significantly higher (P < .05) than in responding patients. A high TS activity with a poor inhibition correlated with no response.. Residual and total TS activity are predictive for response to 5FU. The findings may be applicable for treatment of patients with advanced disease and TS should be evaluated as a prognostic factor in adjuvant chemotherapy studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorodeoxyuridylate; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Remission Induction; Thymidylate Synthase

N-(phosphonacetyl)-L-aspartic acid (PALA) inhibits the enzyme L-aspartic acid transcarbamoylase (ATCase) which is important in de novo pyrimidine synthesis. Low dosages of PALA modulate the in vitro activity of 5-fluorouracil (5-FU) and PALA (250 mg/m2) inhibits pyrimidine synthesis in patients. PALA (250 mg/m2 day 1) was combined with an established 5-FU/folinic acid (FA) regimen [FA (200 mg/m2 over 2 h days 2 + 3) and bolus and 22 h infusional 5-FU (300-500 mg/m2 days 2 + 3)] without the need for dose reduction of 5-FU or FA. 35 patients were entered. Treatment was well tolerated; 4/27 patients experienced > or = ECOG grade 3 toxicity at full 5-FU dosage (500 mg/m2 bolus/infusion). However, the response rate in 33 evaluable patients was only 6.1% [95% confidence intervals (C.I.) 0.2-21.8%]. Median response duration was short (4 months, 95% C.I. 3-6 months) and overall median survival was 10 months (95% C.I. 7-16 months). Although PALA (250 mg/m2) can be combined with full dosage 5-FU/FA, the combination has poor activity in colorectal cancer.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Colonic Neoplasms; Disease Progression; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Phosphonoacetic Acid; Rectal Neoplasms

Fifty patients were randomized to receive adjuvant intraperitoneal 5-fluorouracil (5-FU, 500 mg/m2/day) and intravenous leucovorin (60 mg/m2/day) and 51 to receive placebo after curative surgery for colorectal cancer. Treatment started on the day after surgery and continued for 6 days. One case of stomatitis, one of leucopenia and one case of abnormal liver function tests were the only chemotherapy-related toxic effects. From the second day of treatment, pain during intraperitoneal infusions occurred more frequently in the 5-FU group, although statistical significance was only attained on day 2 (P < 0.05). The groups did not differ substantially regarding any other adverse effects, the incidence of surgical complications, second laparotomies, time from surgery to discharge, or premature treatment terminations. The postoperative course after intraperitoneal 5-FU and intravenous leucovorin was thus not more complicated than that in patients treated with placebo. The tolerance was acceptable and chemotherapy-related toxicity was rare. Thus important prerequisites exist for more widespread use of the present regimen in order to evaluate its impact on survival.

Topics: Adult; Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Infusions, Parenteral; Leucovorin; Male; Middle Aged; Rectal Neoplasms

Colon cancer is one of the major health problems in industrialized countries, and its incidence appears to be increasing. Surgical resectability is the most important prognostic determinant, although despite apparently curative surgery, recurrent tumors are common. Metastatic disease cannot be cured, and thus, there is a need for better adjuvant therapies.. Two hundred and thirty-nine patients with surgically resected colon cancer in Dukes' stage B2 or C were randomly assigned to chemotherapy or observation alone to determine whether adjuvant chemotherapy could effectively reduce the rate of cancer recurrence. One hundred and twenty-one patients in stage B2 and 118 patients in stage C were enrolled in the study. Adjuvant treatment consisted of folinic acid 200 mg/m2, intravenously, plus 5-fluorouracil 400 mg/m2, intravenously, on days 1-5 every 4 weeks for 12 cycles.. In stage B2, no significant difference between the adjuvant arm and the observation arm was noted. In stage C, adjuvant chemotherapy produced an advantage over observation in terms of a reduction in cancer recurrence rate with prolongation of a disease-free interval (P = 0.0016) and an improvement in overall survival (P = 0.0025).. This study shows that folinic acid plus 5-fluorouracil adjuvant chemotherapy is effective in patients with surgically resected Dukes' stage C colon carcinoma.

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Survival Analysis

Because of experimental and preliminary clinical evidence that additional modulation of the biochemical pharmacology and cytotoxicity of 5-fluorouracil (5-FU) and leucovorin (LV) may be possible by combination of these agents with cisplatin (CDDP), the authors undertook a prospective randomized trial in patients with colorectal cancer.. Between 1989 and 1992, 138 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either 5-FU (425 mg/m2) and LV (20 mg/m2) for 5 days, or the combination of 5-FU and LV in the same daily dose plus cisplatin (20 mg/m2), each drug given for 4 consecutive days. In both treatment arms, courses were administered every 28 days, if toxicity allowed, for a total of 6 months or until evidence of tumor progression.. The overall responses (complete and partial response) were 19% and 28% for the 5-FU/LV and the 5-FU/LV/CDDP treatment arms, respectively. Although the three-drug combination appeared superior to 5-FU/LV for time to progression or death (8.5 versus 5.2 months; P = 0.042), there was no evidence that the adoption of cisplatin will translate into a definite survival advantage. A comparative analysis of the toxicities experienced by the patients in the two treatment groups showed a comparable rate, although severe side effects (P < 0.05), specifically stomatitis (P = 0.013), were noticed more frequently in patients treated with 5-FU/LV for 5 days.. These results suggest that the therapeutic index of 5-FU/LV in metastatic colorectal cancer may be improved with the addition of cisplatin. However, the somewhat better therapeutic activity and lower incidence of severe gastrointestinal side effects have to be weighed against additional pharmaceutical charges and the need for a more intense antiemetic regimen.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Rectal Neoplasms; Remission Induction; Stomatitis; Survival Rate

To compare the length of survival and quality of life in patients given combination chemotherapy in addition to supportive care and in patients given only supportive care.. Randomised study.. Gastrointestinal oncology departments.. 40 previously untreated patients with histologically confirmed, measurable colorectal cancer that was locally recurrent or metastatic.. Patients were allocated randomly to receive chemotherapy or only supportive care in a ratio of 2:1 according to performance status, metastatic disease of the liver, and weight loss in the six months before entering the study. Chemotherapy consisted of four week cycles of intravenous leucovorin (200 mg/m2/day) followed by 5-fluorouracil (550 mg/m2/day) and cisplatin (20 mg/m2/day), each drug being given on the first four days of the cycle.. Length of survival and quality of life score with an optimised functional living index-cancer scale.. Overall survival was significantly longer for patients given chemotherapy (11.0 months) than for those receiving supportive care alone (5.0 months; p = 0.006). Despite common association of chemotherapy with mild to moderate gastrointestinal symptoms, there was no significant difference between the two groups in global or subgroup quality of life scores. In patients with abnormal scores before treatment, quality of life seemed better in the chemotherapy arm.. In this sample of patients with disseminated colorectal cancer the chemotherapy regimen was an effective form of palliative treatment.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Palliative Care; Prognosis; Quality of Life; Rectal Neoplasms; Social Support

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Treatment Outcome

Prolonged infusional 5-fluorouracil (5-FU) and bolus 5-FU modulated by leucovorin are associated with higher response rates than bolus 5-FU alone. Cisplatin enhances 5-FU cytotoxicity in some preclinical models.. The authors tested the feasibility of combining concurrent infusional leucovorin (500 mg/m2/d) with protracted infusional 5-FU (200 mg/m2/d) and weekly bolus cisplatin (20 mg/m2) in 22 patients with metastatic colorectal cancer.. Four partial responses (PR) were noticed among 21 evaluable patients (19%). The median time to treatment failure and median survival were 6 months and 11 months, respectively. All but two patients required 5-FU dose reduction after a median of 2 weeks because of mucositis. However, severe mucositis and diarrhea occurred in only 18% and 5% of the patients, respectively. Palmar-plantar erythrodysesthesia of mild to moderate severity occurred in 55% of patients. Megaloblastic changes were evident in the peripheral blood during therapy, and may reflect prolonged DNA-directed toxicity of 5-FU. The median tolerated dose level of 5-FU was 113 mg/m2/d (range, 64-150 mg/m2/d). Mean steady-state plasma concentrations (Cpss) of 5-FU appeared to increase linearly from 0.19 microM to 0.39 microM over the dose range 64 to 200 mg/m2/d. Patients with grade 2 gastrointestinal toxicity had significantly higher 5-FU Cpss than patients with grade 0 or 1 toxicity.. The early onset of toxicity with this regimen of protracted infusional 5-FU/high-dose leucovorin and weekly cisplatin required marked attenuation of the 5-FU dose intensity, and the results were no better than that expected with infusional 5-FU alone.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Survival Analysis; Treatment Failure

This study was designed to evaluate the efficacy of leucovorin-modulated fluorouracil (5-FU) as adjuvant therapy for patients with Dukes' stage B and C colon cancer.. Data are presented from 1,081 patients with Dukes' stage B and C carcinoma of the colon entered into National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol C-03 between August 1987 and April 1989. Patients were randomly assigned to receive either lomustine (MeCCNU), vincristine, and 5-FU (MOF), or leucovorin-modulated 5-FU (LV + 5-FU). The mean time on study was 47.6 months.. Comparison between the two groups indicates a disease-free survival advantage for patients treated with LV + 5-FU (P = .0004). The 3-year disease-free survival rate for patients in this group was 73% (95% confidence interval, 69% to 77%), compared with 64% (95% confidence interval, 60% to 68%) for patients receiving MOF. The corresponding percentage of patients surviving was 84% for those randomized to receive LV + 5-FU and 77% for the MOF-treated cohort (P = .003). At 3 years of follow-up, patients treated with postoperative LV + 5-FU had a 30% reduction in the risk of developing a treatment failure and a 32% reduction in mortality risk compared with similar patients treated with MOF.. Treatment with LV + 5-FU significantly prolongs disease-free survival and results in a significant benefit relative to overall survival. These findings, when considered together with results from a recent meta-analysis demonstrating a benefit from LV + 5-FU in advanced disease, provide evidence to support the concept of metabolic modulation of 5-FU.

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Life Tables; Male; Middle Aged; Neoplasm Staging; Survival Analysis

Leucovorin, given usually by i.v. injection or orally changes to 5, 10-methylene tetrahydrofolate in tumor as well as normal cells. And in normal FdUMP, an active metabolite of 5-FU, binds tightly to thymidylate synthase in the presence of cofactor, 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Phase I study using l-leucovorin (l-LV), an active form of leucovorin, combined with 5-FU, was conducted. In the weekly schedule, 5-FU was fixed to 600mg/m2, and l-LV dose was escalated from 125 mg/m2 to 250mg/m2, if toxicity was acceptable. On the other hand, in the five consecutive-day schedule, 5-FU was fixed to 370mg/m2 and l-LV was escalated from 25mg/m2 to 50mg/m2, 100mg/m2 and 200 mg/m2. l-LV 10mg/m2 was tested as reference. On weekly schedule of l-LV 250mg/m2, grade III diarrhea was seen in 2 cases and grade IV leucopenia was seen in one. In five consecutive-day schedule, at each dose of l-LV, stomatitis, nausea plus vomiting, anorexia, anemia and leucopenia were seen. However, the increase of toxicities were not seen by dose escalation of l-LV. Then, we have been conducted a randomized early phase II study using 250 mg/m2 of l-LV weekly (arm A) and 100mg/m2 (arm B) or 10mg/m2 (arm C) of l-LV for 5 consecutive days in gastric and colorectal cancer by multicenter cooperative study. Plasma concentrations of l-LV were maintained > 10(-5) mol/L for over 5 hrs. after 2 hrs. infusion of 250 mg/m2 of l-LV and for over one hr. after a rapid injection of 100mg/m2 of l-LV.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Rectal Neoplasms; Stomach Neoplasms

We report the results of a phase III trial in which we compared 5-fluorouracil (5-FU) to 5-FU and folinic acid (FA) in 150 previously untreated metastatic colon cancer patients. Patients were randomized in the ratio of 1:2 to receive 5-FU (370 mg/m2, i.v., for 5 days) in arm A or equidose 5-FU plus FA (200 mg/m2, i.v., for 5 days) for arm B, each cycle being repeated every 4 weeks. Five of 49 evaluable arm A patients (10.2%) and 31 of 97 arm B (31.9%) achieved a complete or partial response (p < or = 0.01). Median survival time of arm A patients was 6 months (mean: 6.18), while it was 8 months (mean: 9.01) for arm B cases (p < or = 0.05). In conclusion, our data indicate that FA can enhance 5-FU activity and that this combination is an effective palliative treatment for metastatic colon cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Survival Rate

We conducted a phase I/II trial of 5-fluorouracil (5-FU)/folinic acid (FA) and alpha-2b interferon (IFN) in 43 previously untreated patients with measurable metastatic colorectal cancer. Patients had disease progression prior to therapy consistent of 5-FU 500 mg/m2 (level A) or 600 mg/m2 (level B) as starting dose administered as a 2-hour infusion, FA 200 mg/m2, and alpha-2b IFN 5MU/m2 subcutaneously. All drugs were given on days 1 to 5 and cycles were repeated after 3 to 4 weeks. The aim of the study was to define the maximal tolerable dose (MTD) of 5-FU for this schedule. In the absence of toxicity above MTD, defined as diarrhea and mucositis of World Health Organization grade 2 and leukopenia of World Health Organization, grade 3 5-FU was increased in increments of 100 mg/m2 for further cycles. Twenty-four patients were started on level A; 18 were started on level B. Forty-two patients were evaluable for toxicity, 32 for response. Three of 32 patients achieved a partial response; in 22 of 32 patients, tumor stabilization occurred. Forty percent of patients started on level A developed grade 2 diarrhea; 28% of patients developed grade 2 or 3 mucositis. Of 18 patients on level B, two patients experienced grade 4 mucositis (11%) and grade 3 or 4 diarrhea (11%). One drug-related death in the presence of sepsis occurred. Due to 11% of patients with grade 4 toxicity when started on 600 mg/m2 5-FU and 40% of patients with grade 2 diarrhea when started on level A, MTD as starting dose for 5-FU is 500 mg/m2 as a 2-hour infusion when used in combination with FA and IFN on a day 1 to 5 active schedule. We observed a wide range of 5-FU dose tolerated by individual patients. While some patients experienced severe, mainly gastrointestinal, toxicity on lower levels of 5-FU, others tolerated much higher 5-FU doses (11 patients, 700 mg/m2; 5 patients, 800 mg/m2; and one patient, 900 mg/m2). Our data suggest that double modulation of 5-FU by FA and IFN may not be superior to modulation of 5-FU with either drug alone.

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

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

Modulation of fluorouracil (5-FU) therapy with folinic acid (FA) in advanced colorectal adenocarcinoma produces a doubled increase in remission rates, but one important study with another modulation of 5-FU with interferon alfa 2a (IFN-alpha-2a) had better results. In the fact that both modulations have different mechanisms of interaction, it seems hopeful that both have additive or synergistic effects and they give further increases of remission rates. Twenty-three patients with proven progressive advanced colorectal cancer were treated with 5-FU, FA, and IFN-alpha-2a in three different regimens. IFN-alpha-2a was given subcutaneously in a dose of 5 MioU per day during 5-FU treatment. In the first regimen FA (500 mg/m2) was administered in a short time infusion (30 minutes) while 5-FU (1,000 mg/m2) was given in a 24-hour continuous infusion with weekly intervals. In regimen 2 and 3 FA/5-FU treatment was given on days 1 to 5 every 3 to 4 weeks. The difference was time and dose of the 5-FU infusion (600 mg/m2 in 4-hour versus 350 mg/m2 by push injection). Three patients with isolated liver metastases and one patient with local recurrence of rectal carcinoma received regional therapy with higher 5-FU doses. Dose escalation was carried out in all regimens when possible (toxicity less than or equal to World Health Organization [WHO] grade 1). Objective response rates were reached in nine of 23 patients with two complete remissions (one in regional and systemic treatment) with a mean duration of 6 months. Eight patients had stable disease and six had therapy failure. In pretreated patients no complete remission was reached; three of seven had partial remission, two no change, and two progressive disease. Severe toxicity occurred in 12 of 23 patients with mucositis WHO grade 4 in one patient, grade 3 in two, hematotoxicity grade 3 in three, and cutaneous toxicity in two. Eight of twenty-three patients had alopecia grades 2 and 3. These early results of our phase II study with limited patients shows no significant advantage of double modulation in comparison to the well established results of FA/5-FU therapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Injections, Subcutaneous; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Recombinant Proteins; Rectal Neoplasms

Recent clinical trials have suggested that a combination of folinic acid and 5-fluorouracil (5-FU) may improve response rates and survival in patients with advanced colorectal cancer. However, this regimen has been complicated by potentially life threatening toxicity. Regional delivery of folinic acid via a hepatic artery catheter might be expected to reduce systemic exposure and subsequent adverse effects. The present study compared the pharmacokinetic profiles of intravenous and intra-hepatic arterial infusions of folinic acid in patients with colorectal liver metastases (n = 6) who were being treated with weekly regional infusions of 5-FU. The mean area under the plasma concentration--time curve, the peak plasma concentration and the steady state volume of distribution were 163 micrograms ml-1 h-1 (SD 41), 18.5 micrograms ml-1 (SD 1.2) and 7.41 m-2 (SD 0.44) respectively following intravenous administration of folinic acid compared with 142 micrograms ml-1 h-1 (SD 45), 14.8 micrograms ml-1 (SD 2.4) and 11.21 m-2 (SD 1.22) following intra-hepatic arterial administration (P less than 0.05). Regional folinic acid was therefore associated with a statistically significant reduction in systemic exposure compared with the intravenous route.

Topics: Adenocarcinoma; Colonic Neoplasms; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Metabolic Clearance Rate; Rectal Neoplasms

From February 1987 to December 1988, 34 patients with histologically confirmed advanced colorectal carcinoma were entered in a phase II trial with 5-fluorouracil (5-FU) and folinic acid, for evaluation of treatment effectiveness and toxicity. Our data confirmed that the association 5-FU and folates represents an effective and moderately tolerated palliative treatment, with diarrhea being the only dose-limiting toxicity.

Topics: Clinical Trials as Topic; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin

Sixteen patients with metastatic carcinoma of the colon were treated with a regimen of leucovorin 200 mg/m2, given as a 10-min infusion followed by a median dose of 833 mg/m2 (range 500-1000 mg/m2) 5-fluorouracil every two weeks. For the 16 patients with proven metastatic disease, two-year survival exceeds 50%. Responses were: 2 complete; 4 partial; 4 minor; 3 progression; and 3 not evaluable but without progression to date. Toxicities include: 8 (50%) leukopenia; 9 (56%), 1 severe thrombocytopenia; 9 (56%), 2 severe, diarrhea; 9 (56%), 3 severe, nausea/vomiting; 8 (50%), 1 severe, stomatitis; 7 (44%) conjunctivitis; 6 (38%) alopecia; and 13 (81%), 3 severe, neurotoxicity. Leucovorin appears to exert a dose-dependent beneficial effect on both the response and survival produced by the intermittent high-dose 5-fluorouracil schedule. This benefit first appears to increase substantially when the leucovorin dose is increased from 120 to 200 mg/m2. Findings identify a testable candidate regimen for selected good risk patients. Full selection criteria remain to be identified.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Humans; Leucovorin; Nervous System

Seventy-nine patients with advanced, measurable, metastatic colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either fluorouracil (FUra) administered intravenously at a dose of 370 mg/m2/d for 5 days or the combination of FUra in the same dose and schedule with high-dose continuous infusion leucovorin calcium (500 mg/m2/d) beginning 24 hours before the first dose of FUra and continuing for 12 hours after the completion of FUra therapy. Patients whose disease progressed on treatment with FUra alone were, if eligible, crossed over to receive leucovorin and FUra. Three patients on the FUra plus leucovorin arm of the study were excluded from the analysis because they did not meet eligibility requirements. The treatment arms were well balanced for prognostic criteria including performance status, age, prior radiotherapy, distribution of metastatic sites, and on-study carcinoembryonic antigen (CEA), lactic dehydrogenase, and serum albumin. FUra plus leucovorin was superior to FUra alone for response (P = .0019) and for time to progression or death (log-rank, P = .045). Response rates were 16 of 36 (44%) versus five of 40 (13%), and median time to progression or death was 164 versus 120 days in the two arms of the trial, respectively. Overall survival, however, while longer in the FUra and leucovorin arm was not significantly so. An analysis of the toxicities experienced by the patients in the two treatment groups showed that, except for significantly more stomatitis in the leucovorin arm of the study, the side effects experienced by patients treated with either regimen were comparable. These results suggest that the efficacy of FUra in patients with advanced, measurable, metastatic colorectal cancer can be enhanced significantly by administration of a continuous high-dose infusion of leucovorin calcium.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Colonic Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Prospective Studies; Randomized Controlled Trials as Topic; Rectal Neoplasms; Survival Analysis

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplasm Metastasis; Random Allocation

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Random Allocation; Rectal Neoplasms

We determined the therapeutic effect of fluorouracil (5-FU) in combination with folinic acid (FA) in patients with measurable recurrent or metastatic carcinoma of the colon or rectum by comparing it to standard 5-FU therapy in a prospective randomized controlled trial. Patients were randomized to receive either FA, 200 mg/m2/d for five consecutive days, or nothing. All patients received 5-FU, 370 mg/m2/d for five days on the first course, with subsequent dose modifications to maintain equal toxicity in the two arms. One hundred thirty patients were entered on trial and only five were excluded from the analysis because they did not meet the eligibility criteria or they refused therapy after randomization. The two treatment arms were balanced for 11 clinical characteristics. Patients were evaluated for response at the end of every two treatment courses and toxicity after every course of therapy. Median follow-up was 1.45 years. Dose-limiting toxicity was mucositis and diarrhea on this treatment schedule, although neutropenia was apparent. The response rate was 33% (21 of 63 patients) in the 5-FU and FA arm and was 7% (four of 61 patients) in the 5-FU arm (P less than .0005). Time to disease progression was significantly different in the combination arm as compared with the single-agent arm (P = .023). Overall survival was significantly longer for patients treated with 5-FU and FA as compared with those receiving 5-FU alone (P = .05). The median survival was 12.6 months for patients receiving the combination, and 9.6 months for those receiving 5-FU alone. Our results indicate that the combination of 5-FU and FA is effective treatment for patients with metastatic or recurrent carcinoma of the rectum and colon who have not received prior chemotherapy.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Random Allocation; Rectal Neoplasms

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Colonic Neoplasms; Drug Synergism; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Intravenous; Leucovorin; Methotrexate; Neoplasm Metastasis; Rectal Neoplasms

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Palliative Care; Prospective Studies; Random Allocation; Rectal Neoplasms

The current study was initiated to confirm preliminary reports that 20% or more of patients with colorectal cancer who fail treatment with 5-fluorouracil (FUra) will respond to treatment with either leucovorin plus FUra or with sequential methotrexate, FUra, leucovorin. One hundred two patients with advanced, measureable colorectal cancer who failed treatment with FUra and/or 5-fluorodeoxyuridine (FUdR) were randomized to treatment with either high-dose leucovorin plus FUra (Arm B) or sequential methotrexate, FUra, leucovorin (Arm C). In this interim report, 92 patients were evaluable for toxicity and 89 patients were evaluable for response. Grade 3 or 4 nonhematologic toxicity which was primarily gastrointestinal was experienced by 25% of patients on both treatment arms during at least 1 treatment cycle. Hematologic toxicity was minimal. Among 43 evaluable patients on Arm B, there were 2 complete responses (5%) and 1 minor response (3%). Among 46 evaluable patients on Arm C, there was 1 complete response (2%), 1 partial response (2%), and 6 minor responses (14%). The median time to treatment failure was 2.2 months on Arm B and 3.5 months on Arm C. The median survival was 8.3 months on Arm B and 8.7 months on Arm C. Colorectal cancers that are resistant to FUra are cross-resistant to both experimental combinations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Drug Administration Schedule; Drug Resistance; Floxuridine; Fluorouracil; Humans; Leucovorin; Methotrexate; Rectal Neoplasms

Topics: Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Forecasting; Humans; Leucovorin; Rectal Neoplasms

In this study, 50 patients were randomly assigned to treatment with 5-fluorouracil (FUra) or FUra plus high-dose continuous-infusion folinic acid. Five of 27 evaluable patients in the FUra group versus 10 of 21 patients in the FUra plus folinic acid arm of the study had objective partial remissions, P = 0.02. Time to progression was 3.9 months for FUra and 8.0 months for FUra and folinic acid, P = 0.006; however, median survivals (11.9 versus 14.5 months) were not different in this crossover study. Toxicity in both treatment arms was mild, although patients receiving FUra plus folinic acid experienced significantly more stomatitis than patients treated with FUra alone. This study suggests that high-dose, continuous-infusion folinic acid, which produces a steady-state level of biologically active folates of 10 microM, significantly increases the therapeutic activity of FUra.

Topics: Adenocarcinoma; Biological Availability; Colonic Neoplasms; Fluorouracil; Hematopoiesis; Humans; Infusions, Intravenous; Leucovorin; Rectal Neoplasms; Tetrahydrofolates

The North Central Cancer Treatment Group (NCCTG) and Mayo Clinic are collaborating in an ongoing, prospective, randomized clinical trial of new approaches to the chemotherapy of advanced metastatic colorectal cancer. Single agent 5-fluorouracil (FUra) given by intensive-course rapid intravenous administration serves as a control. Included among the experimental treatments are two regimens consisting of FUra plus leucovorin (folinic acid). One of these regimens uses folinic acid at a dose level of 200 mg/m2 daily for 5 days based on earlier studies by Machover et al. (4). The second regimen uses folinic acid at 1/10 the dose level (20 mg/m2 daily for 5 days), since this lower dose of folinic acid has been shown to produce peak serum levels equivalent to the concentration of folinic acid required in culture medium to produce optimal inhibition of L1210 cells by FUra in vitro, and because of the great expense of folinic acid when given at the higher dose levels. As of January 1986, 78 patients had been randomized to receive treatment with FUra alone or one of the FUra-folinic acid regimens. The toxicity of the folinic acid regimens has been clinically tolerable, with stomatitis and, to a lesser extent, diarrhea being dose-limiting. Hematologic toxicity has been very mild. There is suggestive evidence that folinic acid given at the higher dose level in combination with FUra at a constant dose produces more severe effects on the oropharyngeal mucosa. Preliminary tumor response and survival data remain blinded in accordance with NCCTG policy. Further patient accrual and follow-up are required to assess the therapeutic effect of these folinic acid regimens compared to FUra given alone.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Colonic Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Hematopoiesis; Humans; Leucovorin; Methotrexate; Prospective Studies; Rectal Neoplasms

In order to determine the clinical applicability of the in vitro observation of enhanced cytotoxicity of 5-fluorouracil (5-FU) in the presence of excess reduced folates, the Southwest Oncology Group (SWOG) performed a randomized trial evaluating two dose schedules of 5-FU and folinic acid (FA) in 128 patients with metastatic colorectal cancer. Of 125 eligible patients, 62 were randomized to receive bolus FA (200 mg/m2 days 1 through 4) in addition to 5-FU (1,000 mg/m2 days 1 through 4) by continuous four-day infusion (infusion arm), while 63 were randomized to receive bolus FA (200 mg/m2 days 1 through 5) in addition to 5-FU (325 mg/m2 days 1 through 5) by bolus injection (bolus arm). The toxicities of the two schedules differed, with stomatitis being more severe in the infusion arm and leukopenia being more severe in the bolus arm. The response rates and survival data for the two arms are nearly identical. The median survival of patients on the infusion arm is 11.0 months and of patients on the bolus arm, 10.3 months. The infusion arm produced one complete response (CR) and 12 partial responses (PRs), for a major response rate of 21% of eligible patients. The bolus arm produced three CRs and 11 PRs, for a major response rate of 22% of eligible patients. The response rate produced is minimally superior to recent cooperative group studies of colorectal cancer, but the response rate and survival experience are within the range of experience for treatment with 5-FU alone.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Random Allocation; Rectal 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

We report the results of an expanded trial of 5-fluorouracil (5-FU) combined with high-dose folinic acid for treatment of patients with advanced colorectal or advanced gastric adenocarcinoma. In each treatment course, the patients received both 5-FU (340 to 400 mg/m2/d by intravenous (IV) infusion for a period of 15 minutes) and folinic acid (200 mg/m2/d by IV bolus) for 5 consecutive days, with a 21-day interval between courses. Eighty-six patients with colorectal carcinoma were evaluated. The combined complete and partial response rates were 39% for 54 patients who did not receive prior chemotherapy and 22% for 32 patients who had previously received chemotherapy. Four patients who were previously resistant to 5-FU attained objective responses. The median time to disease progression for the 28 responders was 10 months. The median survival time of responders was 19.5 months, and the probability of their being alive at 2 years was 40%. Of 27 patients with gastric adenocarcinoma, 13 (48%) responded to therapy. Their median time to disease progression was 5.5 months. The median survival time of responders was 11 months, and their probability of being alive at 15 months was 30%. Toxicity was within acceptable limits. Toxic effects included stomatitis, diarrhea, conjunctivitis, skin rash, and mild myeloid hypoplasia. In a separate study, plasma concentrations of L-folates greater than 10(-5) mol/L were achieved after a rapid single IV injection of 200 mg/m2 of folinic acid. Comparisons of our results with those reported in previous studies on 5-FU administered as a single agent suggest that, in advanced colorectal and gastric adenocarcinoma, folinic acid administered in high doses enhances the effectiveness of 5-FU administered concomitantly. Furthermore, some colorectal tumors that were previously resistant to 5-FU become sensitive to this drug. The survival of the patients who responded to therapy was markedly improved over that observed in reported series of untreated patients with advanced colorectal and gastric adenocarcinomas.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Kinetics; Leucovorin; Male; Middle Aged; Rectal Neoplasms; Stomach Neoplasms; Time Factors

Forty-five patients with metastatic colorectal carcinoma were treated with low-dose methotrexate (MTX) and 5-fluorouracil (5-FU) given sequentially. The dose of MTX was 40 mg/m2 intravenously (IV) on days 1 and 8 followed 24 hours later by 5-FU at 600 mg/m2 IV on days 2 and 9; the drugs were recycled every 28 days. Fourteen (32%) of 43 adequately treated patients had a complete or partial response lasting a median of nine months (range, 6-15 + months). Four patients had a minor response and seven patients had stable disease for a median of nine and 10 months, respectively. Toxicity included mucositis in 28 (65%) patients, diarrhea in 18 (40%), nausea in 11 (24%), and vomiting in seven (16%). Hematologic toxicity was mild: six patients had nadir white blood cell counts less than 3.5 X 10(3) cells/microL, and seven patients had a nadir platelet count less than 100 X 10(3) cells/microL. Serial biopsies and blood samples were obtained in selected patients to evaluate the effect of MTX on tissue and lymphocyte phosphoribosylpyrophosphate (PRPP) and PRPP synthetase levels.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Diarrhea; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Lymphocytes; Male; Methotrexate; Middle Aged; Mucous Membrane; Nausea; Pentosephosphates; Phosphoribosyl Pyrophosphate; Phosphotransferases; Prospective Studies; Rectal Neoplasms; Ribose-Phosphate Pyrophosphokinase; Thrombocytopenia; Vomiting

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

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

To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen.. This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged > 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks.. A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis.. Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Oxaliplatin; Rectal Neoplasms; Republic of Korea

Adjuvant chemotherapy of leucovorin-modulated 5-fluorouracil (5-FU/LV), capecitabine, and adding oxaliplatin to 5-FU/LV or capecitabine (FLOX/OX) have been standard regimens for high-risk stage II or III colon cancer (CC). We aimed to evaluate their patterns of use, association with survival, and rate of emergency room visit (ER) or hospitalization during the treatment period. High-risk stage II or III patients aged >65 years diagnosed between 2007 and 2015, underwent colectomy, and received any of these three regimens were selected from SEER and Texas Cancer Registry (TC) linked with Medicare data. Chi-square test, Kaplan-Meier survival curves, Cox regression, and logistic regression were used in data analysis. A total of 5621 (1080 stage II and 4541 stage III) patients with median age of 72 years were included in this study. For stage II, 24.4% used 5-FU/LV, 31.2% used capecitabine, and 44.4% used FLOX/OX; the respective numbers for stage III were 13.8%, 17.9%, and 68.3%. Patients aged <70 years, not in the West region, not in Medicare state-buy-in program, and with no comorbidity were more likely to use FLOX/OX. FLOX/OX was associated with improved overall survival (OS) in stage II and III patients and improved cancer-specific survival in stage III patients compared with 5-FU/LV. The survival benefit of FLOX/OX was sustained in stage III patients aged ≥70 years. Capecitabine had the lowest ER/hospitalization rate with 19.2% in stage II and 28.9% in III. The use of FLOX/OX was associated with improved survival compared with 5-FU/LV among CC patients. Capecitabine was associated with the lowest ER/hospitalization rate.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Medicare; Neoplasm Staging; Oxaliplatin; United States

Fluorouracil (5-FU) pharmacokinetics are variable, leading to a risk of toxicity in some patients and underdosing in others. Therapeutic drug monitoring of 5-FU was shown to reduce toxicity and increase efficacy. This study assessed the clinical utility of starting treatment with 70-80% of BSA calculated dose and titrating according to 5-FU blood levels and toxicity.. A retrospective analysis of a prospectively collected database of 126 patients treated with regimens containing 5-FU bolus and continuous infusion for 46 h for whom the 5-FU blood level was collected at least once. Response,and date of progression, and death were collected for patients with colon and pancreatic cancer.. In multivariate analysis, 5-FU blood levels were correlated with 5-FU dose and with age, albeit a small effect size (coefficient = 0.007). Of patients with colon cancer treated with an initial lower 5-FU dose, 18% had a therapeutic 5-FU blood level. The median survival was similar in patients with metastatic colon cancer treated with lower doses and those treated with a full dose. Of patients with pancreatic cancer treated with lower doses, 40% had therapeutic blood levels. The median survival was 13 months in patients with metastatic pancreatic cancer treated with lower 5-FU doses.. Starting treatment with low 5-FU dose was associated with patient survival comparable to other published data, and a sizeable percentage of patients had therapeutic blood levels. This approach can be considered, especially in elderly and frail patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis.. We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors.. Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61,. In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Oxaliplatin; Prognosis

Safety and effectiveness of aflibercept with 5-fluorouracil/levofolinate/irinotecan have not been reported in Japanese patients with metastatic colorectal cancer (mCRC) in a real-world clinical setting.. This post-marketing surveillance enrolled patients with un-resectable advanced or recurrent mCRC who were prescribed aflibercept from December 2017 to June 2019 in Japan. Data, collected up to 1 year from starting treatment, included patient background, safety, and effectiveness assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or physician's evaluation.. Of 261 patients registered from 64 centers, 235 [53.2% male with a median age of 67 years (range 28-84)] received treatment and were included in the safety analysis. Aflibercept was received at 1st, 2nd, and ≥ 3rd line in 1.3%, 48.1%, and 50.2% of patients, respectively. Median number of treatment cycles was 6 (range 1-22) and relative dose intensity was 75.4% (range 14.3-101.8%). Adverse events (all grades) were reported in 88.5% of patients, including neutropenia (34.5%), proteinuria (24.7%), hypertension (17.0%), diarrhea (17.0%), and decreased appetite (15.3%). Three treatment-related deaths occurred by perforation of the digestive tract, pneumonia and gastrointestinal bleeding, and sudden death. The effectiveness analysis included 198 patients. Overall response rate was 6.1% (1st line, 0%; 2nd line, 10.1%; ≥ 3rd line, 2.1%) and disease control rate was 47.5% (1st line, 100%; 2nd line, 58.6%; ≥ 3rd line, 34.4%).. No new risks of aflibercept were identified in real clinical practice. Effectiveness in patients at the 2nd line was consistent with previous reports.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; East Asian People; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Product Surveillance, Postmarketing; Receptors, Vascular Endothelial Growth Factor; Rectal Neoplasms

Irinotecan is a useful anticancer drug for colorectal cancer treatment. UGT1A1*28 and *6 gene polymorphisms are known risk factors for irinotecan-associated toxicity. However, severe adverse effects due to irinotecan have been observed even in patients who do not harbor UGT1A1*28 or *6. We investigated gene polymorphisms in the whole exome to identify useful biomarkers for irinotecan toxicity other than UGT1A.. A total of 178 patients with metastatic colorectal cancer (mCRC) and 87 patients with pancreatic cancer were treated with FOLFIRI, FOLFOX, FOLFOXIRI, modified FOLFIRINOX, or gemcitabine plus nab-paclitaxel. Genome-wide screening was performed using whole-exome sequencing (WES), and validation analysis was performed using qPCR with a hydrolysis probe.. Using WES after a doublet chemotherapy regimen comprising irinotecan and 5-fluorouracil (n = 15), seven single nucleotide polymorphisms (SNPs) were identified as candidate biomarkers for irinotecan-associated toxicity of neutropenia. Among the seven SNPs, an SNP in R3H domain and coiled-coil containing 1 (R3HCC1; c.919G > A, rs2272761) showed a significant association with neutropenia (>grade 3) after doublet chemotherapy. Patients receiving irinotecan including triplet chemotherapy, FOLFOXIRI for mCRC (n = 23) or modified FOLFIRINOX for pancreatic cancer (n = 40), also showed significant linear trends between R3HCC1 polymorphism and neutropenia (p = 0.017 and 0.046, respectively). No significant association was observed in patients treated with irinotecan-free regimens, FOLFOX for mCRC (n = 66), and gemcitabine plus nab-paclitaxel for pancreatic cancer (n = 47).. Thus, an SNP in the R3HCC1 gene may be a useful biomarker for the toxicity of irinotecan-containing chemotherapy for mCRC and pancreatic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neutropenia; Pancreatic Neoplasms; Polymorphism, Single Nucleotide; Rectal Neoplasms

The benefit of adding the antiangiogenic drug aflibercept to FOLFIRI regime in metastatic colorectal cancer (CRC) patients resistant to or progressive on an oxaliplatin-based therapy has been previously demonstrated. However, the absence of validated biomarkers to predict greater outcomes is a major challenge encountered when using antiangiogenic therapies. In this study we investigated profiles of circulating microRNAs (miRNAs) to build predictive models of response to treatment and survival. Plasma was obtained from 98 metastatic CRC patients enrolled in a clinical phase II trial before receiving FOLFIRI plus aflibercept treatment, and the circulating levels of 754 individual miRNAs were quantified using real-time PCR. A distinct signature of circulating miRNAs differentiated responder from non-responder patients. Remarkably, most of these miRNAs were found to target genes that are involved in angiogenic processes. Accordingly, some of these miRNAs had predictive value and entered in predictive models of response to therapy, progression of disease, and survival of patients treated with FOLFIRI plus aflibercept. Among these miRNAs, circulating levels of hsa-miR-33b-5p efficiently discriminated between responder and non-responder patients and predicted the risk of disease progression. Moreover, the combination of circulating VEGF-A and miR-33b-5p levels improved clinical stratification of metastatic CRC patients who were to receive FOLFIRI plus aflibercept treatment. In conclusion, our study supports circulating miRNAs as valuable biomarkers for predicting better outcomes in metastatic CRC patients treated with FOLFIRI plus aflibercept.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Circulating MicroRNA; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; MicroRNAs; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms

The second-line chemotherapy in metastatic colorectal cancer (mCRC) with FOLFIRI-aflibercept demonstrated an increase in survival compared with FOLFIRI in patients previously treated with oxaliplatin-based regimens. Few data are available in patients treated previously with bevacizumab. Our objective is to evaluate the efficacy and safety of FOLFIRI-aflibercept in second-line treatment in patients who have previously received bevacizumab.. This is a observational, retrospective study of patients with mCRC treated with FOLFIRI-aflibercept in 2nd line in eight hospitals in the Valencian Community. Survival, response, and toxicity were analyzed.. 122 patients with a median age of 61 years were included. 89% of patients had PS 0-1. The median of PFS (progression free survival) and OS (overall survival) was 5.45 (95% CI 4.74-6.15 months) and 10.15 (95% CI 7.47-12.82 months), respectively. Disease control rate 59.8%. The most common grade 3-4 adverse events were neutropenia (13,1%) and asthenia (9%). The presence of hypertension during treatment with FOLFIRI-aflibercept was associated with a survival benefit. Median of OS was 14.45 (95% CI 11.58-17.32) in patients with hypertension vs 7.78 (95% CI 5.02-10.54) in patients without hypertension (p = .001). Our results suggest that the presence of PS 0, primary tumor surgery, metachronous metastases, and the presence of only 1 metastatic location, are favorable prognostic factors associated with better OS.. Our results confirm the value of maintaining angiogenesis inhibition with FOLFIRI-aflibercept in mCRC after progression to a first-line treatment with bevacizumab. The development of hypertension during treatment is a possible predictive marker of response.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Hypertension; Leucovorin; Middle Aged; Neoplasm Metastasis; Recombinant Fusion Proteins; Rectal Neoplasms; Retrospective Studies

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

Fluoropyrimidine (FP) with oxaliplatin-based chemotherapy is the standard first-line treatment for metastatic colorectal cancer (mCRC); however, oxaliplatin-induced neuropathy critically affects the quality of life of patients. Maintenance strategies with FP plus bevacizumab have been well-established; nonetheless, the real-world outcomes of maintenance therapy with FP and cetuximab are unclear. We investigated the clinical outcomes of patients who underwent maintenance therapy with cetuximab.. We retrospectively identified and analyzed patients with mCRC who were treated between 2012 and 2021 with first-line oxaliplatin-based induction chemotherapy (IC) plus biologic agents (either cetuximab or bevacizumab), and underwent maintenance therapy (IC regimen without oxaliplatin) after IC.. In total, 19 patients who were treated with mFOLFOX6 (FP/leucovorin/oxaliplatin) with cetuximab, and 26 patients who were treated with mFOLFOX6 with bevacizumab were included. In the cetuximab group, all patients were KRAS-, NRAS-, and BRAF-wild type, whereas most patients in the bevacizumab group harbored KRAS or BRAF. Maintenance therapy with FP plus biologic agents (either bevacizumab or cetuximab) is a feasible strategy for appropriate mCRC patients according to their RAS/BRAF status. Further large-scale randomized studies are needed to validate the efficacy of anti-epidermal growth factor receptor-based maintenance therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biological Factors; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mutation; Oxaliplatin; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Quality of Life; Rectal Neoplasms; Retrospective Studies

We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan PATIENTS AND METHODS: The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group).. A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively).. POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease Progression; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Postoperative Complications

Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.. We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were assessed.. Antitumor activity of either FOLFIRI or E+C was better as first-line treatment as compared with second-line, with partial cross-resistance seen between a cytotoxic regimen and targeted therapy with an average 62% loss of efficacy for FOLFIRI after E+C and a 45% loss of efficacy of E+C after FOLFIRI (P < 0.001 for both). FOLFIRI-treated models had upregulation of epithelial-mesenchymal transition (EMT) and MAPK pathway activation, where E+C treated models had suppressed MAPK signaling. In contrast, with chemotherapy with E+C, EMT and MAPK signaling remained suppressed. FOLFOX or FOLFIRI, each in combination with E+C, were the most active first-line treatments as compared with E+C or to chemotherapy alone. Furthermore, FOLFOX in combination with E+C as first-line induction therapy, followed by E+C ± 5-FU as maintenance therapy, was the most effective strategy for long-term disease control.. These results support the combination of cytotoxic chemotherapy and molecular-targeted therapy as a promising therapeutic approach in the first-line treatment of BRAFV600E mCRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Mice; Xenograft Model Antitumor Assays

The association between prior bevacizumab (BEV) therapy and ramucirumab (RAM)-induced proteinuria is not known. We aimed to investigate this association in patients with metastatic colorectal cancer (mCRC).. mCRC patients who received folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus RAM were divided into with and without prior BEV treatment groups. The cumulative incidence of grade 2-3 proteinuria and rate of RAM discontinuation within 6 months (6M) after RAM initiation were compared between the two groups.. We evaluated 245 patients. In the Fine-Gray subdistribution hazard model including prior BEV, age, sex, comorbidities, eGFR, proteinuria ≥ 2 + at baseline, and later line of RAM, prior BEV treatment contributed to proteinuria onset (P < 0.01). A shorter interval between final BEV and initial RAM increased the proteinuria risk; the adjusted odds ratios (95% confidence intervals) for the intervals of < 28 days, 28-55 days, and > 55 days (referring to prior BEV absence) were 2.60 (1.23-5.51), 1.51 (1.01-2.27), and 1.04 (0.76-1.44), respectively. The rate of RAM discontinuation for ≤ 6M due to anti-VEGF toxicities was significantly higher in the prior BEV treatment group compared with that in the no prior BEV treatment group (18% vs. 6%, P = 0.02). Second-line RAM discontinuation for ≤ 6M without progression resulted in shorter overall survival of 132 patients with prior BEV treatment (P < 0.01).. Sequential FOLFIRI plus RAM after BEV failure, especially within 55 days, may exacerbate proteinuria. Its escalated anti-VEGF toxicity may negatively impact the overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cohort Studies; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Incidence; Leucovorin; Proteinuria; Ramucirumab; Rectal Neoplasms

Few studies have focused on the impact of single-organ pulmonary metastases on progression-free survival and overall survival in patients with metastatic colorectal cancer. Recognizing differences in prognosis and chemotherapeutic efficacy based on metastasized organs may help in optimizing treatment strategies. The exploratory study was conducted to evaluate the comparative clinical outcomes and prognoses of patients with metastatic colorectal cancer presenting with single-organ pulmonary metastases and treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy.. This retrospective study included 289 patients with metastatic colorectal cancer treated with second-line folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors. The response rate, disease control rate, progression-free survival, and overall survival were assessed in the participants.. Among the 289 patients enrolled, 26 (9.0%) had single-organ pulmonary metastasis with left-sided primary locations, lower levels of tumor markers at the initiation point of chemotherapy, a significantly higher disease control rate (96.2% vs. 76.7%, P = .02), and a longer progression-free survival (median 29.6 months vs. 6.1 months, P < .001) and overall survival (median 41.1 months vs. 18.7 months, P < .001) than patients with other forms of metastatic colorectal cancer. Multivariate analysis showed that single-organ pulmonary metastasis was an independent predictor of longer progression-free survival (hazard ratio 0.35, P = .00075) and overall survival (hazard ratio 0.2, P = .006).. Single-organ pulmonary metastasis was a strong predictor of progression-free survival and overall survival in patients with metastatic colorectal cancer treated with folinic acid, 5-fluorouracil, irinotecan, and vascular endothelial growth factor inhibitors as second-line chemotherapy; this provides preliminary evidence for medical guidelines and clinical decision-making on novel therapeutic strategies for these patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Neoplasm Metastasis; Prognosis; Rectal Neoplasms; Retrospective Studies; Vascular Endothelial Growth Factor A

BRAF V600E mutant-metastatic colorectal cancer (mCRC) is characterized by its short survival time. Treatment approaches vary depending on whether or not the metastases are initially resectable. The benefit of metastasectomy remains unclear, and the optimal first-line treatment is controversial. This study aimed to describe the prognosis of BRAF V600E mutant-mCRC, analyze the recurrence pattern in resectable patients, and explore the optimal first-line treatment for unresectable patients.. Patients diagnosed with BRAF V600E mutant-mCRC between February 2014 and January 2022 in five hospitals were enrolled. Date on clinical and pathological characteristics, treatment features, and survival outcomes were collected.. Of the 220 included patients, 64 initially resectable patients had a significantly longer overall survival (OS) (37.07 vs. 20.20 months, P < 0.001) than initially unresectable patients. Of 156 unresectable patients, 54 received doublet (FOLFOX, XELOX or FOLFIRI) or triplet (FOLFOXIRI) chemotherapies (Chemo), 55 received Chemo plus Bevacizumab (Chemo+Bev), and 33 received vemurafenib plus cetuximab and irinotecan (VIC). The VIC regimen had a better progression-free survival (PFS) (12.70 months) than the Chemo (6.70 months, P < 0.001) and Chemo+Bev (8.8 months, P = 0.044) regimens. Patients treated with VIC had the best overall response rate (60.16%, P < 0.001), disease control rate (93.94%, P < 0.001) and conversional resection rate (24.24%, P = 0.003).. Metastasectomy is beneficial to the survival of patients with BRAF V600E mutant-mCRC. For initially unresectable patients, VIC as first-line therapy is associated with a better prognosis and efficacy than doublet and triplet chemotherapy with or without bevacizumab.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Mutation; Proto-Oncogene Proteins B-raf; Rectal Neoplasms; Vemurafenib

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Oxaliplatin

Few studies have examined the relationship between duration of oxaliplatin-containing adjuvant chemotherapy for stage III colon cancer and mortality in routine practice. We examined the association between treatment with 50% versus >85% of a maximal course of adjuvant therapy (eight cycles of CAPOX, twelve cycles of FOLFOX) and mortality in stage III colon cancer.. Using linked databases, we identified Ontarians aged ≥18 years at diagnosis of stage III colon cancer between 2007 and 2019. In the primary comparison, we compared patients who received 50% or >85% of a maximal course of adjuvant therapy; in a secondary comparison, we evaluated a dose effect across patients who received FOLFOX in one-cycle increments from six to ten cycles against >85% (more than ten cycles) of a maximal course of FOLFOX. The main outcomes were overall and cancer-specific mortality. Follow-up began 270 days after adjuvant treatment initiation and terminated at the first of the outcome of interest, loss of eligibility for Ontario's Health Insurance Program, or study end. Overlap propensity score weights accounted for baseline between-group differences. We determined the hazard ratio, estimating the association between mortality and treatment. Non-inferiority was concluded in the primary comparison for either outcome if the upper limit of the two-sided 95% CI was ≤1.11, which is the margin used in the International Duration Evaluation of Adjuvant Chemotherapy Collaboration.. We included 3546 patients in the analysis of overall mortality; 486 (13.7%) received 50% and 3060 (86.3%) received >85% of a maximal course of therapy. Median follow-up was 5.4 years, and total follow-up was 20,510 person-years. There were 833 deaths. Treatment with 50% of a maximal course of adjuvant therapy was associated with a hazard ratio of 1.13 (95% CI 0.88 to 1.47) for overall mortality and a subdistribution hazard ratio of 1.31 (95% CI 0.91 to 1.87) for cancer-specific mortality versus >85% of a maximal course of therapy. In the secondary comparison, there was a trend toward higher overall mortality in patients treated with shorter durations of therapy, though confidence intervals overlapped considerably.. We could not conclude that treatment with 50% of a maximal course is non-inferior to >85% of a maximal course of adjuvant therapy for mortality in stage III colon cancer. Clinicians and patients engaging in decision-making around treatment duration in this context should carefully consider the trade-off between treatment effectiveness and adverse effects of treatment.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies

For patients with resected stage III colon cancer, 6 months of adjuvant fluoropyrimidine-based chemotherapy has been the standard of care. The IDEA collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy was noninferior to 6 months. Despite failing to meet its primary endpoint, the subgroup analyses demonstrated noninferiority based on regimen and treatment duration when a risk-stratified approach was used.. To evaluate the impact of the results of the IDEA collaboration, we evaluated adjuvant chemotherapy prescribing practice patterns, including planned adjuvant treatment regimen and duration from January 1, 2016, to January 31, 2021. The time period was selected to evaluate chemotherapy prescribing patterns prior to the abstract presentation of the IDEA collaboration in June 2017 and after full manuscript publication in March 2018.. A total of 399 patients with stage III colon cancer who received adjuvant chemotherapy were included in the analysis. A significant increasing trend for use of 3 months of adjuvant chemotherapy was observed after presentation of the IDEA abstract (P<.001). A significant change in CAPOX (capecitabine/oxaliplatin) prescribing was also observed, increasing from 14% of patients prior to presentation of the IDEA abstract to 48% after presentation (P<.001). Comparing 3 months of CAPOX with 6 months of FOLFOX (fluorouracil/leucovorin/oxaliplatin), 3 months of CAPOX use also steadily increased over time (adjusted odds ratio [aOR], 1.28; 95% CI, 1.20-1.37; P<.001). Among subgroups of interest, no differences in adoption of CAPOX were observed. The adoption of 3 months of CAPOX was similar in patients with low-risk cancer (aOR, 1.27; 95% CI, 1.17-1.37) and those with high-risk cancer (aOR, 1.31; 95% CI, 1.16-1.47).. Despite the IDEA collaboration failing to demonstrate noninferiority of 3 months' duration of adjuvant therapy compared with 6 months, the findings have influenced practice prescribing patterns, favoring CAPOX and a shorter duration of planned adjuvant treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Oxaliplatin

To assess the cost-effectiveness of cetuximab in combination with chemotherapy fluorouracil, oxaliplatin, and leucovorin (FOLFOX) or fluorouracil, irinotecan and leucovorin (FOLFIRI) compared to standard chemotherapy alone as a first-line treatment for metastatic colorectal cancer (mCRC) with positive KRAS wild type patients in Indonesia.. A cost-utility analysis applying Markov model was constructed, with a societal perspective. Clinical evidence was derived from published clinical trials. Direct medical costs were gathered from hospital billings. Meanwhile, direct non-medical costs, indirect costs, and utility data were collected by directly interviewing patients. We applied 3% discount rate for both costs and outcomes. Probabilistic sensitivity analysis was performed to explore the model's uncertainty. Additionally, using payer perspective, budget impact analysis was estimated to project the financial impact of treatment coverage.. There was no significant difference in life years gained (LYG) between cetuximab plus FOLFOX/FOLFIRI and chemotherapy alone. The incremental QALY was only one month, and the incremental cost-effectiveness ratio (ICER) was approximately IDR 3 billion/QALY for cetuximab plus chemotherapy. Using 1-3 GDP per capita (IDR 215 million or USD 14,350) as the current threshold, the cetuximab plus chemotherapy was not cost-effective. The budget impact analysis resulted that if cetuximab plus chemotherapy remain included in the benefits package under the Indonesian national health insurance (NHI) system, the payer would need more than IDR 1 trillion for five years.. The combination of cetuximab and chemotherapy for mCRC is unlikely cost-effective and has a substantial financial impact on the system.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Cost-Benefit Analysis; Fluorouracil; Humans; Indonesia; Leucovorin; Oxaliplatin; Rectal Neoplasms

Colorectal cancer (CRC) mainly affects older patients. The pivotal VELOUR phase III trial of aflibercept plus FOLFIRI in metastatic CRC (mCRC) included only 5.9% of patients aged ≥75 years. Herein, we report a preplanned analysis from QoLiTrap, a large prospective observational study evaluating the impact of age on quality of life (QoL), effectiveness, and safety of aflibercept plus FOLFIRI in daily clinical practice in Europe.. Enrolled patients had progressive mCRC, had failed a prior oxaliplatin-based regimen, and had received aflibercept (4 mg/kg) plus FOLFIRI every two weeks until disease progression, death, unacceptable toxicity, or physician/patient decision. Analyses were performed by age classes (<60, 60-64, 65-69, 70-74, and ≥ 75 years). The primary endpoint was the percentage of patients whose global health status (GHS) of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was maintained (i.e., no worsening from baseline by at least 5% over a 12-week treatment). Secondary endpoints included tumor objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety.. Overall, 1277 patients (<60 years, n = 327; 60-64 years, n = 231; 65-69 years, n = 227; 70-74 years, n = 259; and ≥ 75 years, n = 233) were treated, of whom 872 were evaluable for QoL. GHS was maintained in 36.5%, 41.6%, 38.9%, 41.8%, and 44.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. Age did not influence PFS (median 7.8 months), OS (median 14.4 months), or ORR (20.8%). Number of cycles, dose delays for any cause, and dose reductions for adverse events (AEs) were comparable between age classes. Grade ≥ 3 AEs occurred in 47.7%, 51.9%, 51.5%, 55.2%, and 55.8% of patients aged <60, 60-64, 65-69, 70-74, and ≥ 75 years, respectively. The main grade ≥ 3 AEs were hypertension (11.2%) and diarrhea (9%) in patients aged ≥75 years.. The results suggest that aflibercept plus FOLFIRI maintains QoL and retains its activity, including a high objective tumor response, regardless of age and treatment line. In fit older patients, the safety profile seems manageable, with no new safety signals.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Prospective Studies; Quality of Life; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms

The impact of cycle completion rates of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer in real-world practice is unknown. We assessed its impact, and that of treatment modification, on 3-year cancer-specific mortality. Four thousand one hundred and forty-seven patients with pathological stage III colon cancer undergoing major resection from 2014 to 2017 in the English National Health Service were included. Chemotherapy data came from linked national administrative datasets. Competing risk regression analysis for 3-year cancer-specific mortality was performed according to completion of <6, 6-11, or 12 5-fluoropyrimidine and oxaliplatin (FOLFOX) cycles, or <4, 4-7, or 8 capecitabine and oxaliplatin (CAPOX) cycles, adjusted for patient, tumour and hospital-level characteristics. Median age was 64 years. Thirty-two per cent of patients had at least one comorbidity. Forty-two per cent of patients had T4 disease, and 40% had N2 disease. Compared to completion of 12 FOLFOX cycles, cancer-specific mortality was higher in patients completing <6 cycles [subdistribution hazard ratios (sHR) 2.17; 95% CI 1.56-3.03] or 6-11 cycles (sHR 1.40; 95% CI 1.09-1.78) (P < .001). Compared to completion of 8 CAPOX cycles, cancer-specific mortality was higher in patients completing <4 cycles (sHR 2.02; 95% CI 1.53-2.67) or 4-7 cycles (sHR 1.63; 95% CI 1.27-2.10) (P < .001). Dose reduction and early oxaliplatin discontinuation did not impact mortality in patients completing all cycles. Completion of all cycles of chemotherapy was associated with improved cancer-specific survival in real-world practice. Poor prognostic factors may have affected findings, however, patients completing <50% of cycles had poor outcomes. Clinicians may wish to facilitate completion with treatment modification in those able to tolerate it.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Prospective Studies; Survival Rate

To assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC).. We performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).. One hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70-85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3-4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1-2 skin rash (49.1%), G1-2 diarrhea (21.1%) and G1-2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5-11.4), while the median OS was 18.0 months (95% CI: 16.0-19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832).. This study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Exanthema; Fluorouracil; Humans; Leucovorin; Panitumumab; Rectal Neoplasms

Some patients with cancer may present with progressive or persistent disease at a limited number of sites following a period of treatment response. We evaluated the safety and effectiveness of metastasis-directed radiotherapy (MRT) for oligoprogressive or oligopersistent disease in patients receiving systemic treatment for metastatic colorectal cancer (mCRC).. Patients with mCRC who received 5-fluorouracil, leucovorin, and oxaliplatin; 5-fluorouracil, leucovorin, and irinotecan; and/or capecitabine chemotherapy between 2011 and 2020 at a single institution were identified. Then, those who underwent MRT for five or fewer lesion sites while receiving systemic treatment for other metastases were categorized. The primary endpoint was time to change to systemic therapy. Secondary endpoints included MRT-related toxicity, overall survival, and local control.. Among 4157 patients included, 91 (2%) received MRT to limited lesion sites (55 oligoprogressive and 36 oligopersistent) during systemic treatment following a period of treatment response. The median time to change to next-line systemic therapy was 5 months in the overall cohort (measured from the current chemotherapy session) and 9.5 (range, 6.0-40.6) months in the MRT group (measured from the MRT session). No severe toxicity or systemic treatment interruption was observed following MRT. The 1-year local control and overall survival rates were 69% and 99%, respectively.. In patients with oligoprogressive or oligopersistent mCRC, MRT may be performed safely in conjunction with systemic treatment to maximize the benefit of systemic therapy and to prolong the time to change to systemic therapy. Further prospective studies should confirm these findings.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Prospective Studies; Rectal Neoplasms

CALGB 80405 compared the combination of first-line chemotherapy with cetuximab or bevacizumab in the treatment of advanced or metastatic colorectal cancer (mCRC). Although similar clinical outcomes were observed in the cetuximab-chemotherapy group and the bevacizumab-chemotherapy group, biomarkers could identify patients deriving more benefit from either biologic agent.. In this exploratory analysis, the Angiome, a panel of 24 soluble protein biomarkers were measured in baseline plasma samples in CALGB 80405. Prognostic biomarkers were determined using univariate Cox proportional hazards models. Predictive biomarkers were identified using multivariable Cox regression models including interaction between biomarker level and treatment.. In the total population, high plasma levels of Ang-2, CD73, HGF, ICAM-1, IL6, OPN, TIMP-1, TSP-2, VCAM-1, and VEGF-R3 were identified as prognostic of worse progression-free survival (PFS) and overall survival (OS). PlGF was identified as predictive of lack of PFS benefit from bevacizumab [bevacizumab HR, 1.51; 95% confidence interval (CI), 1.10-2.06; cetuximab HR, 0.94; 95% CI, 0.71-1.25; Pinteraction = 0.0298] in the combined FOLFIRI/FOLFOX regimens. High levels of VEGF-D were predictive of lack of PFS benefit from bevacizumab in patients receiving FOLFOX regimen only (FOLFOX/bevacizumab HR, 1.70; 95% CI, 1.19-2.42; FOLFOX/cetuximab HR, 0.92; 95% CI, 0.68-1.24; Pinteraction = 0.0097).. In this exploratory, hypothesis-generating analysis, the Angiome identified multiple prognostic biomarkers and two potential predictive biomarkers for patients with mCRC enrolled in CALGB 80405. PlGF and VEGF-D predicted lack of benefit from bevacizumab in a chemo-dependent manner. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Genotype; Humans; Leucovorin; Phenotype; Vascular Endothelial Growth Factor D

To evaluate the efficacy and safety of apatinib combined with FOLFIRI in the first-line treatment of advanced metastatic colorectal cancer (mCRC) and explore potential factors of efficacy.. Twenty mCRC patients treated at Affiliated Cancer Hospital of Shanxi Medical University from March 2017 to March 2019 were included according to the enrolment criteria. They provided informed consent and were treated with apatinib combined with FOLFIRI according to the scheduled regimen until disease progression or unacceptable toxicity occurred. The primary endpoint was OS. The secondary endpoints included PFS, ORR, DCRand safety. OS and PFS were calculated using Kaplan-Meier curves. Univariate and multivariate Cox regression analyses were used to evaluate independent prognostic factors of OS and PFS. R was used to determine cut-off values for biochemical indicators. Forest maps were drawn for Cox univariate results and the relationships between NLR and ECOG, which were significant in univariate analysis, and OS were represented by Kaplan-Meier curves.. The median OS and PFS were 16.135 months (95% CI: 9.211-22.929) and 6 months (95% CI: 5.425-6.525). Multivariate Cox analysis showed that NLR and CEA were independent prognostic factors. The most common grade 3-4 adverse events were hypertension, diarrhoea, increased alkaline phosphatase, decreased leukocytes and decreased neutrophils.. Apatinib combined with FOLFIRI for the first-line treatment of advanced unresectable mCRC showed good efficacy and safety. The baseline NLR was predictive of efficacy, and a low baseline NLR (HR: 0.2895, P = 0.0084) was associated with improved OS.Clinical Research Registration Number: ChiCTR1800015308.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Pyridines; Rectal Neoplasms

Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance.. We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints.. In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001).. Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Comorbidity; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Retrospective Studies

Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer.. A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed.. One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively.. Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasm Staging; Neoplasm, Residual; Neoplastic Cells, Circulating; Neutrophils; Organoplatinum Compounds; Prognosis; Prospective Studies; Treatment Outcome

Adjuvant chemotherapy is not recommended for patients with average-risk stage II (T3N0) colon cancer. Nevertheless, a subgroup of these patients who are CDX2-negative might benefit from adjuvant chemotherapy. We evaluated the cost-effectiveness of testing for the absence of CDX2 expression followed by adjuvant chemotherapy (fluorouracil combined with oxaliplatin [FOLFOX]) for patients with stage II colon cancer.. We developed a decision model to simulate a hypothetical cohort of 65-year-old patients with average-risk stage II colon cancer with 7.2% of these patients being CDX2-negative under 2 different interventions: (1) test for the absence of CDX2 expression followed by adjuvant chemotherapy for CDX2-negative patients and (2) no CDX2 testing and no adjuvant chemotherapy for any patient. We derived disease progression parameters, adjuvant chemotherapy effectiveness and utilities from published analyses, and cancer care costs from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Sensitivity analyses were conducted.. Testing for CDX2 followed by FOLFOX for CDX2-negative patients had an incremental cost-effectiveness ratio of $5500/quality-adjusted life-years (QALYs) compared with no CDX2 testing and no FOLFOX (6.874 vs 6.838 discounted QALYs and $89 991 vs $89 797 discounted US dollar lifetime costs). In sensitivity analyses, considering a cost-effectiveness threshold of $100 000/QALY, testing for CDX2 followed by FOLFOX on CDX2-negative patients remains cost-effective for hazard ratios of <0.975 of the effectiveness of FOLFOX in CDX2-negative patients in reducing the rate of developing a metastatic recurrence.. Testing tumors of patients with stage II colon cancer for CDX2 and administration of adjuvant treatment to the subgroup found CDX2-negative is a cost-effective and high-value management strategy across a broad range of plausible assumptions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CDX2 Transcription Factor; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Decision Support Techniques; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Markov Chains; Middle Aged; Models, Economic; Neoplasm Staging; Organoplatinum Compounds; Quality-Adjusted Life Years; Risk Assessment

To compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy.. We analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab.. The overall response rate (ORR) was 13.6% (95% confidence interval 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% confidence interval 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752). Patients in the FOLFIRI-bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI-aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group.. FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms

We report a cases report of colorectal cancer who underwent repeated resection for peritoneal recurrences by laparoscopic surgery. In 2013, a 70-year-old woman diagnosed with an ascending colon cancer underwent laparoscopic right hemicolectomy. The pathological diagnosis was tub2, pT4aN1M0, Stage Ⅲb. Postoperative adjuvant chemotherapy(uracil and tegafur/Leucovorin)was administered. PET-CT performed at 25 months after the surgery because of CEA elevation. It revealed a peritoneal recurrence in the pouch of Douglas. The following peritoneal recurrences were removed by laparoscopic Hartmann's procedure. Chemotherapy(5-fluorouracil/levofolinate/oxaliplatin/bevacizumab)was administered 11 courses and after that chemotherapy(5-fluorouracil/levofolinate/bevacizumab)was administered 6 courses. PET-CT performed 37 months after the second surgery revealed a peritoneal recurrence near the right ovary in the pouch of Douglas. The following peritoneal recurrences was removed. Chemotherapy(tegafur/gimeracil/oteracil/bevacizumab)was administered 11 courses. The long-term survival has been continued for 7 years and 7 months after first operation. It was considered that laparoscopic surgery for peritoneal recurrence in colorectal cancer is contributed to one of the surgical procedures in selected patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Laparoscopy; Leucovorin; Peritoneal Neoplasms; Positron Emission Tomography Computed Tomography; Recurrence; Tegafur

The VELOUR study showed the benefit of FOLFIRI-Aflibercept (FA) versus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in second-line treatment. However, only 36% of the included patients were ≥65 years. Thus, we seek to evaluate the efficacy and safety of FA in the elderly population in the context of routine practice.. We conducted an observational, retrospective, multicenter, observational study of patients ≥70 years with mCRC treated with FA after progression to oxaliplatin chemotherapy in routine clinical practice in 9 hospitals of the GITuD group.. Of 388 patients treated with FA between June 2013 and November 2018, 75 patients ≥70 years were included. The median number of cycles was 10 and the objective response (ORR) and disease control rates (DCR) were 33.8% and 72.0%, respectively. With a median follow-up of 27.1 months, median Progression-free survival (PFS) was 6.6 months and median Overall Survival (OS) was 15.1 months. One third fewer metastasectomies were performed in the ≥75 years' subgroup (24 vs. 52%, p = 0.024) and more initial FOLFIRI dose reductions (68 vs. 36%, p = 0.014). ORR (23.8% vs. 38.3%), DCR (42.8% vs. 85.1%), and PFS (4 vs. 7.8 months; p = 0.017) were significantly less, without difference in OS (9.9 vs. 17.1 months; p = 0.129). The presence of prior hypertension (HT) (PFS 7.9 vs. 5.7 months, p = 0.049) and HT ≥ grade 3 during treatment (PFS 7.6 vs. 6.6 months, p = 0.024) were associated with longer PFS. The most frequent grade 3/4 adverse events were: asthenia (21.3%), neutropenia (14.7%), and diarrhea (14.7%). 57.3% required FOLFIRI dose reduction; 34.7% of aflibercept, including discontinuation (5.3% and 18.7%, respectively).. FA combination is effective in patients ≥70 years. The occurrence of HT is predictive of efficacy. Close monitoring of toxicity and initial dose adjustment is recommended.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Oxaliplatin; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms; Retrospective Studies

Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0.. The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples.. A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population.. Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Rectal Neoplasms

Patients with colon cancer who prematurely discontinue postoperative chemotherapy may have an increased risk of disease recurrence and death. This study tested the hypothesis that the quantity and distribution of abdominal adipose tissue predict premature chemotherapy discontinuation.. This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 24-weeks of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposures were body mass index (BMI) and computed tomography-derived abdominal adiposity measures (e.g., visceral, subcutaneous, and intramuscular adipose tissue). The primary endpoint was premature chemotherapy discontinuation, defined as receiving <6 cycles of FOLFOX. Generalized linear models quantified the relative risk (RR) of premature chemotherapy discontinuation adjusted for age, sex, cancer stage, height, and muscle area, using two-sided statistical tests.. Forty-two patients [7.9% (95% CI: 5.7, 10.5)] prematurely discontinued chemotherapy. Visceral adipose tissue [RR: 3.27 (95% CI: 1.26, 8.49)] and intramuscular adipose tissue [RR: 2.79 (95% CI: 1.09, 7.12)] were statistically significantly associated with an increased risk of premature chemotherapy discontinuation. BMI [RR: 2.07 (95% CI: 0.75, 5.73)] and subcutaneous adipose tissue [RR: 2.32 (95% CI: 0.91, 5.94)] were not statistically significantly associated with premature chemotherapy discontinuation.. Among patients with stage II-III colon cancer who initiate postoperative chemotherapy, excess visceral and intramuscular adiposity may be risk factors for the premature discontinuation of chemotherapy.

Topics: Adiposity; Cohort Studies; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity, Abdominal; Oxaliplatin

Colorectal cancer is one of the most commonly diagnosed malignancies globally and nearly half of these patients develop metastatic colorectal cancer (mCRC). The current standard treatment for mCRC includes 5-fluorouracil-based chemotherapy with or without bevacizumab. Nevertheless, a predictive biomarker of efficacy for bevacizumab has not yet been firmly established. This retrospective study aimed to investigate the correlation between tumor calcification and prognosis in mCRC patients who received bevacizumab plus chemotherapy as the first-line treatment. The authors found that tumor calcification was independently associated with improved survival in mCRC patients treated with bevacizumab plus chemotherapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Rectal Neoplasms; Retrospective Studies

The activation of stimulator of interferon genes (STING) was reported to enhance cetuximab-mediated natural killer cell activation and dendritic cell maturation. Polymorphisms in genes in the cyclic GMP-AMP synthase (cGAS)-STING pathway may affect innate immune response. Therefore, we hypothesised that genetic variants in the cGAS-STING pathway may predict the efficacy of cetuximab-based treatment in patients with metastatic colorectal cancer.. Genomic DNA from blood samples of patients enrolled in FIRE-3 (cetuximab arm, n = 129; bevacizumab arm, n = 107) and TRIBE (bevacizumab arm, n = 215) was genotyped using the OncoArray-500K bead chip panel. Seven selected single nucleotide polymorphisms in 3 genes (cGAS, STING and interferon B1 (IFNB1)) were analysed for the association with overall survival and progression-free survival.. In the cetuximab cohort, patients with STING rs1131769 any T allele showed significantly shorter overall survival (36.3 versus 56.1 months) than carriers of C/C in both univariate [hazard ratio (HR) = 2.08; 95% confidence interval (CI): 1.06-4.07; P = 0.03] and multivariate (HR = 2.98; 95% CI: 1.35-6.6; P = 0.0085) analyses; patients carrying IFNB1 rs1051922 G/A and A/A genotype showed a significantly shorter progression-free survival than carriers of G/G allele in both univariate (G/A versus G/G, 10.2 versus 14.1 months, HR = 1.84; 95% CI 1.23-2.76; A/A versus G/G, 10.7 versus 14.1 months, HR = 2.19; 95% CI 0.97-4.96; P = 0.0077) and multivariate analyses (G/A versus G/G, HR = 2; 95% CI 1.22-3.3; A/A versus G/G, HR = 2.19, 95% CI 0.92-5.26, P = 0.02). These associations were not observed in the bevacizumab arm of FIRE-3 or TRIBE.. These results suggest for the first time that germline polymorphisms in STING and IFNB1 genes may predict the outcomes of cetuximab-based treatment in patients with metastatic colorectal cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Interferons; Leucovorin; Membrane Proteins; Nucleotidyltransferases; Rectal Neoplasms

Five-fluorouracil, folinic acid, oxaliplatin and irinotecan (FOLFOXIRI) regimen is used as the first-line treatment for metastatic colorectal cancer (mCRC). The use of capecitabine, an oral fluoropyrimidine pro-drug, is feasible and safe; hence, it provides an interesting alternative to 5-fluorouracil in the abovementioned regimen. This study aimed to evaluate the efficacy and safety of capecitabine, oxaliplatin, and irinotecan (XELOXIRI) regimen use with or without targeted drugs in Chinese patients with mCRC.. We conducted a retrospective, longitudinal cohort study of patients with mCRC who received XELOXIRI regimen with or without targeted drugs (bevacizumab or cetuximab) every 2 weeks between January 2017 and November 2019 at the National Cancer Center/Cancer Hospital, the Chinese Academy of Medical Sciences, and Peking Union Medical College. Treatment efficacy was assessed by investigators by evaluating the objective response rate (ORR) and disease control rate (DCR). Overall survival (OS) was assessed using Cox proportional hazards models. The adverse events were also analyzed.. Sixty-one consecutive patients were examined and followed up for survival. As of November 8, 2021, the median follow-up time was 35.4 months. Disease progression and death occurred in 50 (82%) and 38 (62%) patients, respectively. The median treatment duration of XELOXIRI with or without bevacizumab or cetuximab was 10 cycles (range, 1-12 cycles). The median OS and PFS were 32.2 months (95%CI [24.8-39.6]) and 9.3 months (95% CI [8.1-10.5]), respectively. The ORR of 48 patients with measurable lesions was 70.8%, and the DCR was 89.6%. RAS/BRAF wild-type (HR 0.39; 95% CI [0.16-0.96], p = 0.04) and metastatic organs > 2 (HR 3.25; 95% CI [1.34-7.87], p = 0.009) were independent prognostic factors for OS. The incidence of any grade of adverse events (AEs) was 96.7% (59/61). Grade ≥ 3 AEs included neutropenia (19.7%), leukopenia (9.8%), diarrhea (3.3%), vomiting (3.3%), febrile neutropenia (1.6%), and thrombocytopenia (1.6%). No treatment-related death occurred.. The use of the XELOXIRI regimen with or without a targeted drug was effective, with a manageable toxicity profile in Chinese patients with mCRC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Longitudinal Studies; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Retrospective Studies

Additive chemotherapeutic treatment of UICC-stage -III / IV colon cancer with fluorouracil, leucovorin and oxaliplatin is widely accepted as current standard of treatment after R0-resection. However, as patients.. survival is increasing, long-term side effects of chemotherapeutic agents such as second cancer development are becoming increasingly important.. We therefore investigated a total of 2 856 Patients with UICC-stage III / IV colon cancer, 223 of whom (7.8%) had developed a subsequent second cancer.. Median follow-up was 73.2 months (range 209.9 months, 95%-CI 69.8-76.9). Most frequent second cancers were prostate cancer (18.4%), colon cancer (16.1%), breast cancers (8.1%), lung cancer (8.1%), rectal cancer (4.9%) and uterine cancer (4.9%). However, in comparison to non-treated patients this did not represent a significantly increased risk for subsequent second cancer in patients after treatment with additive chemotherapy. Of interest, our data suggest a significantly decreased second cancer rate in patients treated with FOLFOX compared to FUFOL for additive treatment.. Second cancer development was not increased after additive chemotherapy for colon cancer, which is a novel aspect in the ongoing discussions on reduction of adjuvant treatment to 3 months or treatment of lymph node negative patients. Novelty and Impact Statement To our knowledge, this is the first population-based study analyzing second cancer development after additive chemotherapy in patients with UICC III-IV colon cancer. The results have an important impact on the surveillance and long-term follow-up of cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Neoplasms, Second Primary; Organoplatinum Compounds

In this retrospective study, the authors examined baseline characteristics of and treatment duration and real-world overall survival (rwOS) in 1096 and 684 patients with metastatic colorectal cancer receiving cetuximab as second-line (2L) and third-line (3L) treatment, respectively. The most common cetuximab-based regimens were cetuximab + folinic acid, fluorouracil and irinotecan (2L: 44%; 3L: 32%) and cetuximab + irinotecan (2L: 28%; 3L: 35%). Median treatment duration and rwOS were 3.7 and 14.4 months, respectively, in patients receiving treatment in the 2L cohort. In the 3L cohort, median treatment duration was 3.3 months and rwOS was 12.0 months. This large real-world study provides evidence of rwOS in patients with metastatic colorectal cancer receiving cetuximab-based regimens as 2L or 3L treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Rectal Neoplasms; Retrospective Studies

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Patients with CRC may need chemotherapy (CTx) in a neoadjuvant, adjuvant or palliative setting through the course of the disease. Unfortunately, its effect is limited by chemoresistance and chemotoxicity. Novel more effective and non‑toxic CTx regimens are needed to further improve CRC treatment outcomes. Thus, the present study was designed to test the hypothesis that non‑toxic sulforaphane (SF) is effective against CRC and has additive effects in combination with conventional 5‑fluorouracil, oxaliplatin and folinic acid (FOLFOX) CTx

Topics: Aldehyde Dehydrogenase 1 Family; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Fluorouracil; Humans; Isothiocyanates; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Sulfoxides

Colorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists.. Patients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined.. Five hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08-0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33-0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33-0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38-1.02, p = 0.06).. In resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.

Topics: Antineoplastic Combined Chemotherapy Protocols; Canada; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Testicular Neoplasms

Although several clinical factors which show the benefit of adjuvant chemotherapy (AC) in early-stage colon cancer use for evaluating the risk of relapse, there is no consensus on which risk factors are more reliable. In this study, we evaluated both the utility of MSI and the daily practice of the Turkish oncologists in stage II and III colon cancer.. We conducted an online questionnaire which was consisting of twenty questions including the treatment choices and duration about stage II-III colon cancer depending on sidedness and risk factors for relapse.. More than 65% of the oncologists declared the use of MSI testing in stage II colon cancer without considering any risk factors. In stage 3 colon cancer oncologists had an equal decision "to do or not to do" in MSI testing. More than 50% of the oncologists had preferred XELOX protocol in high-risk stage II (T4N0) colon cancer, while three out of four preferred observation in low-risk stage II (T3N0) patients without risk factors. Two-thirds of the oncologists had preferred 6 months of treatment in stage II colon cancer with at least one risk factor.. Turkish oncologists participating to this trial had declared conflicting results about adjuvant treatment in early-stage colorectal cancer in their daily practice compared with the updated guidelines, especially, MSI evaluation utility in stage III colon cancers, adjuvant chemotherapy (AC) duration, and oxaliplatin adding to AC in elderly and stage II patients.

Topics: Aged; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Neoplasm Recurrence, Local; Neoplasm Staging; Oncologists

FOLFIRINOX and FOLFOXIRI are combination chemotherapy treatments that incorporate the same drug cocktail (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) but exploit an altered dosing regimen when used in the management of pancreatic and colorectal cancer, respectively. Both have proven effective in extending life when used to treat patients with metastatic disease but are accompanied by significant adverse effects. To facilitate improved tumour-targeting of this drug combination, an ultrasound responsive microbubble formulation loaded with 5-fluorouridine, irinotecan and oxaliplatin (FIRINOX MB) was developed and its efficacy tested, together with the non-toxic folinic acid, in preclinical murine models of pancreatic and colorectal cancer. A significant improvement in tumour growth delay was observed in both models following ultrasound targeted microbubble destruction (UTMD) mediated FIRINOX treatment with pancreatic tumours 189% and colorectal tumours 82% smaller at the conclusion of the study when compared to animals treated with a standard dose of FOLFIRINOX. Survival prospects were also improved for animals in the UTMD mediated FIRINOX treatment group with an average survival of 22.17 ± 12.19 days (pancreatic) and 44.40 ± 3.85 days (colorectal) compared to standard FOLFIRINOX treatment (15.83 ± 4.17 days(pancreatic) and 37.50 ± 7.72 days (colon)). Notably, this improved efficacy was achieved using FIRINOX MB that contained 5-fluorouricil, irinotecan and oxaliplatin loadings that were 13.44-fold, 9.19-fold and 1.53-fold lower than used for the standard FOLFIRINOX treatment. These results suggest that UTMD enhances delivery of FIRINOX chemotherapy, making it significantly more effective at a substantially lower dose. In addition, the reduced systemic levels of 5-fluorouracil, irinotecan and oxaliplatin should also make the treatment more tolerable and reduce the adverse effects often associated with this treatment.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Mice; Microbubbles; Oxaliplatin; Pancreatic Neoplasms; Treatment Outcome; Uridine

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colonic Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Fluorouracil; Gastrointestinal Microbiome; Humans; Leucovorin; Metabolomics; Mice; Organoplatinum Compounds; Prevotella; Xenograft Model Antitumor Assays

There is evidence that achieving a dose intensity > 80% in adjuvant colon cancer treatment improves survival. In total, 192 consecutive patients with resected stage III and high-risk stage II colon cancer that received adjuvant chemotherapy were retrospectively analyzed. Patients who received at least 6 weeks of adjuvant therapy were included. The primary objective was to assess the influence of dose index (DI) and relative dose intensity (RDI) on DFS and OS at 3 and 5 years in patients receiving fluorouracil-based doublet therapy with oxaliplatin (FOLFOX) (5-FU and oxaliplatin assessed separately), or capecitabine monotherapy. In the capecitabine group, DFS rates for 3 and 5 years were 66.7% and 57.6%, respectively, while OS rates were 80.3% and 66.7%, respectively. Those who received FOLFOX had DFS rates of 76.9% and 71.2% at 3 and 5 years, respectively. OS rates were 86.4% and 76.7% at 3 and 5 years, respectively. Median RDI was 73.8% for capecitabine and 76.3% and 85.6% for the oxaliplatin and 5-FU components respectively. Based on a multivariate analysis in patients receiving FOLFOX, those with an oxaliplatin DI > 80% had improvements in DFS and OS compared to those with an oxaliplatin DI of ≤80%. Otherwise, there was no significant difference in DFS or OS when comparing patients who achieved an RDI or a DI of above versus below 80% in the patients receiving adjuvant chemotherapy for resected colon cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Humans; Leucovorin; Organoplatinum Compounds; Retrospective Studies

Cancer incidence is rising in low- and middle-income countries, where resource constraints often complicate therapeutic decisions. Here, we perform a cost-effectiveness analysis to identify the optimal adjuvant chemotherapy strategy for patients with stage III colon cancer treated in South African (ZA) public hospitals.. A decision-analytic Markov model was developed to compare lifetime costs and outcomes for patients with stage III colon cancer treated with six adjuvant chemotherapy regimens in ZA public hospitals: fluorouracil, leucovorin, and oxaliplatin for 3 and 6 months; capecitabine and oxaliplatin (CAPOX) for 3 and 6 months; capecitabine for 6 months; and fluorouracil/leucovorin for 6 months. Transition probabilities were derived from clinical trials to estimate risks of toxicity, disease recurrence, and survival. Societal costs and utilities were obtained from literature. The primary outcome was the incremental cost-effectiveness ratio in international dollars (I$) per disability-adjusted life-year (DALY) averted, compared with no therapy, at a willingness-to-pay (WTP) threshold of I$13,006.56.. CAPOX for 3 months was cost-effective (I$5,381.17 and 5.74 DALYs averted) compared with no adjuvant chemotherapy. Fluorouracil, leucovorin, and oxaliplatin for 6 months was on the efficiency frontier with 5.91 DALYs averted but, with an incremental cost-effectiveness ratio of I$99,021.36/DALY averted, exceeded the WTP threshold.. In ZA public hospitals, CAPOX for 3 months is the cost-effective adjuvant treatment for stage III colon cancer. The optimal strategy in other settings may change according to local WTP thresholds. Decision analytic tools can play a vital role in selecting cost-effective cancer therapeutics in resource-constrained settings.

Topics: Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Fluorouracil; Hospitals, Public; Humans; Leucovorin; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; South Africa

Colorectal carcinoma (CRC) is the third most common human cancer. Twist, a basic helix-loop-helix (bHLH) transcription factor, is an epithelial-mesenchymal transition ((EMT) inducer that has been involved in carcinogenesis and chemoresistance. Also, the enhancer of Zeste homolologue2 (EZH2), a member of the polycomb group of genes, had been associated with poor prognosis in several malignancies.. To evaluate the expression of Twist1 and EZH2 in colon carcinoma in Egyptian patients and its relation to clinicopathological parameters, prognosis, and survival.. Twist1 and EZH2 expressions were evaluated immunohistochemically in 50 cases of colorectal tumors (12 colon adenomas and 38 colon carcinomas) and 20 samples from normal colonic mucosa.. The expression of Twist1 and EZH2 was significantly higher in colon adenoma and carcinoma than that in normal colonic mucosa (P < 0.05). Twist1 and EZH2 expressions were associated with decreased tumor differentiation, advanced stage, and lymph node metastasis. Twist1 and EZH2 expressions were significantly related to 3-year disease-free survival (P = 0.005 and 0.002 respectively) and 3-year overall survival (P = 0.045 and 0.039, respectively).. Twist1 and EZH2 may serve as prognostic predictors for colon carcinoma and may have a potential role as therapeutic targets in patients with colon carcinoma in the future.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma; Colonic Neoplasms; Disease-Free Survival; Egypt; Enhancer of Zeste Homolog 2 Protein; Epithelial-Mesenchymal Transition; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nuclear Proteins; Organoplatinum Compounds; Prognosis; Prospective Studies; Risk Assessment; Twist-Related Protein 1; Young Adult

To identify distinct trajectories of toxicity in colorectal cancer (CRC) patients after adjuvant chemotherapy and its impact on quality of life (QoL) and psychological symptoms.. A prospective, multicenter study was conducted in 157 patients. A latent class analysis defined the unobserved latent constructs that can be predicted as symptom clusters, considering the intensity of four types of adverse events (AEs). Patients completed EORTC-QLQ-C30, BSI-18, PDRQ-9, and DRS scales.. Ninety-six percent had some degree of toxicity, with grades 3-4 being the most common: neurotoxicity (7.2%), hematological (13.1%), digestive (5.2%), and skin toxicity (1.4%). Three distinct latent classes were identified (high [72.5%], mild [16.9%], and low [10.6%] toxicity). Patients with high toxicity had the worst QoL scores and moderately high somatization and psychological distress scores.. Adjuvant chemotherapy for CRC was associated with frequent toxicity that negatively impacted QoL and psychological wellbeing.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Decision Making; Emotions; Female; Fluorouracil; Humans; Latent Class Analysis; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Physician-Patient Relations; Prospective Studies; Pyridines; Quality of Life; Spain

Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing.. The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin).. Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk.. Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Databases, Factual; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Logistic Models; Male; Middle Aged; Nausea; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Sex Factors; Stomatitis; Thrombocytopenia; Vomiting

Topics: Antineoplastic Combined Chemotherapy Protocols; Ataxia Telangiectasia Mutated Proteins; Camptothecin; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoadjuvant Therapy; Organoplatinum Compounds; Panitumumab; Treatment Outcome

The IDEA collaboration showed that the type and duration of adjuvant chemotherapy in stage III colon cancer (CC) could be adjusted according to the schedule of chemotherapy and the level of risk. We aimed at evaluating the implementation of IDEA's results in real-life practice for stage III CC.. All clinicians registered in the French oncology cooperative groups GERCOR, FFCD, and UNICANCER GI mailing lists were invited to participate to an online anonymized nationwide survey from January 30, 2019 to March 31, 2019. Proportions were compared using the χ. A total of 213 physicians answered the survey. Of these, 173 (81%) considered that 3 months of adjuvant chemotherapy was the new standard of care for low-risk (pT1-3/N1) stage III CC, and 99% considered that 6 months remained the standard of care for high-risk (pT4 and/or pN2) stage III CC. In patients under 70 years, capecitabine and oxaliplatin (CAPOX) for 3 months was prescribed by 74% of the participants in low-risk CC, whereas 6 months of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was preferred for high-risk CC in 94% of cases. For patients over 70 years with good performance status and no comorbidities, 172 (81%) physicians prescribed oxaliplatin-based chemotherapy for low-risk CC (3 months, 144 of 172%; 88%), and 200 (94%) physicians prescribed oxaliplatin-based adjuvant chemotherapy for high-risk CC (6 months, 199 of 200%; 99.5%).. The IDEA results have been practice-changing as French physicians have implemented 3 months of CAPOX for patients with low-risk stage III CC, substituting from 6 months of FOLFOX, which remains the preferred regimen for high-risk patients.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; France; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Practice Patterns, Physicians'; Risk Assessment; Surveys and Questionnaires; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease Progression; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Precision Medicine; Receptor, ErbB-2; Receptor, ErbB-4; RNA-Seq; Treatment Outcome; Vascular Endothelial Growth Factor A

Home-based chemotherapy (HC) is a new treatment alternative to hospital-based chemotherapy treatment (IP) and is administered via portable intravenous pumps at the patient's home. HC reduces the demand for inpatient bed capacity in hospitals and reduces the cost of an infusion. This study takes a societal perspective while conducting the cost-utility and budget impact analyses (BIA) of HC and IP with an mFOLFOX6 regimen on patients with stage III colon cancer. We conducted a cost-utility analysis with a 6-month time horizon. The parameter inputs for the model were gathered from a retrospective cohort study on patients diagnosed with stage III colon cancer at Ramathibodi Hospital, Bangkok. The resource usage of HC and IP was determined based on medical records. The per-unit direct medical, home health service, and adverse events (AE) management costs were gathered from the standard cost list. The health outcome of treatment was measured in terms of quality-adjusted life years. Disutility related to AE was calculated. We conducted a sensitivity analysis for the uncertainty results and performed BIA based on the societal perspective on a 1-year time horizon. HC provided a cost-saving of $1,513.37 per patient for the period of treatment. Thus, assuming 526 patients per year, the use of HC could achieve a cumulative annual cost-saving of $828,436. HC is a cost-saving strategy compared to IP for stage III colon cancer treatment. We recommend that the service reimbursement should include national standardization in chemotherapy regimens as well as practice guidelines and protocols to prevent serious AEs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Follow-Up Studies; Home Care Services; Humans; Leucovorin; Male; Middle Aged; Oxaliplatin; Prognosis; Retrospective Studies; Self-Management

Cancer initiating cells (CICs) drive tumor formation and drug-resistance, but how they develop drug-resistance characteristics is not well understood. In this study, we demonstrate that chemotherapeutic agent FOLFOX, commonly used for drug-resistant/metastatic colorectal cancer (CRC) treatment, induces overexpression of CD44v6, MDR1, and oncogenic transcription/translation factor Y-box-binding protein-1 (YB-1). Our study revealed that CD44v6, a receptor for hyaluronan, increased the YB-1 expression through PGE2/EP1-mTOR pathway. Deleting CD44v6, and YB-1 by the CRISPR/Cas9 system attenuates the in vitro and in vivo tumor growth of CICs from FOLFOX resistant cells. The results of DNA:CD44v6 immunoprecipitated complexes by ChIP (chromatin-immunoprecipitation) assay showed that CD44v6 maintained the stemness traits by promoting several antiapoptotic and stemness genes, including

Topics: Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B; Biomarkers; Cell Differentiation; Cell Self Renewal; Colonic Neoplasms; CRISPR-Cas Systems; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Profiling; Gene Knockout Techniques; Humans; Hyaluronan Receptors; Immunophenotyping; Leucovorin; Neoplastic Stem Cells; Organoplatinum Compounds; Signal Transduction; Y-Box-Binding Protein 1

We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial.. Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated.. A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%).. Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neurotoxicity Syndromes; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Sensory Receptor Cells; Survival Rate; Time Factors; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Neural Networks, Computer; Oxaliplatin; Retrospective Studies

Previous studies on oxaliplatin and fluoropyrimidines as adjuvant therapy in older patients with stage III colon cancer (CC) produced conflicting results.. We assessed the impact of age on time to tumour recurrence (TTR), disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) in 2360 patients with stage III CC (1667 aged <70 years and 693 ≥ 70 years) randomised to receive 3 or 6 months of FOLFOX or CAPOX within the frame of the phase III, TOSCA study.. Older patients compared with younger ones presented more frequently an Eastern Cooperative Oncology Group performance status equal to 1 (10.5% vs 3.3%, p < 0.001), a greater number of right-sided tumours (40.9% vs 26.6%, p < 0.001), and were at higher clinical risk (37.2% vs 33.2%, p = 0.062). The treatments were almost identical in the two cohorts (p = 0.965). We found a greater proportion of dose reductions (46.7% vs 41.4%, p = 0.018), treatment interruptions (26.1% vs 19.3%, p < 0.001) and a higher proportion of recurrences (24.2% vs 20.3%, p = 0.033) in the older patients. The multivariable analysis of the TTR did not indicate a statistically significant effect of age (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 0.98-1.44; p = 0.082). The HR comparing older with younger patients was 1.34 (95% CI: 1.12-1.59; p = 0.001) for DFS, 1.58 (95% CI: 1.26-1.99; p < 0.001) for OS, and 1.28 (95% CI: 0.96-1.70; p = 0.089) for CSS.. Worse prognostic factors and reduced treatment compliance have a negative impact on the efficacy of oxaliplatin-based adjuvant therapy in older patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Oxaliplatin; Prognosis; Survival Rate

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. Patients were classified into low risk and high risk, suggesting low-risk patients may be offered only 3 months of treatment. In this study, we aimed to assess the benefit of oxaliplatin in the adjuvant setting per IDEA risk groups, using data from 3 large adjuvant phase III studies, namely Multicenter International Study of Oxaliplatin/Fluorouracil/ Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC), C-07, and XELOXA.. Using the MOSAIC, C-07, and XELOXA previously published studies, we identified 2810 low-risk and 2124 high-risk patients with stage III colon cancer. We used Cox regression model to evaluate the magnitude of survival differences between IDEA risk groups, according to oxaliplatin use. Based on design similarity and equivalent follow-up data, MOSAIC and C-07 were pooled, whereas XELOXA was analyzed separately. Subgroup analyses were also performed for T4 and/or N2 patients.. Individuals with IDEA low and high risk derived overall survival benefit from the addition of oxaliplatin to adjuvant chemotherapy, with adjusted hazard ratios of 0.79 (0.66-0.95) and 0.84 (0.71-0.99), respectively. Among individuals with IDEA high risk, those with T4 disease did not gain overall survival benefit from addition of oxaliplatin with hazard ratio of 0.95 (0.71-1.27). Similar results were demonstrated using data from the XELOXA study.. IDEA risk classification per se does not predict benefit from addition of oxaliplatin to adjuvant chemotherapy in stage III colon cancer. T4 disease may predict lack of benefit from oxaliplatin addition.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Time Factors

to describe, using data from a cancer registry in a well-defined French population, the therapeutic strategies and survival of patients with metastatic colon cancer (mCC).. all patients with synchronous mCC diagnosed within the 2005-2014 period recorded in the digestive cancers registry of Burgundy were included.. 1286 mCC patients were included (57% male), of which 34.5% did not receive any antitumor treatment. Both, advanced age (≥75 years) and the Charlson comorbidity score ≥2 were significantly associated with the absence of antitumor treatment. Among the patients treated with chemotherapy, 59 and 33% received at least two and three lines, respectively. Most patients treated with chemotherapy (68%) did not receive first-line targeted therapy. Of patients aged ≥75 years, 57% received no chemotherapy and 56% of treated patients had first-line treatment only.. this population-based study shows that more than one-third of patients with mCC receive no chemotherapy and that only 59% of treated patients receive treatment beyond the first line. This study also highlights the fact that more than half of patients ≥75 years do not get any antitumor treatment. In patients <75 years, the proportion of patients receiving chemotherapy and/or undergoing curative intent surgery tended to increase over time.

Topics: Adenocarcinoma; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Palliative Care; Registries; Retrospective Studies

Topics: Colonic Neoplasms; Humans; Leucovorin; Neoadjuvant Therapy; Prospective Studies; Surgical Stomas

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

Traditionally, adjuvant treatment for colon cancer has been 6 months of combination chemotherapy. Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients. The results were pooled in the International Duration Evaluation of Adjuvant therapy (IDEA) collaboration. Although this did not meet the noninferiority endpoint, a preplanned subgroup analysis by chemotherapy regimen did demonstrate noninferiority for capecitabine and oxaliplatin. Additionally, risk stratification by T and N stage was defined.. In an effort to understand the real-life impact of these results, 4 months after the IDEA results, an online survey was distributed to clinicians to ask their approach to the adjuvant treatment of patients with stage III colon cancer.. The survey was completed by 458 clinicians from 12 countries. Assuming that 6 months of treatment was the pretrial standard of care, 89.5% of clinicians reported they had changed practice to prescribe 3 months of treatment for some patients. For patients with low-risk stage III disease, there was a preference for 3 months, and for patients with high-risk stage III disease, most clinicians still prescribed 6 months at that time. Overall, capecitabine and oxaliplatin regimen was the most popular. There were important differences in responses depending on the location of respondent and T and N stage of disease.. This survey shows that the IDEA collaboration has been practice changing but reveals important differences in the way results are interpreted by individual clinicians.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Drug Administration Schedule; Equivalence Trials as Topic; Female; Fluorouracil; Health Care Surveys; Humans; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Practice Patterns, Physicians'; Risk

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Netherlands; Organoplatinum Compounds; Randomized Controlled Trials as Topic

Although adjuvant chemotherapy can have an impact on physical activity (PA), PA level has not been studied in patients with stage II-III colon cancer. This study investigated PA levels during and between chemotherapy cycles.. We objectively measured PA levels for 2 weeks during the 2nd and 11th chemotherapy cycles. In addition, self-reported PA levels were assessed before chemotherapy initiation, during 2nd, 6th, and 12th chemotherapy cycles. This study included 22 men and 33 women with stage II-III colon cancer patients (57 ± 9 years).. Before the initiation of chemotherapy, most cancer patients were minimally active. Compared with the 1st week of chemotherapy, moderate- and light-intensity PA levels significantly increased during the 2nd week of chemotherapy. Patients increased moderate- and light-intensity PA from 217.4 to 290.3 min per week and from 585.7 to 657.8 min per week, respectively (p < 0.01). PA levels did not show any difference between the 2nd and 12th cycles when objectively measured, or between baseline and 2nd, 6th, and 12th cycles when self-reported.. PA levels during chemotherapy cycles are initially low, and then increase towards the end of the cycle; however, PA levels do not change between chemotherapy cycles. Future work with broader and larger samples size is recommended.

Topics: Accelerometry; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Exercise; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Prospective Studies

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Decision-Making; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Oxaliplatin; Time Factors

This study aimed to evaluate the safety and feasibility of self-expanding metallic stent (SEMS) followed by neoadjuvant chemotherapy prior to elective surgery for obstructing left-sided colon cancer.. Eleven consecutive patients with obstructing left-sided colon cancer between May 2014 and November 2015 were included retrospectively. All patients received SEMS followed by neoadjuvant chemotherapy. The primary outcome measure was stoma and laparoscopic surgery.. Chemotherapy was with two cycles of CAPOX (54.5%) or three cycles mFOLFOX6 (45.5%). Median serum albumin and hemoglobin levels before surgery were significantly higher than before neoadjuvant chemotherapy (p = 0.01 and p = 0.008 respectively) and before SEMS (p = 0.01 and p = 0.003 respectively). Median bowel wall thickness proximal to the upper edge of tumor was significantly more before neoadjuvant chemotherapy than before stent (p = 0.003), and significantly less before surgery than before neoadjuvant chemotherapy (p = 0.003). No patient underwent stoma creation. Laparoscopic surgery was performed in nine (81.8%) patients. No local recurrence or metastases developed over median cancer-specific follow-up of 44 months (range, 37-55 months).. SEMS followed by neoadjuvant chemotherapy prior to elective surgery appears to be safe and well tolerated in patients with obstructing left-sided colon cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Drug Therapy; Feasibility Studies; Female; Fluorouracil; Humans; Intestinal Obstruction; Laparoscopy; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Self Expandable Metallic Stents; Serum Albumin, Human; Treatment Outcome

Topics: Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Oxaliplatin

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration aimed to evaluate whether 3 months of adjuvant chemotherapy are noninferior to 6 months. Our study objectives were to characterize medical oncologists' perspectives toward the results of the IDEA collaboration and to evaluate how IDEA impacted prescribing patterns of adjuvant FOLFOX and CAPOX in colon cancer.. A list of questions developed by four medical oncologists regarding IDEA results were formulated and distributed online to gastrointestinal medical oncologists globally. Descriptive statistics and chi-square tests were used to summarize information.. Of 174 responses, 145 were complete and analyzed. Responses were obtained globally from South America (53%); the U.S. and Canada (28%); Europe, Australia, and New Zealand (12%); and Asia (7%). Most clinicians (98%) were aware of the IDEA study. Prior to IDEA, clinicians preferred FOLFOX over CAPOX (81% vs. 19%). Subsequent to IDEA, 55% of clinicians preferred CAPOX over FOLFOX (odds ratio, 5.0; 95% confidence interval, 3.0-8.5; p < .01 compared with pre-IDEA). Two thirds (68%) of responders tailored duration of adjuvant therapy based on risk stratification. Most oncologists (76%) were more willing to discontinue oxaliplatin early if toxicities develop after the results of IDEA. Half of responders (50%) found that IDEA increased their confidence in decision making for adjuvant treatment; 36% were unchanged, and 15% indicated decreased confidence. Less than half (48%) were comfortable communicating the study results and the concept of a noninferiority trial with patients.. IDEA appears to have shifted clinician preference from FOLFOX to CAPOX for adjuvant therapy, and most clinicians now use a risk-stratified approach in determining duration of adjuvant therapy. Patient education resources may facilitate better communication of IDEA results to patients.. This global survey illustrates that most gastrointestinal medical oncologists now use a risk-stratified approach for determining the duration of adjuvant chemotherapy for stage III colon cancer. Clinicians are five times more likely to choose CAPOX over FOLFOX after the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration results.

Topics: Antineoplastic Combined Chemotherapy Protocols; Australia; Canada; Chemotherapy, Adjuvant; Colonic Neoplasms; Europe; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; New Zealand; Oncologists

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: Chemotherapy, Adjuvant; Colonic Neoplasms; Humans; Leucovorin; Oxaliplatin; Tegafur

Treatment selection markers are generally sought for when the benefit of an innovative treatment in comparison with a reference treatment is considered, and this benefit is suspected to vary according to the characteristics of the patients. Classically, such quantitative markers are detected through testing a marker-by-treatment interaction in a parametric regression model. Most alternative methods rely on modeling the risk of event occurrence in each treatment arm or the benefit of the innovative treatment over the marker values, but with assumptions that may be difficult to verify. Herein, a simple non-parametric approach is proposed to detect and assess the general capacity of a quantitative marker for treatment selection when no overall difference in efficacy could be demonstrated between two treatments in a clinical trial. This graphical method relies on the area between treatment-arm-specific receiver operating characteristic curves (ABC), which reflects the treatment selection capacity of the marker. A simulation study assessed the inference properties of the ABC estimator and compared them with other parametric and non-parametric indicators. The simulations showed that the estimate of the ABC had low bias, power comparable to parametric indicators, and that its confidence interval had a good coverage probability (better than the other non-parametric indicator in some cases). Thus, the ABC is a good alternative to parametric indicators. The ABC method was applied to data of the PETACC-8 trial that investigated FOLFOX4 versus FOLFOX4 + cetuximab in stage III colon adenocarcinoma. It enabled the detection of a treatment selection marker: the DDR2 gene.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bias; Biomarkers; Cetuximab; Colonic Neoplasms; Computer Simulation; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Research Design; ROC Curve

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

A 71-year-old woman with advanced ascending colon cancer was admitted to our hospital. Abdominal computed tomography( CT)revealed locally advanced sigmoid colon cancer with suspected invasion of the liver and duodenum. The clinical stage of the disease was cT4bN3M1a, cStage Ⅳa, with wild-type RAS and UGT1A1 expression. An ileostomy was performed because of bowel obstruction. The patient received 6 courses of FOLFOXIRI plus bevacizumab(Bev). The only adverse event was Grade 3 neutropenia. Laparoscopic right hemicolectomy with lymph node dissection was performed. The pathological diagnosis was the absence of viable, Grade 3 carcinoma cells. This result suggested that preoperative FOLFOXIRI plus Bev chemotherapy is useful for the treatment of locally advanced colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colon, Ascending; Colonic Neoplasms; Duodenum; Female; Fluorouracil; Humans; Leucovorin; Liver; 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

The synchronous diagnosis of two or more primary malignancies in a patient is overall rare. This is a case report of a 70-year-old female with a history of skin squamous cell carcinoma presenting with occult hematochezia. Colonoscopy and biopsy results confirmed a microsatellite stable (MMS) adenocarcinoma in the ascending colon, and subsequent computed tomography (CT) scans identified a 3.2 cm right colonic mass and a 5.0 cm mass in the pancreatic body. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) confirmed the presence of pancreatic ductal adenocarcinoma (PDAC). The patient underwent neo-adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin) chemotherapy prior to the simultaneous distal pancreatectomy and right hemicolectomy for both pancreatic and colonic tumors. The pathology diagnoses included moderately differentiated pancreatic ductal carcinoma (PDAC) with histiocyte-like features (tumor stage: ypT3N1M0) and moderately differentiated colonic adenocarcinoma, intestinal type (tumor stage: ypT3N0M0). To the best of our knowledge, this is the first documented case of synchronous primary colonic adenocarcinoma and PDAC in the English literature.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Carcinoma, Squamous Cell; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasms, Multiple Primary; Oxaliplatin; Pancreatic Neoplasms; Skin Neoplasms

Topics: Aged; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colon; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Metastasis; Organoplatinum Compounds

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Humans; Leucovorin; Oxaliplatin; Tegafur

A male patient in his 80s, diagnosed with rectal cancer, underwent transverse colon resection(pT3, pN0, cM0, and pStage Ⅱa, RAS wild-type, BRAF-mutant). However, 19 months later, intraperitoneal metastasis was detected and the patient received 8 courses of mFOLFOX6 plus bevacizumab. Following the observation of an allergic reaction that was attributable to oxaliplatin, the regimen was changed to a total of 7 courses of sLV5FU2 plus bevacizumab. Subsequently, a marked decrease was observed in intraperitoneal metastasis. The patient completed sLV5FU2 plus bevacizumab chemotherapy. At 1 year after the marked decrease, the metastatic recurrence was not exacerbated.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colon, Transverse; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Peritoneal Neoplasms

Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma. It is known that these drugs have been associated with cardio- and neurotoxicity. We investigated the effects of 5-FU ± oxaliplatin on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer.. Twenty-nine patients with prior colectomy for stage II-III adenocarcinoma and clinical indication for adjuvant chemotherapy were allocated to receive 5-FU (n = 12) or 5-FU + oxaliplatin (n = 17), according to the oncologist's decision. All the analyses were performed just before and after the end of chemotherapy. Cardiac function was assessed by echocardiography and speckle tracking, and cardiac autonomic control was assessed by heart rate variability (HRV). Vascular endothelial function was assessed by flow-mediated dilation (FMD). Muscle sympathetic nerve activity (MSNA) was directly recorded by microneurography technique, and muscle blood flow by venous occlusion plethysmography. Physical capacity was evaluated by cardiopulmonary exercise test.. Chemotherapy (pooled data) did not significantly change left ventricular ejection fraction (58 ± 1 vs. 55 ± 2%, p = .14), longitudinal strain (-18 ± 1 vs. -18 ± 1%, p = .66), and HRV. Likewise, chemotherapy did not significantly change FMD, muscle blood flow, and MSNA (33 ± 2 vs. 32 ± 1 bursts/min, p = .31). Physical capacity was not significantly changed in both groups. Similar findings were observed when the patients were subdivided in 5-FU and 5-FU + oxaliplatin treatment groups. 5-FU and 5-FU + oxaliplatin did not significantly change cardiac function, HRV, vascular responses, MSNA, and physical capacity.. This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity.. Adjuvant chemotherapy with 5-fluorouracil (5-FU) and oxaliplatin increases recurrence-free and overall survival in patients with colon adenocarcinoma; however, these drugs have been associated with cardio- and neurotoxicity. This study investigated the effects of these drugs on cardiac function, vascular responses, neurovascular control, and physical capacity in patients with colon cancer. It was found that 5-FU and oxaliplatin did not significantly change cardiac function, cardiac autonomic control, vascular endothelial function, muscle sympathetic nerve activity, and physical capacity. This study provides evidence that adjuvant treatment with 5-FU ± oxaliplatin is well tolerated and does not promote changes compatible with long-term cardiotoxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Stroke Volume; Ventricular Function, Left

An oxaliplatin-based chemotherapy regimen improves the survival outcomes of patients with stage III colon cancer. However, its complications are well-known.. The purpose of this study was to distinguish between the survival outcomes of patients who underwent curative resection for stage III colon cancer with oxaliplatin chemotherapy and those who underwent such resection without oxaliplatin chemotherapy.. This was a retrospective analytical study based on prospectively collected data.. This study used data on patients who underwent surgery at our hospital between January 2010 and December 2014.. A cohort of 254 consecutive patients who underwent curative resection for stage III colon cancer was included in this study. The patients were divided into 2 groups: patients with isolated pericolic lymph node metastasis (n = 175) and those with extrapericolic lymph node metastasis (n = 79).. Clinicopathologic features and 3-year survival outcomes were analyzed with and without oxaliplatin therapy in the pericolic lymph node group.. The pericolic lymph node group showed significantly improved overall survival compared with the extrapericolic lymph node group at a median follow-up of 48.5 months (95.8% vs 77.8%; p < 0.001). In contrast, there was no significant difference in overall survival (99.0% vs 92.0%; p = 0.137) and disease-free survival (89.1% vs 88.2%; p = 0.460) between the oxaliplatin and nonoxaliplatin subgroups of the pericolic lymph node group. Multivariate analysis showed that the administration of oxaliplatin chemotherapy to the pericolic lymph node group did not lead to a significant difference in the overall survival (p = 0.594).. The study was limited by its retrospective design and single institutional data analysis.. This study suggests that the anatomic extent of metastatic lymph nodes could affect patient prognosis, and the effect of oxaliplatin-based adjuvant chemotherapy may not be prominent in stage III colon cancer with isolated pericolic lymph node metastasis.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Prognosis; Retrospective Studies; Risk Factors; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colon, Ascending; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Mesocolon; Neoadjuvant Therapy; Organoplatinum Compounds; Robotic Surgical Procedures

A 66-year-old male diagnosed with transverse colon cancer was admitted to our hospital. Computed tomography, colonoscopy, and esophagogastroduodenoscopy revealed locally advanced cancer with invasion of the gastric antrum. We staged the disease as cT4a, cN2, cM0, Stage ⅢB, with wild-type RAS expression. We performed an ileostomy prior to administering chemotherapy. The patient received 4 courses of modified FOLFOXIRI plus bevacizumab and 2 courses of FOLFIRI. The size of the tumor noticeably decreased after chemotherapy. The patient experienced grade 3 neutropenia, anorexia, and oral mucositis during chemotherapy. We performed a right hemicolectomy(D3), partial gastrectomy and ileum resection after administering neoadjuvant chemotherapy. The pathological stage of the disease was ypT2, ypN0, ypM0, ypStageⅠ, and the effect of the chemotherapy was Grade 1b. After the resection, he received mFOLFOX6 and CapeOX for 3 months as adjuvant chemotherapy. He remained cancer-free for 1 year and 3 months after the surgery. This result suggests that preoperative modified FOLFOXIRI plus bevacizumab chemotherapy is a useful regimen for the treatment of locally advanced colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colon, Transverse; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Pyloric Antrum

Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Dihydropyrimidine Dehydrogenase Deficiency; Female; Fluorouracil; Glucuronosyltransferase; Humans; Irinotecan; Leucovorin; Middle Aged; Mutation; Tomography, X-Ray Computed

A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results.. In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025.. With median follow-up of 72·3 months (IQR 72·2-72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4-83·3) with 3 months of therapy and 82·8% (81·8-83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95-1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5-83·6) versus 81·2% (79·2-82·9; HR 0·96 [0·85-1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3-83·8) and 83·8% (82·6-85·0; HR 1·07 [0·97-1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02-1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded.. Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration.. US National Cancer Institute.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Multicenter Studies as Topic; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Humans; Leucovorin; Liver Failure, Acute; Male; Tegafur

Polymorphic variants in IL-17A gene were differentially associated with colorectal cancer (CRC) susceptibility but their link with response and toxicity to CRC treatment have not yet been evaluated. We investigated association between seven IL-17A variants with the response and toxicity to CRC treatment in 294 patients with CRC. IL-17A genotyping was done by real-time PCR. MAF of rs3748067 was significantly higher in CRC cases resistant to FOLFOX treatment (R+) than non resistant (R-). Significantly higher rs3804513 MAF was noted in R+ versus R- colon cancer (CC). Higher rs2275913 and rs10484879, and reduced rs3804513 MAF were seen in rectal cancer (RC) tolerant to FOLFOX (T+) compared to (T-) patients. Strong association of rs3819025, rs3804513, and rs7747909 was found with tolerance to RC treatment. rs3748067 was associated with FOLFOX tolerance in CC but not RC. Significant higher frequency of AGGCAGG and GAGCAGG haplotypes was seen among R + CC, thus assigning non-favorable nature to these haplotypes. Higher and lower frequencies of GAGTAAG and AGGCTGA haplotypes, respectively, were observed in T + RC, thereby assigning FOLFOX-tolerant and non-tolerant nature to these haplotypes. The obtained results suggest that IL-17A variants and haplotypes may be a target for future management of CRC treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Cross-Sectional Studies; Drug Resistance, Neoplasm; Female; Fluorouracil; Genotyping Techniques; Humans; Interleukin-17; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Rectal Neoplasms; Retrospective Studies; Treatment Outcome

Local tumor immune response and host immunity have been suggested as important prognosticators respectively in colorectal cancer. However, the utility of combination of these parameters remains inconclusive. The aim of this study was to investigate the combinational impact of local and host tumor immune response, as determined by tumor-infiltrating lymphocytes (TILs) and neutrophil-to-lymphocyte ratio (NLR), in patients with stage III colon cancer. Patients with stage III colon cancer homogeneously treated with surgery followed by FOLFOX chemotherapy between Jan 2007 and Aug 2013 were included retrospectively. Hematoxylin and eosin (H&E) stained tumor sections of local inflammatory infiltrate (TILs) were classified as 0-3 by the Klintrup-Mäkinen grading method. NLR was measured within 1 month of surgery. The association of NLR and TILs with survival, alone or combined, were measured using multivariate Cox proportional hazard regression analysis. Among 137 patients, 75 (54.7%) were identified as the high TIL group (TILs 2 and 3) and 97 (70.8%) as the low NLR group (NLR < 3). Of the patients with high TILs, 51 (68%) had a low NLR. In univariate analysis, operation time, complications, lymph node ratio (LNR), stage, TILs, and high TILs with low NLR were significantly associated with overall survival(OS). Multivariate Cox regression identified operation time, stage, and TILs as independent risk factors for OS. When high TILs with low NLR vs. others was entered into multivariate analysis, this also proved to be a significant predictor of OS (HR 4.1, 95% CI 1.1-14.2, P = 0.025), with an increased C-index and lower AIC value compared to TILs. Measuring TILs using H&E stained sections could stratify the prognosis of stage III colon cancer. Considering host immunity, using the combination of TILs and NLR, allowed the prognosis to be stratified in more detail.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Inflammation; Leucovorin; Lymphocytes; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Neutrophils; Organoplatinum Compounds; Prognosis

Aflibercept plus 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a second-line treatment for metastatic colorectal cancer. This ancillary exploratory analysis of data in Japanese people was aimed at exploring the relationship between a set of potential prognostic biomarkers and efficacy endpoints following aflibercept plus FOLFIRI therapy. Sixty-two patients with metastatic colorectal cancer received aflibercept (4 mg/kg) plus FOLFIRI every 2 weeks. Seventy-eight potential protein biomarkers were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and at pre-dose 3 (day 1 of treatment cycle 3) were measured in all patients by ELISA. Relationships between these levels and efficacy endpoints were assessed. Ten potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001), with the greatest changes occurring in placental growth factor (median: +4716%) and vascular endothelial growth factor receptor 1 (+2171%). Baseline levels of eight potential biomarkers correlated with overall survival in a univariate Cox regression analysis: extracellular newly identified receptor for advanced glycation end-products binding protein, insulin-like growth factor-binding protein 1, interleukin-8, kallikrein 5, pulmonary surfactant-associated protein D, tissue inhibitor of metalloproteinases 1, tenascin-C, and tumor necrosis factor receptor 2. None correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Preliminary data show that these eight biomarkers could be associated with overall survival. ClinicalTrials.gov identifier: NCT01882868.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asian People; Biomarkers, Tumor; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Insulin-Like Growth Factor Binding Protein 1; Interleukin-8; Japan; Kallikreins; Leucovorin; Placenta Growth Factor; Prognosis; Progression-Free Survival; Prospective Studies; Pulmonary Surfactant-Associated Protein D; Receptor for Advanced Glycation End Products; Receptors, Tumor Necrosis Factor, Type II; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Rectal Neoplasms; Regression Analysis; Tenascin; Tissue Inhibitor of Metalloproteinase-1; Vascular Endothelial Growth Factor Receptor-1

Oxaliplatin is a key part of the standard treatment for colorectal cancer which is formally contraindicated in patients with severe renal dysfunction. Here, we investigated a safe and efficient dosing schedule of oxaliplatin in folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen by monitoring total and free platinum concentrations in plasma.. A 47-year-old female with chronic hemodialysis was diagnosed with left-sided colon cancer and underwent colectomy. One year later, she was presented with omentum metastasis and needed further treatment.. The computed tomography (CT) scanning revealed multiple omental nodules. Positron emission tomography-CT (PET-CT) showed increased uptake of the nodules.. The patient was treated with FOLFOX therapy every 3 weeks. The oxaliplatin began with 50 mg/m and gradually increased 85 mg/m as in the standard regimen. A 4-hour dialysis was started 1 hour after the end of oxaliplatin infusion.. The free platinum concentration time curve showed a biomodel pattern. The Cmax of the 1st peak we observed in our patients at the standard dose is comparable to patients with normal renal function. This patient was treated with FOLFOX for 12 courses. No apparent adverse effect was observed during the treatment.. The FOLFOX can be safely administered in hemodialysis patients on a long-term basis. Dose reduction of oxaliplatin is not necessarily needed if hemodialysis is performed soon after the infusion. Further studies are needed to distinguish between active and inactive oxaliplatin products during the 2nd peak of the free platinum concentration curve in this population.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Glomerulonephritis; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Renal Dialysis

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

Topics: Adenocarcinoma, Mucinous; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Male; Mesenteric Veins; Mesentery; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Thrombectomy; Treatment Outcome; Venous Thrombosis

Topics: Antineoplastic Combined Chemotherapy Protocols; Biopsy; Camptothecin; Colonic Neoplasms; Drug Eruptions; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Middle Aged; Panitumumab; Prednisolone; Purpura; Skin; Staphylococcal Skin Infections; Staphylococcus aureus; Vasculitis, Leukocytoclastic, Cutaneous

After curative resection of stage II colon cancer, adjuvant chemotherapy with 5-fluorouracil/leucovorin (FL) or capecitabine is selectively recommended. However, there is little evidence of the effect of capecitabine on oncologic outcome in geriatric patients with stage II colon cancer compared to that of FL. The aim of this study was to determine the difference in recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in patients older than 70 years of age with stage II colon cancer receiving capecitabine and FL.. Patients over 70 years of age diagnosed with primary pathologic stage II colon cancer at the Seoul National University Hospital from January 2005 to December 2015 were included. A prospectively collected database was analyzed retrospectively. Patients were separated into an FL group and a capecitabine group. The primary outcomes were RFS, CSS, and OS.. Of the 154 included patients, 96 patients received FL and 58 patients received capecitabine. There was no difference between the two groups in RFS, CSS, or OS (p = 0.763, p = 0.221, and p = 0.470, respectively) as measured by Kaplan-Meier analysis with log-rank test. Administration of capecitabine as compared to FL was not a factor affecting RFS (hazard ratio [HR] 0.503, 95% confidence interval [CI] 0.145-1.745), CSS (HR 1.519, 95% CI 0.348-6.629), or OS (HR 0.941, 95% CI 0.290-3.053) on multivariable analysis.. Capecitabine is a safe regimen in terms of oncologic outcomes compared with FL in older patients with stage II colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Multivariate Analysis; Neoplasm Recurrence, Local; Neoplasm Staging; Retrospective Studies; Risk Factors; Treatment Outcome

Shortly after the year 2000, randomized trials demonstrated that patients with metastatic colon cancer treated with infusional 5-fluorouracil (5-FU)/leucovorin with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) had a comparable progression-free survival benefit, superior to patients who received 5-FU/leucovorin alone. Factors associated with the initial receipt of the FOLFOX or FOLFIRI regimen are unknown. Our goal was to investigate the patterns and predictors of use for first-line FOLFOX and FOLFIRI.. We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked data set to identify patients with newly diagnosed stage IV colon cancer between the years 2005 and 2013 who received either first-line FOLFOX or FOLFIRI. We used logistic regression to assess demographic and clinical predictors for FOLFOX versus FOLFIRI. Survival was compared by Kaplan-Meier models.. Overall, 3000 patients (79.3%) received FOLFOX and 785 (20.7%) FOLFIRI. FOLFOX was associated with later year of diagnosis (odds ratio [OR] = 0.66, 95% confidence interval [CI], 0.54 to 0.82 for 2011-2013 vs. 2005-2007), being female (OR = 0.82; 95% CI 0.69 to 0.98), and living in the southern region of the United States. FOLFIRI was associated with having a higher comorbidity index (OR = 1.33; 95% CI, 1.07 to 1.67 for >1 comorbidity score vs. 0). There was no survival difference observed between the two treatments.. The majority of SEER-Medicare patients received FOLFOX and not FOLFIRI as a first-line treatment for stage IV colon cancer. Several demographic and clinical factors were associated with the use of each specific regimen. No survival difference was detected for the 2 groups.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Utilization; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Medicare; Neoplasm Staging; Organoplatinum Compounds; Progression-Free Survival; SEER Program; United States

Adjuvant therapy improves the prognosis of stage II & III colon cancer patients. Unfortunately, most patients do not benefit from this treatment. PePITA (NCT00994864) is a prospective, multicenter, non-randomized study whose primary objective is to predict the outcome of adjuvant therapy in colon cancer.. The primary objective was to determine the prognostic and predictive value of circulating tumor cell (CTC) detection before therapy and after one course of preoperative FOLFOX.. Out of the 58 first patients accrued in PePiTA trial, 36 patients participated in the CTC companion study, of whom 32 had at least one evaluable sample. Only 5 patients (14, 95% CI = 5-30%) had ≥1 CTC/22.5 ml blood in at least one of the two timepoints with 2 patients having ≥1 CTC/22.5 ml at baseline (6, 95% CI: 1-19%). The detection rate of patients with CTCs at baseline being lower than expected, the inclusion of patients in the PePiTA CTC substudy was stopped. The limited sample size did not allow us to investigate the prognostic and predictive value of CTCs in locally advanced colon cancer.. Our data illustrate the need for further standardized studies in order to find the most reliable prognostic/predictive biomarker in early-stage colon cancer.. This trial was prospectively registered at Jules Bordet institute ( NCT00994864 ) on the October 14, 2009.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Predictive Value of Tests; Prognosis; Prospective Studies; Sample Size; 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

This study explores the effect of preoperative radiotherapy combined with FOLFOX chemotherapy on patients with locally advanced colon cancer (LACC). Data of 102 patients with LACC were retrospectively analyzed. All received surgical resection plus postoperative FOLFOX chemotherapy; whereas 58 patients underwent preoperative radiotherapy combined with FOLFOX chemotherapy (CRT group, combined with radiotherapy treatment group), 44 patients did not undergo radiotherapy (non-CRT group). Short- and long-term effects as well as operative complications were compared. The optical density values of the caudal-related homeobox transcription factor 2 and inhibitor of growth 4 in lesions, and malignant molecules including vascular endothelial growth factor and cathepsin-D in serum were compared. The CRT group showed higher total pathological complete tumor response rate and resection rate, and lower incidence of incisional infection than the non-CRT group (all

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Cetuximab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Oxaliplatin

This study aimed to evaluate the efficacy and safety profile of capecitabine and oxaliplatin (CAPOX) and 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimens as adjuvant treatment in patients with stage III colon cancer.. A total of 243 patients who received CAPOX and FOLFOX chemotherapy between 2014 and 2018 for stage III colon cancer in two centers were retrospectively studied. Among the patients, 106 (43.6%) and 137 (56.4%) were treated using CAPOX and FOLFOX regimens, respectively. Efficacy, treatment-related side effects, and overall survival rates with these two regimens were compared.. The rate of disease progression was significantly higher in the presence of moderately/poorly differentiated histology, and KRAS and NRAS mutations. An increased number of metastatic lymph nodes and prolonged time from surgery to chemotherapy significantly increased disease progression. Patients who received CAPOX were significantly older than those who received FOLFOX. Disease progression, metastasis, and mortality rates were significantly higher in the FOLFOX arm than in the CAPOX arm. There was no significant difference in the overall survival rate between the two regimens.. The CAPOX regimen is preferred in older patients. Disease progression, metastasis, and mortality rates are higher with FOLFOX than with CAPOX.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

Panitumumab is an EGFR inhibitor used for the treatment of metastatic colorectal cancer (mCRC), even if its use is related to skin toxicity.. We report the development of forearm panniculitis in two women during the treatment with Panitumumab (6 mg/Kg intravenous every 2 weeks) + FOLFOX-6 (leucovorin, 5- fluorouracil, and oxaliplatin at higher dosage) for the treatment of mCRC.. In both patients, clinical, laboratory and radiological evaluation documented the presence of a local panniculitis, probably related to panitumumab (Naranjo score: 6). Panatimumab discontinuation and antimicrobial + corticosteroid treatment induced a remission of skin manifestations.. We reported for the first time the development of panniculitis during Panitumumab treatment, and we documented that the treatment with beta-lactams to either fluoroquinolones or oxazolidinone in the presence of corticosteroid improves clinical symptoms in young patients with mCRC, without the development of adverse drug reactions or drug-drug interactions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colon, Descending; Colonic Neoplasms; Female; Fluorouracil; Forearm; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Panitumumab; Panniculitis

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

We present the case of a 59 year old patient with a rare mutation in BRAF codon 594, who progressed rapidly on all classical therapies but experienced a clear and long lasting response on treatment with Regorafenib.. Little is known about therapies that can be effective in the rare

Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoembryonic Antigen; Cetuximab; Colonic Neoplasms; Exons; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Mutation; Organoplatinum Compounds; Phenylurea Compounds; Proto-Oncogene Proteins B-raf; Pyridines; Tomography, X-Ray Computed; Treatment Outcome

Colon cancer remains a major cause of mortality worldwide. Following adequate surgical resection of lymph node-positive colon cancer, the standard of care since 2004 has been to administer an oxaliplatin-containing regimen (eg, FOLFOX or CAPOX) for 6 months. These regimens have consistently improved oncologic outcomes compared with non-oxaliplatin therapies in multiple adjuvant randomized controlled trials. However, oxaliplatin-induced cumulative dose-dependent neurotoxicity is a major cause of morbidity that can persist years after treatment. The IDEA collaboration is a study that pooled data from 6 concurrent phase 3 trials comparing 3 vs 6 months of adjuvant FOLFOX or CAPOX to evaluate whether a shorter duration of therapy could maintain efficacy while reducing neurotoxicity. In this article, we review the history of adjuvant therapy in stage III colon cancer and comprehensively detail the results of the IDEA collaboration. A risk-based approach focusing on efficacy, toxicity, and patient selection is emphasized to guide discussions regarding the optimal duration of adjuvant therapy in stage III colon cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Fluorouracil; Guideline Adherence; Humans; Leucovorin; Levamisole; Meta-Analysis as Topic; Multicenter Studies as Topic; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Practice Guidelines as Topic; Prognosis; Prospective Studies; Risk; Treatment Outcome

The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) aimed to investigate whether a 3 months (3M) of oxaliplatin/fluoropyrimidine-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) administration in 3-year disease-free survival (3yDFS) in high-risk (HR) stage II or stage III colon cancer (CC).. Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX.. In total 1115 patients, 413 with HR stage II and 702 with stage III CC, were randomized. The median follow-up was 67.0 (38.3-126.0) months. Overall, 394 DFS events (202 in 3M arm and 192 in 6M arm) where recorded. The 3yDFS rate was 77.2% [95% confidence interval (CI) 72.1% to 82.3%] for 3M and 77.9% (72.6% to 82.5%) for 6M of treatment [hazard ratio (HR) 1.05 (95% CI 0.61-1.55); P = 0.647]. Eighty DFS events (3M N = 41; 6M N = 39) were observed in HR stage II patients for a 3yDFS rate of 82.7% and 83.4%, respectively (HR 1.05; 95% CI 0.68-1.63, P = 0.829). For stage III patients, 314 DFS events (3M N = 161 and 6M N = 153) were observed, for a 3yDFS rate of 72.9% for 3M versus 74.1% for 6M (HR 1.06; 95% CI 0.81-1.42, P = 0.622). For HR stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% for 3M and 79.3% for 6M (HR 1.21; 95% CI 0.54-2.70). For HR stage II patients receiving CAPOX the 3yDFS rate was 85.4% for 3M and 83.8% for 6M (HR 0.99; 95% CI 0.59-1.67). For stage III patients receiving FOLFOX4, the 3yDFS rate was 71.5% for 3M and 77.3% for 6M (HR 1.18; 95% CI 0.74-1.86). For stage III patients receiving CAPOX, the 3yDFS rate was 74.5% for 3M and 74.7% for 6M (HR 0.99; 95% CI 0.70-1.44).. The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that the 3yDFS is dependent on the administered adjuvant regimen and the choice and duration of regimen should be personalized.. NCT01308086.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Disease-Free Survival; Duration of Therapy; Female; Fluorouracil; Follow-Up Studies; Greece; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Patient Selection; Survival Rate; Time Factors; Young Adult

Intussusception is a common in pediatric age group. But it is rare in adults. And intussusception caused by tumor account for 1% of bowel obstructions in adult. Intussusception is an extremely rare cause of abdominal pain in pregnancy. In particular, cases of Intussusception due to colorectal cancer during pregnancy have never been reported in Korea. Our patient is a 34 years old woman who presented at 14 weeks of her second pregnancy. She presented with right lower abdominal discomfort and intermittent palpable mass which was usually spontaneously resolved. In the MRI study, pathologic asymmetric wall thickening was still noted and ileocolic intussusception was noted, and in colonoscopy, there was ulcerofungating mass around ileocecal valve which may be a leading point of intussusception. Biopsy was done. Pathologic finding was poorly differentiated adenocarcinoma. Under the patient agreement, we performed dilatation and curettage and laparoscopic right hemicolectomy and lymph node dissection. Now she is receiving a FOLFOX chemotherapy.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Humans; Intussusception; Laparoscopy; Leucovorin; Lymph Nodes; Magnetic Resonance Imaging; Organoplatinum Compounds; Pregnancy; Ultrasonography

Atypical features of Posterior reversible encephalopathy syndrome (PRES) (diffusion restriction, involvement of corpus callosum & white matter tracts along posterior limbs of internal capsule) were seen in a patient after oxaliplatin administration (FOLFOX- 4 regimen). Findings were most obvious on diffusion weighted images, similar to acute methotrexate neurotoxicity, and resolved completely on follow up.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Oxaliplatin; Posterior Leukoencephalopathy Syndrome; Prognosis

There were recurrences in 29 of the 166 patients (17.4%). Measuring the area under the receiver operating characteristic curve, the cut-off value of SUV. The results of this study suggest that high fluorodeoxyglucose uptake of the primary mass in high-risk stage II and stage III colon cancer does not significantly correlate with DFS.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Colectomy; Colonic Neoplasms; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Positron Emission Tomography Computed Tomography; Prognosis; Proportional Hazards Models; Republic of Korea; Retrospective Studies; Risk Assessment; ROC Curve; Sensitivity and Specificity; Survival Analysis; Treatment Outcome

Purpose First, to assess drug utilization rates of capecitabine plus oxaliplatin (CAPOX) versus 5-fluorouracil plus oxaliplatin (mFOLFOX6) regimens in the treatment of stage IIB and stage III colon cancer. Second, to assess patient characteristics used to select CAPOX versus FOLFOX therapy, dose-limiting toxicities, dose intensities and treatment completion rates. Methods Patients with resected stage IIB or stage III colon cancer from five British Columbia Cancer Agency centres treated with CAPOX or mFOLFOX6 were selected for the analysis. Protocol utilization rates, patient characteristics and toxicities of the two regimens were collected and compared by descriptive statistics. Results A total of 306 patients were included over study period. mFOLFOX6 is the most commonly used regimen with 69% utilization rate. CAPOX patients were younger (57 years old vs. 62 years old, p < 0.01), but no other significant differences were found. CAPOX was associated with more dose-limiting toxicities compared to mFOLFOX6 (95% vs. 82%, p < 0.01). Fewer patients completed the intended 24-week course of CAPOX compared to mFOLFOX6 (67% vs. 82%, p < 0.01). Conclusion FOLFOX is the most commonly utilized adjuvant treatment option for stage IIB and stage III colon cancer in British Columbia, and is associated with better tolerability and higher treatment completion rates.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drainage; Edema; Fluorouracil; Genital Diseases, Male; Humans; Leucovorin; Lower Extremity; Lymphatic Metastasis; Male; Mobility Limitation; Organoplatinum Compounds; Scrotum

FOLFOX chemotherapy is widely used as an adjuvant treatment for advanced colon cancer. The duration of adjuvant chemotherapy is usually set to 6 months, which is based on a former study of 5-fluorouracil/leucovorin chemotherapy. However, the FOLFOX regimen is known to have complications, such as peripheral neuropathy. The aim of this study was to compare the survival rates and complications experienced by patients receiving either 4 or 6 months of FOLFOX chemotherapy.. Retrospective data analysis was performed for stage II and III patients who underwent radical resection of colon cancer. We compared the 5-year survival rates and the occurrence of complications in patients who completed only 8 cycles of FOLFOX chemotherapy with patients who completed 12 cycles of chemotherapy.. Among 188 patients who underwent adjuvant FOLFOX chemotherapy for stage II or III colon cancer, 83 (44.1%) completed 6 months of FOLFOX chemotherapy and 64 (34.0%) patients discontinued after 4 months of chemotherapy. The 5-year overall survival and disease-free survival rates did not show a significant difference. Patients in the 6-month group had peripheral neuropathy more frequently (p = 0.028).. Five-year overall and disease-free survival were not significantly different between the 2 groups. Large-scale prospective studies are necessary for the analysis of complications and survival rates.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Neutropenia; Organoplatinum Compounds; Peripheral Nervous System Diseases; Retrospective Studies; Survival Rate

A 27-year-old woman with colon cancer and liver metastasis was referred to our hospital. Colectomy and colostomy were performed to improve her ileus. Following 13 sessions of oxaliplatin-based chemotherapy (OC) with mFOLFOX6 + bevacizumab, thrombocytopenia and frequent peristomal bleeding occurred. Computed tomography showed severe ascites, splenomegaly, significant collateral veins around the stoma, and severe stenosis of the hepatic veins (HV) and inferior vena cava (IVC). Ultrasound elastography showed high liver (and spleen) stiffness values. Repeated OC appeared to cause IVC stenosis as a result of worsening sinusoidal obstruction syndrome (SOS), and peristomal variceal bleeding. After ultrasound-guided percutaneous embolization, bleeding did not recur. Unfortunately, the patient died of liver dysfunction caused by severe SOS. The incidence of OC-induced SOS is reported to be about 50%; however, there is apparently no report of OC-induced HV and IVC stenosis, and in most cases, portal hypertension is improved after OC cessation. This is the first report of OC-induced severe HV and IVC stenosis resulting in refractory peristomal variceal bleeding and eventual death.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Constriction, Pathologic; Embolization, Therapeutic; Fatal Outcome; Female; Fluorouracil; Gastrointestinal Hemorrhage; Hepatic Veins; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Surgical Stomas; Thrombocytopenia; Varicose Veins; Vena Cava, Inferior

Capecitabine and oxaliplatin (CAPOX) and folinic acid, fluorouracil, and oxaliplatin (FOLFOX) are both used in the adjuvant treatment of colon cancer, and while their efficacy is assumed to be similar, they have not been directly compared. We reviewed the toxicity profiles, relative dose intensity (RDI), and survival associated with these regimens across a multi-institutional cohort.. We identified 394 consecutively treated patients with stage III colon cancer who received an oxaliplatin-containing regimen. RDI was defined as the total dose received divided by the intended total dose if all cycles were received.. FOLFOX was associated with increased mucositis (6.2% vs. 0.7%, P = .0069) and neutropenia (25.9% vs. 8.6%, P < .0001), while CAPOX was associated with increased dose-limiting toxicities (DLTs) (90.7% vs. 80.2%, P = .0055), diarrhea (31.8% vs. 9.0%, P < .0001), and hand-foot syndrome (19.9% vs. 2.1%, P < .0001). Higher median RDI of fluoropyrimidine (93.7% vs. 80.0%, P < .0001) and oxaliplatin (87.2% vs. 76.3%, P < .0001) was noted for patients receiving FOLFOX. Reducing the duration from 6 to 3 months would have prevented 28.7% of FOLFOX and 20.5% of CAPOX patients from ever experiencing a DLT (P = .0008). Overall survival did not differ by regimen (hazard ratio = 0.73; 95% confidence interval 0.45-1.22; P = .24). However, CAPOX was associated with improved disease-free survival (3-year disease-free survival 83.8% vs. 73.4%, P = .022), which remained significant in high-risk (T4 or N2) (P = .039) but not low-risk patients (P = .19).. CAPOX may be associated with improved disease-free survival despite greater toxicities and lower RDI. Reducing adjuvant chemotherapy duration to 3 months would prevent 26% of patients from ever experiencing a DLT.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies

Combination therapies with cetuximab (Erbitux. The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective.. We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum.. Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of £50,000 per quality-adjusted life-year gained, applicable to end-of-life treatments.. Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Colorectal Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Models, Economic; Organoplatinum Compounds; Panitumumab; Proto-Oncogene Proteins p21(ras); Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis

A 44-year-old woman with advanced metastatic colon cancer received chemotherapies comprising oxaliplatin and capecitabine (XELOX), irinotecan hydrochloride, leucovorin calcium and fluorouracil irinotecan (FOLFIRI)/panitumumab and mFOLFOX6/bevacizumab. Fifteen months later, she presented with the acute onset of a headache, drowsiness and seizure with a fever and hypertension. Brain magnetic resonance imaging (MRI) indicated bilateral regions of signal hyperintensity in the white matter with spasms of bilateral cerebral arteries apparent on magnetic resonance angiography. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and treatments resulted in improvement of the MRI findings, but the patient experienced cerebral infarction and ultimately died of deterioration of cancer on day 26 after the onset of PRES.

Topics: Adult; Antineoplastic Agents, Immunological; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Female; Humans; Irinotecan; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Posterior Leukoencephalopathy Syndrome; Treatment Outcome

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

Topics: Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin

Comorbidity has a detrimental effect on cancer survival, however, it is difficult to disentangle its direct effect from its influence on treatment choice. In this study we assessed the effect of comorbidity on survival in patients who received standard treatment for resected stage II and III colorectal cancer (CRC).. In total, 230 CRC patients, 68 rectal (29.6%) and 162 colon cancer (70.4%) treated with surgical resection and neoadjuvant/adjuvant chemotherapy from December 2002 to December 2009 at Humanitas Cancer Center were retrospectively reviewed. The key independent variable was the Charlson Comorbidity Index (CCI) score, measured as a continuous variable. The differences between groups for categorical data were tested using the χ. Median follow-up was 113 (range, 8.2-145.0) months. Median age was 63 (range, 37-78) years. In univariate analysis CCI score was significantly associated with poorer disease-free survival (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.52-1.80; P < .001), and overall survival (OS; HR, 1.55; 95% CI, 1.41-1.71; P < .001). Factors associated with poorer outcome also included (stage III vs. stage II, P < .029) and age (age >70 vs. ≤70 years, P < .001). After adjusting for these factors, a significant negative prognostic role of CCI score was still observed (adjusted HR for OS, 1.59; 95% CI, 1.43-1.76; P < .001).. Among CRC patients who underwent surgical resection and chemotherapy, a higher CCI score was associated with poorer outcome and might predict long-term survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemoradiotherapy; Chemotherapy, Adjuvant; Colon; Colonic Neoplasms; Comorbidity; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Progression-Free Survival; Rectal Neoplasms; Rectum; Retrospective Studies

The tumour-stroma ratio (TSR) has proven to be an independent prognostic factor in colon cancer.. Haematoxylin eosin tissue slides of patients from the AVANT trial were microscopically scored for TSR and categorised as stroma -low or stroma -high. Scores were correlated to the primary and secondary endpoint disease-free survival (DFS) and overall survival (OS).. Patients with stroma-high tumours (N = 339, 28%) had a significantly shorter DFS (p < 0.001) compared to stroma-low tumours (N = 824, 68%). In the bevacizumab-FOLFOX-4 arm, DFS was significantly shorter compared to FOLFOX-4 in stroma-low tumours, with a hazard ratio (HR) of 1.94 (95% CI 1.24-3.04; p = 0.004). In stroma-high tumours a trend for better DFS was seen in bevacizumab-FOLFOX-4 vs. FOLFOX-4 (HR 0.61 (95% CI 0.35-1.07; p = 0.08)). For bevacizumab-XELOX vs. FOLFOX-4, this was not seen (stroma-low HR 1.07 (95% CI 0.64-1.77; p = 0.80); stroma-high HR 0.78 (95% CI 0.47-1.30; p = 0.35)). OS showed the same pattern for bevacizumab-FOLFOX-4 vs. FOLFOX-4 with a HR of 2.53 (95% CI 1.36-4.71; p = 0.003) for stroma-low and HR 0.50 (95% CI 0.22-1.14; p = 0.10) for stroma-high tumours. For bevacizumab-XELOX vs. FOLFOX-4, HR 1.13 (95% CI 0.55-2.31; p = 0.74) for stroma-low tumours and HR 0.74 (95% CI 0.37-1.51; p = 0.41) for stroma-high tumours.. This exploratory analysis suggests a significantly shorter DFS and OS in stroma-low tumours with addition of bevacizumab to intravenous oxaliplatin-based chemotherapy, contrary to stroma-high tumours, where a beneficial trend is observed.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Prognosis; Stromal Cells

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Equivalence Trials as Topic; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Rectal Neoplasms; Treatment Outcome

The current study originates from the assumption that, in tumors, levels of naturally occurring pyridoxal 5'-phosphate (PLP) are too small to allow conversion of tetra hydro pteroylglutamate (H

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Colonic Neoplasms; Drug Synergism; Fluorouracil; Folic Acid; HCT116 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; Intracellular Space; Leucovorin; Mice; Pyridoxal Phosphate

Colon cancer is common in the elderly, but owing to under representation in clinical trials, the benefit of standard therapies is uncertain in this age group. We aimed to clarify the efficacy and complications of adjuvant oxaliplatin and fluoropyrimidine chemotherapy for patients 70 years and older with stage III colon cancer.. All patients with stage III colon adenocarcinoma were identified from an Australian cancer registry (2006-2013). Multivariable Cox hazard regression was used to determine prognostic factors for all-cause mortality. Chemotherapy complications were quantified using discontinuation rates, hospital admissions, and mortality for 12 months after starting chemotherapy.. A total of 2164 patients fulfilled our inclusion criteria, including 1080 (49.9%) patients ≥ 70 years. Patients ≥ 70 years were less likely to receive adjuvant chemotherapy (60.7% vs. 89.6%) or oxaliplatin doublet chemotherapy (18.8% vs. 71.2%). Older patients receiving oxaliplatin were more likely to cease treatment early (18.7% vs. 7.6%) and require hospital admission (67.0% vs. 53.5%). The addition of oxaliplatin provided an overall survival benefit for patients < 70 years (hazard ratio, 0.44; 95% confidence interval, 0.3-0.6; P < .0001) and for patients ≥ 70 years (hazard ratio, 0.64; 95% confidence interval, 0.5-0.9; P = .005).. Despite a modestly increased rate of hospital admission and early chemotherapy cessation, we demonstrate a persistent survival benefit for the addition of oxaliplatin to a fluoropyrimidine as adjuvant treatment for stage III colon cancer in elderly patients.

Topics: Adenocarcinoma; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Australia; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colon; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Registries; Treatment Outcome

Oxaliplatin, a chemotherapeutic agent for colorectal cancer, has been associated with pathological evidence of sinusoidal endothelial injury in the liver. However, esophagogastric varices are a poorly recognized outcome of oxaliplatin-based chemotherapy. We report a 78-year-old man, whose past history of colon cancer was resection and treatment with mFOLFOX6 for 20 weeks, as adjuvant chemotherapy. After 3.5-year follow-up of the oxaliplatin-based chemotherapy, he was diagnosed with esophageal varices without liver dysfunction, indicating that the hepatotoxicity caused by oxaliplatin could be prolonged after its administration. Patients who have received oxaliplatin-based chemotherapy should be followed up carefully over the long term.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Esophageal and Gastric Varices; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin

Patients with metastatic colon cancer can be treated with alternating courses of FOLFOX6 and FOLFIRI in order to reduce their adverse events. We report 2 patients with para-aortic lymph node metastasis treated with 4 courses each of FOLFOX6 and FOLFIRI in combination with bevacizumab, which led to a complete response. Case 1: The patient was a 53-year-old woman with transvers colon cancer tub2 pSS, ly3, v2, n4, H0, P0. Case 2: The patient was a 60-year-old woman with upper rectal cancer tub1 pSS, ly3, v3, n4, H0, P0. The administration of tegafur/uracil plus oral Leucovorin was continued for 6 months. Furthermore, only the administration of oral doxifluridine was continued for 4 years. Complete response has been maintained for over 5 years since resection. Four courses each of FOLFOX6 and FOLFIRI in combination with bevacizumab will not only provide a remission rate of 100% but will also be effective radical therapy for patients with para-aortic lymph node metastasis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aorta; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Time Factors; 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

Targeted drug delivery to colon cancer cells can significantly improve the efficiency of treatment. We firstly synthesized carboxyl-modified mesoporous silica nanoparticles (MSN⁻COOH) via two-step synthesis, and then developed calcium leucovorin (LV)-loaded carboxyl-modified mesoporous silica nanoparticles based on galactosylated chitosan (GC), which are galectin receptor-mediated materials for colon-specific drug delivery systems. Both unmodified and functionalized nanoparticles were characterized by scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR), nitrogen sorption, and dynamic light scattering (DLS). Drug release properties and drug loading capacity were determined by ultraviolet spectrophotometry (UV). LV@MSN⁻COOH/GC had a high LV loading and a drug loading of 18.07%. In vitro, its release, mainly by diffusion, was sustained release. Cell experiments showed that in SW620 cells with the galectin receptor, the LV@MSN⁻COOH/GC metabolized into methyl tetrahydrofolic acid (MTHF) and 5-fluorouracil (5-FU)@MSN⁻NH₂/GC metabolized into FdUMP in vivo. MTHF and 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) had combined inhibition and significantly downregulated the expression of thymidylate synthase (TS). Fluorescence microscopy and flow cytometry experiments show that MSN⁻COOH/GC has tumor cell targeting, which specifically recognizes and binds to the galectin receptor in tumor cells. The results show that the nano-dosing system based on GC can increase the concentrations of LV and 5-FU tumor cells and enhance their combined effect against colon cancer.

Topics: Antineoplastic Agents; Cell Death; Cell Line, Tumor; Cell Survival; Chitosan; Colonic Neoplasms; Drug Carriers; Drug Delivery Systems; Drug Liberation; Galactose; Glycosylation; Humans; Leucovorin; Nanoparticles; Porosity; Silicon Dioxide; Spectroscopy, Fourier Transform Infrared; Static Electricity; Thermogravimetry; Thymidylate Synthase

This case study describes a 37-year-old Caucasian male with pruritic papules and plaques-some with central erosion-on the arms, neck, and trunk that appeared after chemotherapy with FOLFOX (folinic acid, fluorouacil, and oxiliplatin) for colon cancer. A histological examination showed features of neutrophilic eccrine hidradenitis. To the best of our knowledge, this is the first reported case of neutrophilic eccrine hidradenitis due to FOLFOX.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Hidradenitis; Humans; Leucovorin; Male; Organoplatinum Compounds

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

This is the case report of a woman with more than 70 years and good PS, with diagnosis of right sided, BRAF mutated and MSI-high colon cancer, diffusively metastatic to lymph nodes. The treatment sequencing of FOLFOXIRI bevacizumab (I line) and FOLFIRI aflibercept (II line) allowed to maximally shrink the disease burden and dramatically extend survival thanks to the treatments' intensification (due to BRAF mutation-related aggressiveness) and the immune-modulating effects of anti-angiogenic treatments (due to immune-suppressive burden associated with MSI-high status).

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Mutation; Proto-Oncogene Proteins B-raf; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins

A 69-year-old female was admitted to our hospital due to general malaise and appetite loss. On physical examination, a tumor was palpable in the upper left abdomen. A complete blood count revealed anemia. An abdominal computed tomography suggested ileus secondary to transverse colon cancer. Transverse colectomy with D3 lymph node dissection was performed. The final diagnosis was moderately differentiated tubular adenocarcinoma, StageⅡ, T4aN0M0. The tumor marker level was re-elevated at 9 months after surgery; computed tomography and lower gastrointestinal endoscopy indicated local recurrence. The patient underwent a second laparotomy; however, it became an exploratory surgery due to aggressive local invasion. FOLFOX therapy was initiated from postoperative day 55 for tumor control. Tumor markers decreased markedly after 5 courses of therapy, and a complete response was achieved at 6 months after the second surgery. Subsequently, 29 courses of FOLFOX therapy were administered for 2 years and 1 month. At this time, the patient discontinued chemotherapy at her desire. No signs of recurrence have been observed at 6 years after withdrawal.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Neoplasm Recurrence, Local; Organoplatinum Compounds

A 75-year-old male underwent adjuvant chemotherapy with tegafur uracil(UFT)plus Leucovorin(LV)after surgery for transverse colon cancer(pT3pN0M0, ly1, v2, pStageⅡ). Although he had diarrhea(Grade 3)and vomiting(Grade 2)from day 15, he continued to take the medicine at his own discretion. He visited a hospital because of acute renal failure from severe dehydration. He went into shock after evacuation, and the computed tomography(CT)finding suggested a diagnosis of spontaneous esophageal rupture at the lower esophagus. We made a diagnosis of intrathoracic perforation of the esophagus by using thoracic drainage. Then, we performed an operation for mediastinal drainage via a transabdominal approach and the lesser omentum. He started ingestion from POD36 and transferred to another hospital on POD85. He had no disease recurrence in our outpatient care. We think that the spontaneous esophageal rupture occurred because of the frequent vomiting caused by the continued chemotherapy despite the severe side effects. Treatments must be selected by considering patients' life background and medical compliance, and common guidance in taking medications must be provided to elderly patients at the start of chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colon, Transverse; Colonic Neoplasms; Esophageal Diseases; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Rupture, Spontaneous; Tegafur; Uracil

The purpose of this study was to estimate the impact of metronomic therapy with oral tegafur-uracil (UFUR) following an intravenous FOLFOX regimen as surgical adjuvant chemotherapy on the overall survival (OS) and disease-free survival (DFS) of stage III colon cancer patients. From the retrospective database of patients who underwent a surgical resection for colorectal cancer at the Tri-Service General Hospital from October 2008 through December 2014, stage III colon carcinomas treated with radical R0 resection were reviewed. One hundred thirty two patients were treated with a FOLFOX regimen (comparison group), and 113 patients were treated with the same regimen followed by additional oral UFUR (UFUR group). The clinical characteristics and mean age of the comparison and UFUR groups were similar. Furthermore, for all study patients, DFS was not significantly different between the two groups. However, 5-year OS rates were 86.8% and 68.5% in the UFUR and comparison groups, respectively (p = 0.0107). Adding UFUR to a FOLFOX regimen was found to significantly improve the OS in patients with stage III colon cancer. UFUR as a maintenance therapy following FOLFOX regimen as an alternative therapeutic option for the treatment of stage III colon cancer patients.

Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Rate; Tegafur; Uracil

The occurrence of Chemotherapy-induced neutropenia (CIN) was reported to be a predictor of better survival in several cancers. The objective of our study is to evaluate the relationship between the timing of CIN and prognosis.. Between June 2012 and August 2014, 290 patients with confirmed metastatic colon cancer received at least one cycle of mFOLFOX6 as first-line chemotherapy were eligible for assessment as all patients group. Of the 232 received at least six cycles of mFOLFOX6 and survived 150 days after treatment were considered as landmark group. Timing of CIN was categorized into absence, early-onset and late-onset CIN groups. The end of cycle 3 was the cutoff to differentiate early-onset or late-onset. The correlation between timing of CIN with survival was analyzed by Kaplan-Meier method and Cox proportional hazards model.. In all patients group, the median survival of patients without neutropenia, early-onset and late-onset neutropenia were 6.7, 20.7 and 12.8 months (P < 0.001). The patients with early-onset and late-onset CIN had better prognosis than CIN absence by multivariate analysis. Findings were much the same for landmark group.. In conclusion, timing of CIN is an independent predictor of prognosis in metastatic colon cancer patients received mFOLFOX6, whereas an early-onset of CIN predicts longer survival.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Induction Chemotherapy; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neutropenia; Organoplatinum Compounds; Prognosis; Treatment Outcome

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

Oxaliplatin is one of the most commonly used drugs for patients with colorectal cancer. It has rarely been associated with disseminated intravascular coagulation (DIC) with only 3 previously reported cases. In all those instances, the patients had started receiving oxaliplatin, developed evidence of DIC during the course of planned treatment, and recovered with supportive care. We report a case of a 71-year-old man with colorectal cancer treated successfully with an oxaliplatin-based regimen who had disease relapse after 3 years. When treated again with oxaliplatin, he developed signs of an acute hypersensitivity reaction, and eventually had signs and symptoms consistent with DIC despite appropriate management. This case is unique in that a DIC reaction evolving from a hypersensitivity reaction occurred after the patient had already tolerated the drug years earlier. It suggests a possible immune-mediated etiology to this rare occurrence that should be kept in mind while utilizing this commonly employed drug.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Creatinine; Disseminated Intravascular Coagulation; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Organoplatinum Compounds; Oxaliplatin; Recurrence

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 prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use.. According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data.. Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients.. Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphocytes; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Multivariate Analysis; Organoplatinum Compounds; Predictive Value of Tests; Prognosis; Prospective Studies; Survival Analysis

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

There is increasing interest in immune function in combination with chemotherapy for cancer treatment. However, the effects of chemotherapy on the human immune system remain to be determined. The aim of this study was to investigate the prognostic impact of lymphocyte and neutrophil counts in colon cancer patients who were treated with curative surgery and adjuvant chemotherapy.. Two hundred thirty-one patients with colon cancers who underwent curative surgery and FOLFOX adjuvant chemotherapy between November 2005 and December 2011 were included. Oncologic outcomes were analyzed with neutrophil count, lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR) before and after chemotherapy.. The 5-year DFS rate was lower in colon cancer patients with low lymphocyte count during chemotherapy (61.9 vs. 76.7%, P = 0.026). Cox multivariate analysis demonstrated that low lymphocyte count during chemotherapy was independently associated with poor disease-free survival (HR 1.829; 95% CI 1.096-3.050; P = 0.021) in colon cancer patients who underwent FOLFOX adjuvant chemotherapy.. Lymphocyte count during chemotherapy is a strong predictor of worse disease-free survival in colon cancer patients who have undergone FOLFOX adjuvant chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphocyte Count; Male; Middle Aged; Multivariate Analysis; Neutrophils; Organoplatinum Compounds; Prognosis; Young Adult

Stroke mimics, especially those involving chemotherapy related neurotoxicity, can confound the clinical diagnosis of acute stroke. Here we describe the case of a 63year-old male with a recent history of stage IIIC colon cancer who presented with confusion on the second day of modified FOLFOX6 (5-fluorouracil/oxaliplatin) chemotherapy and subsequently received alteplase, tissue plasminogen activator therapy (tPA), for presumed ischemic stroke. Magnetic resonance imaging scans after tPA administration did not reveal evidence of an infarction and the patients' neurological symptoms resolved completely after discontinuation of 5-fluorouracil (5-FU). Although this patient did not experience any side effects from tPA, fibrinolytic therapy may have been avoided with a better understanding of potential chemotherapy related adverse reactions. Our experience suggests that 5-FU induced reversible encephalopathy can present with acute stroke-like symptoms and emergency medicine personnel evaluating patients for tPA treatment should be aware of this differential diagnosis.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aphasia; Brain Diseases; Colonic Neoplasms; Confusion; Diagnosis, Differential; Fibrinolytic Agents; Fluorouracil; Headache; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Stroke; Tissue Plasminogen Activator

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

To evaluate the prognostic value of chemotherapy-induced neutropenia (CIN) in metastatic colon cancer undergoing first-line chemotherapy with FOLFOX.. Data were collected from a retrospective survey of 158 consecutive metastatic colon cancer patients who had undergone FOLFOX chemotherapy. The clinicopathological characteristics and chemotherapy features of the patients were analyzed as potential prognostic factors. The patients were stratified by the decreased level of CIN to three groups: large decreased level (the number of neutrophil decreased more than 1.0×10. According to a multivariate COX model, decreased level of CIN was a independent prognostic factor of colon cancer patients. Hazard ratios of death were 0.687 (95% CI: 0.381-0.812, P=0.016) for patients with large decreased level of CIN and 0.817 (95% CI: 0.527-0.939, P=0.027) for those with small decreased level of CIN compared with those of absent neutropenia patients. Median overall survival was 12.9 months (95% CI: 10.4-15.4) for patients without neutropenia (A) compared with 20.8 months (95% CI: 18.3-23.1) for patients with large-decreased level of CIN (L) and with 17.3 months (95% CI: 16.2-18.8) for those with small-decreased level of CIN (S vs. L, P=0.018; L vs. A, P=0.009; S vs. A, P=0.011).. Our results demonstrate that the decreased level of CIN is a predictor of prognosis in patients with metastatic colon cancer undergoing FOLFOX chemotherapy. Patients who have experienced large decreased level of CIN haave longer survival time than small decreased level of CIN or absent patients. To monitor CIN decreased level timely and adjust chemotherapy drug dose may help improve the prognosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neutropenia; Organoplatinum Compounds; Prognosis; Retrospective Studies

Diabetic patients are at a higher risk of carcinogenesis and death from cancer, including colorectal cancer, than healthy individuals. The efficacy of cancer chemotherapy in the diabetic condition remains unclear. In this study, we investigated the efficacy of anticancer agents oxaliplatin and fluorouracil in streptozotocin (STZ)-treated hyperglycemic mice.. Starting 7 days after transplantation of colonic adenocarcinoma colon-26 cells, STZ-treated and control mice were intraperitoneally administered oxaliplatin, fluorouracil, and levofolinate (FOLFOX) every 2 weeks.. Tumor growth was delayed in STZ-treated mice compared to control mice. The tumor volume was significantly smaller after treatment with FOLFOX in control mice, but not in STZ-treated mice. Despite delayed tumor growth, and regardless of whether they received treatment, survival was shorter in STZ-treated mice than in control mice.. Cancer chemotherapy with oxaliplatin and fluorouracil was less effective and survival was shorter in hyperglycemia.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Blood Glucose; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Fluorouracil; Interleukin-6; Leucovorin; Male; Mice, Inbred BALB C; Organoplatinum Compounds; Serum Albumin; Streptozocin; Time Factors; Tumor Burden

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: Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Time Factors

Topics: Adenocarcinoma; Adult; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Cyclophosphamide; Doxorubicin; Fluorouracil; Humans; Hyperpigmentation; Leucovorin; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Organoplatinum Compounds; Prednisone; Rituximab; Vincristine

We report a case of a 79-year-old man who developed severe therapy-related pancytopenia from tegafur uracil(UFT)and Leucovorin(LV)as adjuvant chemotherapy for ascending colon cancer. Laparoscopic right hemicolectomy resection was performed for the ascending colon cancer. Pathohistological analysis revealed that the ascending colon tumor was moderately differentiated tubular adenocarcinoma(T3, N1, M0, and Stage III a). Postoperative adjuvant chemotherapy with UFT and LV was administered. After 2 courses of chemotherapies, severe thrombocytopenia(Grade 4)and neutropenia(Grade 4)were noted. Platelet and granulocyte-colony stimulating factor(G-CSF)were transfused. Furthermore, red blood cell transfusions were given for anemia(Grade 3). Dihydropyrimidine dehydrogenase(DPD)deficiency was suspected as the cause of the pancytopenia, and the ratio of dihydrouracil(DHU)and uracil(URA)was measured. However, the result was negative for DPD deficiency. Bone marrowaspiration revealed that therapy-related leukemia(TRL)and therapy-related myelodysplastic syndrome(T-MDS)were not the causes of the pancytopenia either. A total of 230 units of platelet transfusions and 20 units of red blood cell transfusions have been given for 32 weeks, and the patient currently requires routine blood transfusions. Fortunately, infection and bleeding never occurred. Subsequently, the patient should be monitored carefully.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colon, Ascending; Colonic Neoplasms; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Male; Pancytopenia; Platelet Transfusion; Tegafur

A 68-year-old man with abdominal mass and anorexia was diagnosed with transvers colon cancer invading the abdominal wall. Considering the difficulty of curative resection, we first performed ileostomy. After surgery, the patient received mFOL FOX6 with bevacizumab as neoadjuvant chemotherapy. After 10 course of the regimen, computed tomography revealed shrinkage of the lesion, with the efficacy evaluated as a partial response. The patient underwent right hemicolectomy and partial resection of the abdominal wall. The pathological findings was ypT3(SS), ypN3, ly0, v1, ypPM0, ypDM0, ypRM0, ypStage III b. On histopathological examination, the efficacy of the chemotherapy was evaluated as Grade 1b. The patient received adjuvant chemotherapy with mFOLFOX6 and remains well without any evidence of recurrence more than 7 months after surgery.

Topics: Abdominal Wall; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Neoadjuvant Therapy; Neoplasm Invasiveness; Organoplatinum Compounds

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging

The impact of microsatellite instability (MSI) on survival in stage III colon cancer treated with adjuvant 5-fluorouracil-oxaliplatin combination (FOLFOX) chemotherapy is not clear. We evaluated the association between MSI and survival in this population.. We analyzed 598 patients with curatively resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy. We determined MSI status using polymerase chain reaction amplification; tumors were classified as high MSI (MSI-H, ≥2 unstable markers), low MSI (MSI-L, 1 unstable marker), or microsatellite stable (MSS, no unstable marker).. Of 598 patients, 8.4% showed MSI-H. Tumors classified as MSI-H were more commonly located in the ascending colon (54.0 vs. 27.7%, p < 0.0001) and had poorly differentiated features (32.0 vs. 8.0%, p < 0.0001). After the median follow-up of 52.8 months, 5-year disease-free (DFS) and overall survival (OS) rates were 77.0 and 85.9%, respectively. In univariate analysis, pathologic T4 (pT4) and pathologic N2 (pN2) was associated with reduced DFS (p < 0.0001 and p < 0.0001, respectively) and OS (p = 0.002 and p = 0.001, respectively), whereas MSI status did not affect either DFS (p = 0.114) or OS (p = 0.525). In patients with pN2 tumors; however, MSI-H was associated with better survival compared with MSS/MSI-L; DFS and OS in patients with MSI-H/pN2 were comparable to those in patients with pN1 tumors.. In patients with stage III colon cancer treated with adjuvant FOLFOX, pT4 and pN2 was associated with reduced survival, but MSI status alone did not affect survival.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colon, Ascending; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Microsatellite Instability; Middle Aged; Neoplasm Grading; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Survival Rate; Tumor Burden; Young Adult

Although several major trials of treatment for stage III colon cancer have been reported, no study has compared oral adjuvant chemotherapy regimens using tegafur-uracil in combination with leucovorin (UFT/LV) and capecitabine (CAPE) alone. This study compared the oncologic outcomes of treatment with these 2 oral regimens.. Records of patients with stage III colon cancer who underwent curative surgery and adjuvant chemotherapy from April 2007 and September 2014 were retrospectively reviewed.. A total of 258 patients with stage III colon cancer received oral adjuvant chemotherapy with UFT/LV (n = 157, 61%) and CAPE (n = 101, 39%). The overall rate of completion of scheduled treatment was 78.6%. Significantly fewer patients on UFT/LV completed the regimen compared with those on CAPE (117, 74.5% vs. 86, 85.1%; P < .01). There were no significant differences in oncologic outcome between UFT/LV and CAPE in terms of 3-year overall survival rates (OS; 95.8% vs. 92.4%, P = .45) and 3-year relapse-free survival rates (RFS; 82.7% vs. 79.3%, P = .8).. The 3-year RFS and OS were similar for both regimens, yielding an excellent outcome. The selection of adjuvant chemotherapeutic regimens must be based on the patient's status as well as considering the incidences of adverse events, medical cost, and administration convenience.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Retrospective Studies; Tegafur; Treatment Outcome; Uracil

Cardiac metastasis from colorectal cancer is rare. There is little evidence supporting the effectiveness of chemotherapy, and standard therapy for metastatic cardiac tumors has not been established.. A 76-year-old woman presented with a right ventricle tumor that was detected incidentally on screening cardiac ultrasonography. The initial computed tomography (CT) scan showed the cardiac tumor, which was approximately 40 mm in size, and multiple pulmonary nodules. Serum levels of tumor markers CEA and CA19-9 were elevated aberrantly. The suspected primary tumor, a well-differentiated adenocarcinoma of the transverse colon with wild-type KRAS was found by colonoscopy, and treatment with 5-fluorouracil, leucovorin, and oxaliplatin (modified FOLFOX6) plus panitumumab was initiated. After 4 courses of the therapy, a CT scan showed that the cardiac tumor size had markedly decreased and the pulmonary nodules had diminished. The serum levels of CEA and CA19-9 were also markedly decreased. After 12 courses of chemotherapy during 10 months of treatment, the patient continued to show a partial response, and she remained asymptomatic with continuation of the treatment through 15 courses.. To the best of our knowledge, this is the first report of the efficacy of combination therapy using cytotoxic and molecular targeted agents against cardiac metastasis from colon cancer.

Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Heart Neoplasms; Humans; Leucovorin; Organoplatinum Compounds; Panitumumab; Tomography, X-Ray Computed

Patients with locally advanced colon cancer (LACC) have a relatively poor prognosis despite radical resection and adjuvant chemotherapy. This study investigated the treatment efficacy and toxicity of neoadjuvant chemoradiotherapy in patients with LACC.. We retrospectively reviewed 36 patients with LACC preoperatively treated with chemotherapy and radiotherapy. Patients were administered chemoradiotherapy, which comprised radiotherapy and neoadjuvant chemotherapy involving a 5-fluorouracil, leucovorin, and oxaliplatin regimen every 2 weeks.. Median age was 64 years (45-86 years) and median follow-up period was 23.5 months (5.0-49.1 months). Seven (19.4%) patients developed grade 3 or 4 adverse events during neoadjuvant concurrent chemoradiotherapy. Pathologic responses were not evaluated in two patients who did not undergo radical resection. Of the 34 patients who underwent surgery, nine (26.4%) achieved a pathologic complete response (pCR). The 2-year estimated overall survival and disease-free survival rates were 88.7% and 73.6%, respectively.. Our results demonstrated that neoadjuvant chemoradiotherapy is feasible and safe. A prominent pCR rate with an acceptable toxicity profile suggests that the multimodality therapy might be a treatment option for patients with LACC.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Rate

Undertreatment has been frequently reported in the elderly cancer patient population. For this reason, we aimed to characterize adjuvant chemotherapy (AC) use among elderly patients (EPs) with stage III colon cancer (CC) and to identify potential reasons for undertreatment.. Patients diagnosed with stage III CC between 2008 and 2010 were included in this review. Multivariate Cox regression models were constructed to evaluate the associations between AC and cancer-specific, disease-free, and overall survival and to determine whether these were modified by age.. We identified 810 patients: 423 (52%) men, 423 (52%) young patients (YPs), and 603 (74%) received AC. Compared with YPs, EPs were less likely to receive AC (57% vs. 91%; P < .01), particularly 5-fluorouracil and oxaliplatin (FOLFOX) (32% vs. 74%, P < .01). Frequent reasons for nontreatment included age, comorbidities, and perceived minimal benefit from AC. When AC was given, EPs had similar rates of treatment discontinuations (34% vs. 26%; P > .05) and dose reductions (63% vs. 61%; P > .05) as YPs. Reasons for treatment interruptions included side effects, progressive disease, and patient choice. Receipt of either FOLFOX or capecitabine was correlated with improved cancer-specific survival, disease-free survival, and overall survival compared with surgery alone; this effect was not modified by age.. Elderly patients with stage III CC frequently received either no AC or capecitabine monotherapy because of advanced age and comorbidities. The effect of AC on survival was similar across age groups, with comparable side effects and rates of treatment modifications. AC should not be withheld because of advanced age alone.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Health Services Misuse; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Proportional Hazards Models

Evidence suggests that CAPOX (capecitabine and oxaliplatin) has efficacy similar to 5-fluorouracil and oxaliplatin (mFOLFOX6) in the adjuvant treatment of colon cancer. CAPOX is partly administered orally and associated with a 3-week rather than a 2-week treatment cycle. A population-based cost-minimization analysis was conducted from the health care payer and societal perspectives to evaluate the potential cost savings of replacing mFOLFOX6 with CAPOX.. We applied treatment and toxicity data from phase III trials of CAPOX and FOLFOX-based regimens to the adjuvant colon cancer population in British Columbia, Canada. In this cost-minimization analysis we compared the total costs associated with chemotherapy medications, drug administration and delivery, hospital and clinic visits, treatment-related toxicities, and central venous access devices. Costs to patients in terms of lost time and travel were also considered. It was assumed that patients would receive either 8 cycles of CAPOX or 12 cycles of mFOLFOX6.. From the payer perspective, the use of CAPOX resulted in cost savings of $5339 CAD per patient compared with the use of mFOLFOX6. From a societal perspective, CAPOX was also associated with savings of $6080 CAD per patient. The greatest cost savings with CAPOX were attributed to fewer visits for chemotherapy treatment and decreased central venous access device usage. CAPOX was also associated with reduced loss of time and decreased travel for patients because of the requirement of fewer clinic visits.. Replacement of mFOLFOX6 with CAPOX in the adjuvant treatment of colon cancer might be associated with potential cost savings from the payer and societal perspectives.

Topics: Antineoplastic Combined Chemotherapy Protocols; British Columbia; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Costs and Cost Analysis; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cardiotoxicity; Chemotherapy, Adjuvant; Colonic Neoplasms; Coronary Vasospasm; Diltiazem; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Nifedipine; Organoplatinum Compounds; Vasodilator Agents

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

Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown.. A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons.. Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden.. These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Databases, Factual; Endpoint Determination; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Randomized Controlled Trials as Topic

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Mass Index; Body Surface Area; Canada; Cohort Studies; Colonic Neoplasms; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; France; Humans; Leucovorin; Male; Middle Aged; Nervous System Diseases; Organoplatinum Compounds; Population Surveillance

Over the past decade, oncology therapies have trended toward orally administered regimens, and there has been growing attention on evaluation of factors that affect adherence. There has not been a rigorous investigation of factors associated with adherence to intravenous (i.v.) and oral anticancer drugs in the setting of metastatic colorectal cancer (mCRC).. To (a) assess potential patient-specific factors related to adherence to mCRC chemotherapy regimens and (b) compare adherence with IV versus oral dosage forms.. A retrospective analysis was performed using the Optum Oncology Management claims database. Patients aged 18 years and older diagnosed with mCRC between July 1, 2004, and December 31, 2010, who were insured by a commercial health plan were included in the study. Adherence to i.v. and oral chemotherapy regimens was assessed using the National Comprehensive Cancer Network (NCCN) guidelines as the standard for expected cycle/regimen duration. The most commonly prescribed chemotherapy regimens were assessed. Adherence was evaluated using the medication possession ratio (MPR), calculated as the number of days a patient was covered by their chemotherapy regimen, according to NCCN guidelines, divided by the number of days elapsed from the first to the last infusion of that regimen. For most analyses, the MPR was considered a continuous variable that could take on values between 0 and 1. In other analyses, a dichotomous categorical variable designated if the MPR was at least 0.8 versus less than 0.8. The Wilcoxon rank sum, Kruskal-Wallis, and Student's t-test were used to detect differences in continuous measures between patients receiving oral capecitabine therapy versus i.v. chemotherapy. The chi square test (X(2) test) or Fisher's exact test was used to assess differences in the dichotomous MPR variable. Generalized estimating equation (GEE) models were used for regimen-level analyses to account for correlated responses within individuals.. A total of 6,780 patients were included in the analysis, virtually all (98%) with commercial insurance coverage and the remaining (2%) with Medicare Advantage. Patients with mCRC received 17,095 regimens of chemotherapy, including 2,252 regimens of oral capecitabine. Of the 17,095 regimens, 6,780 (40%) were first-line regimens (i.e., the first time mCRC was treated for a given patient). The most common chemotherapy regimen, regardless of line of therapy, was FOLFOX (2,991 regimens, 17.5% of all regimens used). FOLFOX-based therapies with or without bevacizumab were the most common regimens for first- and second-line chemotherapy, while oral capecitabine treatment was the most commonly prescribed regimen for patients in third- or fourth-line therapy. Overall, medication adherence across all regimens was relatively high, with a mean MPR of 0.87 (SD = 0.17). Evaluation of the distribution of i.v. and oral capecitabine regimens revealed that 28% of all regimens were associated with an MPR of less than 0.8. The average MPR was clinically similar, but statistically higher for i.v. chemotherapy regimens (0.881) compared with oral capecitabine regimens (0.799; P < 0.0001). In the multivariable GEE model, lung or liver metastases were associated with a higher MPR, while lower Charlson Comorbidity Index and oral anticancer therapy were associated with lower MPR. Furthermore, as line of therapy increased, the difference in MPR between patients receiving oral capecitabine and i.v. chemotherapy increased.. This analysis determined that adherence with i.v. chemotherapy regimens was clinically similar, but statistically higher, compared to oral capecitabine therapy. The difference in adherence rates between the 2 routes of administration increased as the line of anticancer regimen increased. These results suggest that there should be an increased focus on improving adherence rates in patients receiving oral capecitabine.

Topics: Administration, Intravenous; Administration, Oral; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Medicare Part C; Medication Adherence; Neoplasm Metastasis; Organoplatinum Compounds; Retrospective Studies; United States

Low methylation status of LINE-1 in tumors is associated with poor survival in patients with colon cancer. Eastern Cooperative Oncology Group performance status (ECOG-PS) is a method to assess the functional status of a patient. We retrospectively evaluated the relationship between ECOG-PS and LINE-1 methylation in colorectal cancers (CRCs) and their prognostic impact in CRC or colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX).. LINE-1 methylation and microsatellite instability were analyzed in stage III or high-risk stage II CRCs (n = 336). LINE-1 methylation levels were correlated with clinicopathological features, including PS and recurrence-free survival (RFS). The association between the tumoral LINE-1 methylation level and PS was observed (OR = 2.56, P < 0.001). Differences in LINE-1 methylation levels in cancer tissue between the PS 0 and 1 groups were significant in patients older than 60 years (P = 0.001), the overweight body mass index group (P = 0.005), and the stage III disease group (P = 0.008). Prognostic significances of LINE-1 methylation status or combined PS and LINE-1 methylation statuses were identified in stage III colon cancers, not in stage III and high-risk stage II CRCs. Low LINE-1 methylation status was closely associated with a shorter RFS time. The difference between PS(0)/LINE-1(high) and PS(≥1)/LINE-1(low) was significant, which suggests that colon cancer patients with concurrent PS(≥1)/LINE-1 (low) have a higher recurrence rate.. PS was associated with LINE-1 methylation in CRC tissue. LINE-1 methylation was associated with RFS in stage III colon cancer patients who were treated with adjuvant FOLFOX chemotherapy. Combined PS and LINE-1 methylation status might serve as a useful predictor of cancer recurrence.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA Methylation; Female; Fluorouracil; Humans; Leucovorin; Long Interspersed Nucleotide Elements; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Analysis; Treatment Outcome

The effect of individual dose adjustment of 5-fluorouracil (5-FU) based on pharmacokinetic monitoring on the outcome of FOLFOX for metastatic colorectal cancer was analyzed retrospectively.. Twenty patients with metastatic colorectal cancer underwent FOLFOX chemotherapy from January 2005 to December 2013 at the Niitsu Medical Center Hospital. The sample group included 11 patients in whom 5-FU doses were adjusted individually based on pharmacokinetic monitoring according to an algorithm to maintain the area under the curve (AUC) in the range of 20-25 mg·h/L (Group A) and 9 patients in whom 5-FU doses were adjusted conventionally based on body surface area (Group B).. The objective response rate was 63% and 33% in Group A and Group B, respectively (p=0.174). The median overall survival was 34 months and 14 months in Group A and Group B, respectively (p=0.036). There were 4 cases of Grade 3 toxicity (2 in Group A, 2 in Group B; p=0.636) and no cases of Grade 4 toxicity or treatment-related death.. Pharmacokinetically guided dose adjustment of 5-FU may improve the outcome of FOLFOX for metastatic colorectal cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Rectal Neoplasms; Recurrence; Retrospective Studies

This study was aimed to assess the feasibility and short-term outcomes of adjuvant systemic chemotherapy with either S-1/oxaliplatin (SOX) or mFOLFOX6 (FOLFOX)after curative resection of distant metastases from colorectal cancer. We retrospectively examined 16 patients who underwent R0 resection of colorectal metastases, including the liver (n=6), lung (n=5), lymph node (n=3), and peritoneum (n=2), followed by chemotherapy with SOX (n=7) or FOLFOX (n=9) until disease progression. The mean recurrence-free survival was 13.2 months in the SOX group and 16.9 months in the FOLFOX group. The mean overall survival was 17.9 and 22.9 months, respectively. The number of given courses were 6.5 and 11.0, respectively. Although sensory neuropathy was observed in 38% of the patients, relative dose intensity was higher than 80%. Adjuvant chemotherapy with SOX or FOLFOX was feasible and effective. Further randomized prospective trials are warranted to confirm these results.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Rectal Neoplasms; Recurrence; Retrospective Studies; Tegafur

Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study.. Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN.. Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences.. Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Peripheral Nervous System Diseases; Pharmacogenetics; Polymorphism, Single Nucleotide

The aim of this study was to provide insight in the use, intensity and toxicity of therapy with capecitabine and oxaliplatin (CAPOX) and capecitabine monotherapy (CapMono) among elderly stage III colon cancer patients treated in everyday clinical practice.. Data from the Netherlands Cancer Registry were used. All stage III colon cancer patients aged ≥70 years diagnosed in the southeastern part between 2005 and 2012 and treated with CAPOX or CapMono were included. Differences in completion of all planned cycles, cumulative dosages and toxicity between both regimens were evaluated.. One hundred ninety-three patients received CAPOX and 164 patients received CapMono; 33% (n = 63) of the patients receiving CAPOX completed all planned cycles of both agents, whereas 55% (n = 90) of the patients receiving CapMono completed all planned cycles (P < 0.0001). The median cumulative dosage capecitabine was lower for patients treated with CAPOX (163,744 mg/m(2), interquartile range [IQR] 83,397-202,858 mg/m(2)) than for patients treated with CapMono (189,195 mg/m(2), IQR 111,667-228,125 mg/m(2), P = 0.0003); 54% (n = 105) of the patients treated with CAPOX developed grade III-V toxicity, whereas 38% (n = 63) of the patients treated with CapMono developed grade III-V toxicity (P = 0.0026). After adjustment for patient and tumour characteristics, CapMono was associated with a lower odds of developing grade III-V toxicity than CAPOX (odds ratio 0.54, 95% confidence interval 0.33-0.89). For patients treated with CAPOX, the most common toxicities were gastrointestinal (29%), haematological (14%), neurological (11%) and other toxicity (13%). For patients treated with CapMono, dermatological (17%), gastrointestinal (13%) and other toxicity (11%) were the most common.. CAPOX is associated with significantly more grade III-V toxicities than CapMono, which had a pronounced impact on the cumulative dosage received and completion of all planned cycles. In this light, CapMono seems preferable over CAPOX.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Multivariate Analysis; Netherlands; Organoplatinum Compounds; Oxaliplatin

One-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here, we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-tetrahydrofolate (10-formyl-THF), and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis, with the mitochondrial pathway required in nutrient-poor conditions.

Topics: Aminoimidazole Carboxamide; Carbon; Cell Compartmentation; Cell Proliferation; Colonic Neoplasms; CRISPR-Cas Systems; Cytosol; Folic Acid; Formates; Gene Knockout Techniques; Gene Library; Glycine; Glycine Hydroxymethyltransferase; HCT116 Cells; HEK293 Cells; Humans; Leucovorin; Metabolic Networks and Pathways; Methylenetetrahydrofolate Dehydrogenase (NADP); Mitochondria; Mutation; NADP; Ribonucleotides; Serine; Xenograft Model Antitumor Assays

Iatrogenic ileostomies are routinely placed during colorectal surgery for the diversion of intestinal contents to permit healing of the distal anastomosis prior to elective reversal. We present an interesting case of spontaneous closure of a diverting ileostomy without any adverse effects to the patient. A 65-year-old woman, positive for hereditary non-polyposis colorectal cancer type-I, with locally invasive cancer of the distal colon underwent en-bloc total colectomy, hysterectomy, and bilateral salpingoophorectomy with creation of a proximal loop ileostomy. The ostomy temporarily closed without reoperation at 10 weeks, after spontaneously reopening, it definitively closed, again without surgical intervention at 18 weeks following the original surgery. This rare phenomenon has occurred following variable colorectal pathology and is poorly understood, particularly in patients with aggressive disease and adjunct perioperative interventions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Ileostomy; Leucovorin; Organoplatinum Compounds

Topics: Adenocarcinoma; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Diseases; Colonic Neoplasms; Colonic Polyps; Colonoscopy; Endoscopic Mucosal Resection; Female; Fluorouracil; Humans; Intestinal Perforation; Irinotecan; Leucovorin

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

A modified complete mesocolic excision (mCME) technique for the treatment of right-sided colon cancer recently was shown by Hohenberger and colleagues to provide impressive long-term oncologic outcomes. This report aims to describe the authors' experience with robotic right colectomy using mCME. The safety, feasibility, and efficacy of this procedure are measured by complications, conversion rates, and 4-year oncologic outcomes.. A retrospective study analyzed 100 consecutive patients who underwent robotic right colectomy with mCME and intracorporeal anastomosis at the authors' institution between November 2005 and November 2013. Intra- and postoperative clinical outcomes, pathologic data, and survival were analyzed.. Robotic right colectomy with mCME was successfully performed for all the patients. No conversions or intraoperative complications occurred. The major complication rate (Dindo 3 or 4) was 4 %. During a median follow-up period of 48.5 months (range 24-114 months), the survival rates were 94.5 % for disease-specific survival, 91.4 % for disease-free survival, and 90.3 % for overall survival.. The authors' experience confirms the feasibility and safety of mCME for the treatment of right-sided colon cancer. This technique provided satisfying short-term outcomes with promising 4-year oncologic results. However, the real benefits of the CME technique should be evaluated further by well-conducted randomized studies before its adoption in routine practice is recommended.

Topics: Adult; Aged; Aged, 80 and over; Anastomotic Leak; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Conversion to Open Surgery; Disease-Free Survival; Feasibility Studies; Female; Fluorouracil; Follow-Up Studies; Hemoperitoneum; Humans; Intraoperative Complications; Leucovorin; Male; Mesocolon; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Robotic Surgical Procedures; Survival Rate; Time Factors

A 57-year-old woman had been diagnosed with sigmoid colon cancer at surgery for ovarian cancer, and underwent simultaneous radical resection. Because of the pathological diagnosis of sigmoid cancer with ovarian metastasis, adjuvant chemotherapy was scheduled, with Leucovorin(LV)25 mg. This was immediately followed with 5-fluorouracil(5-FU)500 mg, via a 2-hour systemic intravenous infusion daily for 5 consecutive days, with courses repeated at 5 weeks, followed by maintenance once every 1 or 2 weeks for 2 years. There had been no evidence of recurrence for 10 years after surgery; however, peritoneal recurrence and a thyroid tumor were found using computed tomography(CT)at the 10-yearsur veillance. Chemotherapy with mFOLFOX6+bevacizumab was initiated because the peritoneal recurrence was determined to be unresectable and because of the metastasis to the thyroid. Chemotherapy was maintained, except for oxaliplatin(L-OHP)due to toxicity, with shrinkage of the peritoneal tumor; however, it was difficult to maintain the chemotherapy due to toxicity. Eleven months after initiation of chemotherapy, lung and bone metastases were detected, and she subsequently died.

Topics: Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Staging; Recurrence

MicroRNA (miR)-21 is overexpressed in most solid tumors and a high expression of miR-21 in tumor tissue is associated with a poor clinical outcome. The aim of this study was to clarify the association between the miR-21 expression in the tumor and the chemotherapeutic outcomes and survival for unresectable metastatic colon cancer (CC).. Formalin-fixed, paraffin-embedded (FFPE) samples of primary tumor were obtained from 32 patients who underwent primary tumor resection and received palliative chemotherapy for unresectable metastatic CC. MiR-21 was extracted from the FFPE and the expression of miR-21 was evaluated using quantitative real time-polymerase chain reaction (RT-PCR). The expression of miR-21 was calculated with 2-ΔΔCT.. A high miR-21 expression was associated with reduced progression-free survival (PFS) (p=0.0109) and tended to reduce overall survival (OS) (p=0.0675).. miR-21 expression might be a useful prognostic marker for chemotherapeutic outcome and survival in patients with unresectable metastatic CC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; MicroRNAs; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis; Real-Time Polymerase Chain Reaction

Although KRAS mutation has a predictive role in stage IV colorectal cancer (CRC) patients treated with anti-EGFR therapy, there have been controversies in the prognostic impact of KRAS mutation in stage II or III disease. The purpose of this study was to assess the prognostic impact of KRAS and BRAF mutation in patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX).. KRAS exon 2 and BRAF codon 600 were analyzed in patients with stage II and III CRC who underwent curative resection followed by adjuvant FOLFOX. Clinicopathologic features and disease-free survival (DFS) were compared.. Among a total of 437 patients, mutational data of KRAS and BRAF were available in 388 and 433 patients, respectively. KRAS mutation (codon 12 and 13) and BRAF V600E mutation was found in 26.5 and 3.7 % of patients. DFS was significantly worse in the KRAS mutant patients compared to KRAS wild type patients (3-year DFS 79 and 92 %, p = 0.006). Multivariate analysis revealed KRAS mutation as an independent negative prognostic factor for DFS (adjusted hazard ratio 2.30, 95 % confidence interval 1.23-4.32). Among the various subtypes of KRAS mutation, G13D (3-year DFS 76 %, p = 0.008) was significantly associated with poor DFS, while G12D was not associated with prognosis (3-year DFS 86 %, p = 0.61). There was no association between BRAF mutation and DFS.. KRAS mutation has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Mutation; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Survival Rate

The purpose of this study was to elucidate the effect of decreased muscle mass on the toxicity and survival of patients with colon cancer treated with adjuvant chemotherapy after surgery.. We reviewed the data of 229 consecutive patients with stage III colon cancer who received adjuvant oxaliplatin, 5-fluorouracil, and leucovorin chemotherapy at a single center between 2003 and 2010. Baseline muscle mass was assessed by measuring the cross-sectional area of the psoas muscle at the level of the fourth lumbar vertebra on computed tomography images. Effects of muscle mass on toxicity of chemotherapy and survival were assessed.. The median age of the 229 patients was 61 years (range, 28-80) and 134 (58.5 %) were men. The mean psoas muscle mass index (PI, psoas muscle area divided by height(2) [mm(2)/m(2)]) was 548.3. A 1 SD decrement in the PI was associated with an increase in all grade 3-4 toxicities in univariate (OR = 1.69, 95 % CI = 1.18-2.27) and multivariate (OR = 1.56, 95 % CI = 1.05-2.38) analyses. In univariate analysis, the PI was not associated with overall survival. However, multivariate analysis showed that a 1 SD decrement in the PI increased the hazard of overall mortality by 85 % (HR = 1.85, 95 % CI = 1.10-3.13). This effect of the PI on mortality was maintained in subgroup analyses, especially in older and obese patients.. Decreased muscle mass was associated with increased risk of grade 3-4 toxicity and poor prognosis in patients with stage III colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Muscle, Skeletal; Obesity; Organoplatinum Compounds; Oxaliplatin; Sarcopenia

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Combinations; Female; Humans; Leucovorin; Male; Oxonic Acid; Tegafur; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Combinations; Female; Humans; Leucovorin; Male; Oxonic Acid; Tegafur; Uracil

In Thailand, there has been no economic evaluation study of adjuvant chemotherapy for stage III colon cancer patients after resection.. This study aims to evaluate the cost-utility of all chemotherapy regimens currently used in Thailand compared with the adjuvant 5-fluorouracil/leucovorin (5-FU/LV) plus capecitabine as the first-line therapy for metastatic disease in patients with stage III colon cancer after resection.. A cost-utility analysis was performed to estimate the relevant lifetime costs and health outcomes of chemotherapy regimens based on a societal perspective using a Markov model.. The results suggested that the adjuvant 5-FU/LV plus capecitabine as the first-line therapy for metastatic disease would be the most cost-effective chemotherapy.. The adjuvant FOLFOX and FOLFIRI as the first-line treatment for metastatic disease would be cost-effective with an incremental cost-effectiveness ratio of 299,365 Thai baht per QALY gained based on a societal perspective if both prices of FOLFOX and FOLFIRI were decreased by 40%.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Markov Chains; Middle Aged; Neoplasm Staging; Quality-Adjusted Life Years; Thailand

We conducted a prospective, observational study of aspirin and COX-2 inhibitor use and survival in stage III colon cancer patients enrolled in an adjuvant chemotherapy trial. Among 799 eligible patients, aspirin use was associated with improved recurrence-free survival (RFS) (multivariable hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.28 to 0.95), disease-free survival (DFS) (HR = 0.68, 95% CI = 0.42 to 1.11), and overall survival (OS) (HR = 0.63, 95% CI = 0.35 to 1.12). Adjusted HRs for DFS and OS censored at five years (in an attempt to minimize misclassification from noncancer death) were 0.61 (95% CI = 0.36 to 1.04) and 0.48 (95% CI = 0.23 to 0.99). Among 843 eligible patients, those who used COX-2 inhibitors had multivariable HRs for RFS, DFS, and OS of 0.53 (95% CI = 0.27 to 1.04), 0.60 (95% CI = 0.33 to 1.08), and 0.50 (95% CI = 0.23 to 1.07), and HRs of 0.47 (95% CI = 0.24 to 0.91) and 0.26 (95% CI = 0.08 to 0.81) for DFS and OS censored at five years. Aspirin and COX-2 inhibitor use may be associated with improved outcomes in stage III colon cancer patients.

Topics: Adult; Age Factors; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Aspirin; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Cyclooxygenase 2 Inhibitors; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Odds Ratio; Prospective Studies; Sex Factors; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disseminated Intravascular Coagulation; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

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

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

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

Adjuvant chemotherapy improves survival in Dukes C colon cancers post-curative resection. However, the evidence for a role with Dukes B lesions remains unproven despite frequent use for disease characterized by poor prognostic features. In view of limited Asia-specific data, this study aimed to determine survival outcomes and identify prognostic factors in a tertiary teaching hospital in Malaysia.. A total of 116 subjects who underwent curative surgery with and without adjuvant chemotherapy for Duke B and C primary colon adenocarcinomas diagnosed from 2004-2009 were recruited and data were collected retrospectively. Five-year overall survival (OS) and disease free survival (DFS) were analysed using Kaplan-Meier survival analysis and log-rank (Mantel-Cox) test. Prognostic factors were determined using Cox proportional hazards regression with both univariate and multivariate analyses.. The survival analysis demonstrated a 5-year OS of 74.0% for all patients, with 74.9% for Dukes C subjects receiving chemotherapy compared to 28.6% in those not receiving chemotherapy (p=0.001). For Dukes B disease, the 5-year survival rate was 82.6% compared to 75.0% for subjects receiving and not receiving chemotherapy, respectively (p=0.17). Independent prognostic factors identified included a CEA level more than 3.5 ng/ml (hazard ratio (HR)=4.78; p=0.008), serosal involvement (HR=3.75; p=0.028) and completion of chemotherapy (HR= 0.20; p=0.007).. In a regional context, this study supports current evidence from the West that adjuvant chemotherapy improves survival in Dukes C colon cancers post curative surgery. However, although a clear benefit has yet to be proven for Dukes B disease, our results suggest survival improvement in selected cases.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Lymphatic Metastasis; Malaysia; Male; Middle Aged; Neoplasm Grading; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Postoperative Period; Prognosis; Retrospective Studies; Survival Rate; Young Adult

Although adjuvant chemotherapy is a standard treatment in stage III colon cancer, its benefit is not as clear for stage II patients. In this retrospective analysis, we aimed to evaluate the survival of patients with low-risk stage II colon cancer, the efficacy of adjuvant chemotherapy in high-risk stage II colon cancer patients, and prognostic factors in stage II disease.. One hundred and seventeen patients who were diagnosed with stage II colon cancer between January 2006 and December 2011 were included in the study. Patients were stratified into two groups as being low-risk and high-risk according to risk factors for stage II disease. Adjuvant 5-fluorouracil-based chemotherapy were administered to the patients with risk factors.. Ninety-four patients were treated with adjuvant chemotherapy due to high risk factors and 23 were monitored without treatment. Median follow-up time was 43 months. In terms of disease free survival and overall survival, adjuvant chemotherapy did not provide a statistically significant difference. Univariate analysis demonstrated that bowel obstruction was the major risk factor for shortened disease-free survival, while bowel perforation and perineural invasion were both negative prognostic factors for overall survival.. The recommendation of adjuvant chemotherapy for stage II colon cancer is not clear. In our study, it was found that adjuvant chemotherapy did not contribute to survival in high-risk stage II patients. Due to the fact that prognosis of stage II patients is good, many more patients will be needed for statistically significant differences in survival. Adjuvant chemotherapy containing 5 fluorouracil is being used to high-risk stage II patients although it is not a standard treatment approach.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Prognosis; Retrospective Studies; Risk Factors; Severity of Illness Index; Survival Rate; Turkey

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Panitumumab

We report a case of an 83-year-old woman who developed tumor lysis syndrome (TLS) 5 days after FOLFIRI+cetuximab (Cmab) therapy. A huge ascending colon cancer measuring 10 cm in diameter and with peritoneal dissemination was diagnosed. Following successful therapy with FOLFIRI alone, FOLFIRI+Cmab was administered. On day 5, TLS was diagnosed with hyperuricemia, hyperkalemia, hyperphosphatemia, and an increase in serum creatinine. Intravenous furosemide, volume loading, and glucose-insulin therapy resulted in improvement of laboratory data in 2 days. However, she died on the 34th day due to multiple organ failure caused by aspiration pneumonia following small intestine functional ileus. Although TLS is a rare complication in colon cancer, its onset must be taken into consideration. Also, risk assessment and preventive therapy for TLS should be performed before cancer treatment.

Topics: Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colon, Ascending; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Tumor Lysis Syndrome

Given the paucity of information on dose intensity, the objective of this study is to describe the use of adjuvant chemotherapy for stage III colon cancer, focusing on relative dose intensity (RDI), overall survival (OS) and disease-free survival (DFS).. Retrospective cohort of 367 patients diagnosed with stage III colon cancer in 2003-2008 and treated at 19 VA medical centers. Kaplan-Meier curves summarize 5-year OS and 3-year DFS by chemotherapy regimen and RDI, and multivariable Cox proportional hazards regression was used to model these associations.. 5-fluorouracil/leucovorin (FU/LV) was the most commonly initiated regimen in 2003 (94.4%) and 2004 (62.7%); in 2005-2008, a majority of patients (60%-74%) was started on an oxaliplatin-based regimen. Median RDI was 82.3%. Receipt of >70% RDI was associated with better 5-year OS (p < 0.001) and 3-year DFS (P = 0.009) than was receipt of ≤70% RDI, with 5-year OS rates of 66.3% and 50.5%, respectively and 3-year DFS rates of 66.1% and 52.7%, respectively. In the multivariable analysis of 5-year OS, oxaliplatin + 5-FU/LV (versus 5-FU/LV) (HR = 0.55; 95% CI = 0.34-0.91), >70% RDI at the first year (HR = 0.58; 95% CI = 0.37-0.89) and married status (HR = 0.66; 95% CI = 0.45-0.97) were associated with significantly decreased risk of death, while age ≥75 (versus 55-64) (HR = 2.06; 95% CI = 1.25-3.40), Charlson Comorbidity Index (HR = 1.17; 95% CI = 1.06-1.30), T4 tumor status (versus T1/T2) (HR = 5.88; 95% CI = 2.69-12.9), N2 node status (HR = 1.68; 95% CI = 1.12-2.50) and bowel obstruction (HR = 2.32, 95% CI = 1.36-3.95) were associated with significantly increased risk. Similar associations were observed for DFS.. Patients with stage III colon cancer who received >70% RDI had improved 5-year OS. The association between RDI and survival needs to be examined in studies of adjuvant chemotherapy for colon cancer outside of the VA.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Risk Factors; Survival Analysis; Treatment Outcome; Veterans

FOLFOX-based adjuvant chemotherapy is a benefit for high-risk stage II and stage III colon cancer after curative resection. But, the prognostic factor or predictive marker for the efficacy of FOLFOX remains unclear. This study was aimed to identify the prognostic value and cumulative impact of adjuvant FOLFOX on the stage II and III colon cancer patients.. A total of 196 stage II and III colon cancer patients were retrospectively enrolled in prospectively collected data. They underwent curative resection followed by FOLFOX4 adjuvant chemotherapy. The oncological outcomes included the 5-year disease-free survival (DFS) rate and 5-year overall survival (OS) rate. Cox-regression analysis was performed to identify the prognostic value, and its cumulative impact was analyzed.. The 5-year DFS rate of the patients was 71.94% and the 5-year OS rate was 81.5%. The prognostic values for the 5-year DFS rate and 5-year OS rate were T4 stage and preoperative anemia in a multivariate analysis. Each patient group who had no prognostic value, single, or both factors revealed 95.35%, 69.06%, and 28.57% in the 5-year DFS rate, respectively (p < 0.0001). The 5-year OS rate also showed the significant differences in each group who had no prognostic value, single, or both factors revealed 100%, 79.3%, and 45.92%, respectively (p < 0.0001).. Our results showed similar efficacy to MOSAIC study in stage II and stage III colon cancer patients treated with adjuvant FOLFOX chemotherapy after curative resection. Patients who had T4 stage and/or preoperative anemia showed worse prognosis than patients without any prognostic value. These findings suggest that FOLFOX could not be effective in the patients with T4 stage colon cancer accompanied by preoperative anemia.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Preoperative Care; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

A 72-year-old woman was admitted to our hospital because of muscle weakness and was diagnosed as having polymyositis. Whole-body evaluation revealed advanced transverse colon cancer, and we therefore considered it likely that the patient had paraneoplastic myositis. We performed a curative surgical resection for colon cancer, after which her serum creatine phosphokinase(CPK)level greatly decreased. Steroid therapy was administered postoperatively. However, her CPK levels remained persistently high, even after steroid pulse therapy, and we considered that this was due to steroid-resistance myositis. We administered chemotherapy for colon cancer using 5-fluorouracil plus Leucovorin(5-FU/LV), after which the CPK levels gradually decreased. There have been few previous reports of polymyositis associated with colon cancer and a standard treatment for paraneoplastic myositis has not been established. Most clinicians believe that treatment of the primary tumor may contribute to an improvement of myositis, and in our case, tumor resection and chemotherapy were effective.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colon, Transverse; Colonic Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Polymyositis

A 71-year-old female patient underwent urgent laparotomy due to severe right lower quadrant abdominal pain and fever. Macroscopically duplex coecal and transverse colon cancer as well as a sigmoid or left ovarian cancer were suspected. Pathological findings revealed synchronous left ovarian and transverse colonic neoplasms. Both primaries metastatized to their regional lymph nodes. Furthermore, the ovarian cancer infiltrating the sigmoid colon gave distant metastasis in the coecum, too. Ovarian cancer histology showed papillary adenocarcinoma, and transverse colon cancer was a tubular adenocarcinoma. The affected lymph nodes were clearly distinguished by immunohistochemistry staining: ovarian metastases were CK7 positive, and colonic metastases were CK20 and CEA positive. The patient was treated with combinated chemotherapy: FOLFOX-4 two weekly and paclitaxel monotherapy every other week. The patient tolerated this combined treatment well. The authors conclude that multiple synchronous neoplasms can be treated with individualized chemotherapeutic protocol with good efficacy and few adverse reactions.

Topics: Abdominal Pain; Adenocarcinoma; Adenocarcinoma, Papillary; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Colonic Neoplasms; Drug Administration Schedule; Female; Fever; Fluorouracil; Humans; Immunohistochemistry; Keratin-20; Keratin-7; Laparotomy; Leucovorin; Lymphatic Metastasis; Neoplasms, Multiple Primary; Organoplatinum Compounds; Ovarian Neoplasms; Paclitaxel; Precision Medicine; Treatment Outcome

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

Studies have demonstrated that patients with stage III colon cancer who receive adjuvant FOLFOX (5-fluorouracil and oxaliplatin) chemotherapy experience an improved disease-free (DFS) and overall survival (OS). However, the magnitude of benefit among patients who discontinue FOLFOX early is not well known. We sought to examine the rate of FOLFOX treatment completion, determine the factors associated with adherence, and explore the relationship between duration of FOLFOX treatment and survival.. We analyzed patients diagnosed with stage III colon cancer from 2006 to 2010 and initiated at least 1 cycle of adjuvant FOLFOX at any 1 of 5 regional cancer centers in British Columbia. Logistic regression models were constructed to determine the clinical factors associated with treatment completion, which was defined as receipt of ≥ 10 cycles of FOLFOX. Kaplan-Meier methods and Cox regression that accounted for known prognostic factors were used to evaluate the relationship between early FOLFOX discontinuation and DFS and OS.. We identified 616 patients: median age of 62 years (range, 26-80), 321 (52%) men, 536 (87%) with T3/4 tumors, and 245 (40%) with N2 disease. Among them, 183 (30%) received < 10 and 433 (70%) received ≥ 10 cycles. Adjusting for covariates, female sex and the absence of obstruction or perforation were each associated with receiving ≥ 10 cycles of FOLFOX (odds ratio [OR], 1.61; 95% confidence interval [CI], 1.12-2.32; P = .01 and OR, 1.82; 95% CI, 1.08-3.05; P = .02, respectively). In multivariate analyses, early discontinuation of FOLFOX did not affect DFS or OS (hazard ratio [HR], 1.16; 95% CI, 0.82-1.63; P = .40 and HR, 1.07; 95% CI, 0.70-1.61; P = .76, respectively).. Early discontinuation of FOLFOX was not associated with differences in survival outcomes, lending support to clinical trials that are under way to evaluate the efficacy of shorter durations of therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; British Columbia; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Logistic Models; Male; Medication Adherence; Middle Aged; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Proportional Hazards Models; Sex Factors; Survival Rate; Time Factors; Treatment Outcome

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Cryptogenic Organizing Pneumonia; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Lung Diseases, Interstitial; Male; Organoplatinum Compounds

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

Epithelial cell adhesion molecule (EpCAM) is known to be overexpressed in epithelial cancers associated with enhanced malignant potential, particularly colorectal carcinoma (CRC) and head and neck squamous cell carcinoma (HNSCC). However, it is unknown whether progression of malignance can be directly inhibited by targeting EpCAM. Here, we have generated five novel monoclonal antibodies (mAbs) against EpCAM. One of these anti-EpCAM mAbs, EpAb2-6, was found to induce cancer cell apoptosis in vitro, inhibit tumor growth, and prolong the overall survival of both a pancreatic cancer metastatic mouse model and mice with human colon carcinoma xenografts. EpAb2-6 also increases the therapeutic efficacy of irinotecan, fluorouracil, and leucovorin (IFL) therapy in a colon cancer animal model and gemcitabine therapy in a pancreatic cancer animal model. Furthermore, EpAb2-6, which binds to positions Y95 and D96 of the EGF-II/TY domain of EpCAM, inhibits production of EpICD, thereby decreasing its translocation and subsequent signal activation. Collectively, our results indicate that the novel anti-EpCAM mAb can potentially be used for cancer-targeted therapy.

Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Camptothecin; Cell Adhesion Molecules; Cell Line, Tumor; Cell Survival; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Epithelial Cell Adhesion Molecule; Flow Cytometry; Fluorouracil; HCT116 Cells; Humans; Irinotecan; Leucovorin; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Vitamin B Complex; Xenograft Model Antitumor Assays

The aim of this study was to examine the specific chemoregimens selected for adjuvant therapy in the patients with stage III colon cancer. We investigated the trends in chemotherapeutic prescribing patterns and looked for adequate therapeutic setting for these patients.. 288 patients presenting with stage III colon cancer and undergoing adjuvant therapies after curative surgery for more than 3-month were enrolled between January 2006 and December 2011. Demographic characteristics and therapeutic factors were analyzed, including age, gender, histological grade, tumor sizes, tumor location, pathologic stage, performance status, serum carcinoembryonic antigen, regimens selection, interval from the operation to the start of adjuvant therapy and prolonged adjuvant therapy. Kaplan- Meier methods were utilized for drawing survival curves and Cox model was used to analyze survival, prognostic factors.. The analysis showed that the patients aged under 70 received more intensive therapies than those aged over 70 (P<0.001). Later, advanced analysis in therapeutic factors was conducted between the patients aged under 70 and those over 70. In the patients aged under 70, significant differences in 4-year overall survival (OS) were noted between UFUR (oral tegafur-uracil plus leucovorin) groups and FOLFOX (5-FU plus oxaliplatin) [65.6% versus (vs) 89.8%, relative risk (RR) 3.780, 95% confidence interval (CI) 1.263-11.315, P = 0.017]. There were also differences in 4-year OS between these patients with and without oxaliplatin-contained regimens (92.1% vs 83.4%, respectively, RR 0.385, 95% CI 0.157-0.946, P = 0.037). In addition, the patients who received intravenous or combined therapy also had higher 4-year OS than those only received oral regimens (92.1% vs 76.6%, P = 0.077), though the finding did not reach statistical significance. In contrast to the survival benefits of above therapeutic settings for the patients aged under 70, there was less advantage in the old patients when they received intensive therapies or even oxaliplatin-contained regimens. Prolonged cycles of adjuvant therapy resulted in no significant benefit to survival rates regardless of ages.. The adequate individualized therapeutic strategy plays an important role for stage III colon cancer. Our findings suggested that benefit of oxaliplatin-contained therapy is limited to patients aged under 70 and oral fluoropyrimidines may be an effective option for old patients. In addition, prolonged adjuvant setting is suggested to be unbeneficial for managing stage III colon cancer.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Precision Medicine; Prognosis; Retrospective Studies; Tegafur

Gastric cancer frequently disseminates to the liver, lung, and bone via hematogeneous, lymphatic, or peritoneal routes. However, gastric adenocarcinoma that metastasize to the colon and that shows typical linea platisca pattern on colonofiberscopy has rarely been reported. Recently, the authors experience a case of advanced gastric cancer with colonic metastases in a 55-year-old female patient. Multiple colonic lymphoid hyperplasias were detected on colonofiberscopy and biopsy revealed metastatic gastric cancer to the colonic wall. She was treated with mFOLFOX (5-FU, oxaliplatin, leucovorin) and has achieved stable disease status without disease progression. Herein, we report a rare case of signet ring-cell gastric cancer which metastasized to the colon in the form of multiple colonic lymphoid hyperplasias.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Gastroscopy; Humans; Hyperplasia; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Stomach Neoplasms; Tomography, X-Ray Computed

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

To analyze the impact of platelet count on the prognosis of stage II-III colorectal cancer receiving adjuvant chemotherapy.. Clinical and follow-up data of 286 patients with stage II-III colorectal cancer receiving adjuvant FOLFOX chemotherapy from March 2003 to October 2011 were analyzed retrospectively. Associations of baseline blood platelet count before chemotherapy and nadir blood platelet count during chemotherapy with relapse and death after adjuvant chemotherapy were analyzed by ROC curve and the optimal cutoff was selected. The association of the blood platelet count and the prognosis was analyzed by Kaplan-Meier and Cox regression model.. ROC curve showed the baseline blood platelet count was associated with recurrence (AUC=0.588, P=0.034). The optimal cutoff affecting recurrence was 276×10(9)/L. Kaplan-Meier showed those with baseline platelet count >276×10(9)/L receiving adjuvant chemotherapy had worse disease free survival (DFS) than those with baseline platelet count ≤276×10(9)/L, whose 5-year disease free survival(DFS) was 66% and 80% respectively (P=0.013). Cox regression analysis revealed baseline platelet count >276×10(9)/L was an independent unfavorable factor for DFS of adjuvant chemotherapy in colorectal cancer (HR=1.865, 95% CI: 1.108-3.141, P=0.019).. Colorectal cancer patients receiving adjuvant chemotherapy with baseline platelet count >276×10(9)/L have worse prognosis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Platelet Count; Prognosis; Recurrence; Retrospective Studies

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 report a case of aggressive resection of synchronous and asynchronous peritoneal dissemination of colon cancer, including metastasis to the inguinal hernia sac. A 68-year-old man who was examined for anemia was diagnosed with ascending colon cancer. He underwent right hemicolectomy and resection of the disseminated tumors at the omentum and peritoneum near the Treitz ligament (moderately differentiated tubular adenocarcinoma, pT4a [SE] N0M1P2H0, stageⅣ). After 1 year 6 months, he was readmitted for intestinal obstruction due to the recurrence of peritoneal dissemination, and underwent partial resection of the ileum, liver, and right kidney. In the CT scan examination before surgery, right inguinal hernia and tumor were identified, and hernioplasty with resection of the inguinal tumor was subsequently performed after intestinal obstruction resolution. All tumors were identified as peritoneal dissemination of the colon cancer tumors by pathological examination. After surgery, he was treated with mFOLFOX6 for 6 months and survived without signs of recurrences despite the absence of treatment. Even in cases of peritoneal recurrence of colon cancer, aggressive resection may improve the prognosis in some cases.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Fluorouracil; Hernia, Inguinal; Humans; Leucovorin; Male; Organoplatinum Compounds; Peritoneal Neoplasms; Recurrence

5-Fluorouracil (5-FU) is commonly administered as a therapeutic agent for the treatment of various aggressive cancers. Severe toxic reactions to 5-FU have been associated with decreased levels of dihydropyrimidine dehydrogenase (DPD) enzyme activity. Manifestations of 5-FU toxicity typically include cytopenia, diarrhea, stomatitis, mucositis, neurotoxicity, and, in extreme cases, death. A variety of genetic variations in DPYD, the gene encoding DPD, are known to result in decreased DPD enzyme activity and to contribute to 5-FU toxic effects. Recently, it was reported that healthy African American individuals carrying the Y186C DPYD variant (rs115232898) had significantly reduced DPD enzyme activity compared with noncarriers of Y186C. Herein, we describe for the first time, to our knowledge, an African American patient with cancer with the Y186C variant who had severe toxic effects after administration of the standard dose of 5-FU chemotherapy. The patient lacked any additional toxic effect-associated variations in the DPYD gene or the thymidylate synthase (TYMS) promoter. This case suggests that Y186C may have contributed to 5-FU toxicity in this patient and supports the use of Y186C as a predictive marker for 5-FU toxic effects in individuals of African ancestry.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Black or African American; Colonic Neoplasms; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Fatal Outcome; Female; Fluorouracil; Genetic Markers; Heat-Shock Proteins; Humans; Leucovorin; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Peptide Fragments; Polymorphism, Genetic; Precision Medicine; Stomatitis

A 64-year-old woman presented to our hospital with subcutaneous tumors in the right thoracic region. After undergoing a thorough medical evaluation, she was diagnosed with multiple skin metastases arising from cancer of the descending colon. Surgical resection of the primary lesion was performed and FOLFIRI (5-fluorouracil, levofolinate calcium, irinotecan) and cetuximab chemotherapy for the metastases was initiated. The patient subsequently entered remission and did not experience any major side effects. This case report details an effective therapy for colon cancer with multiple skin metastases and presents a discussion of the expression profiles of epidermal growth factor receptor in both the primary and metastatic lesions.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Skin Neoplasms

The treatment of metastatic colon cancer (mCC) utilizes either combination therapies or sequential monotherapy followed by combination therapy in subsequent lines of treatment. Patients often receive therapy consisting of oxaliplatin with intravenous 5-fluoruacil (5-FU) (FOLFOX) or oral capecitabine (CAPOX). A retrospective analysis was performed comparing median dose intensity (MDI), overall survival (OS), progression-free survival (PFS), and toxicity profiles of these two regimens in mCC.. One hundred twenty-two mCC patients (pts) received either FOLFOX6 (n = 46) or CAPOX (n = 76). Age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis were balanced between groups. MDI was compared by calculating a percent of target dose achieved in the average cycle for each patient and taking the median of this value.. Oxaliplatin MDI trended towards being lower in those treated with CAPOX compared to FOLFOX (87.5 vs 93 %, p = 0.0874), and capecitabine (CA) MDI was significantly lower than 5-FU (82.0 vs 100 %, p < 0.0001). There was a trend to more dose-limiting toxicities (DLTs) in pts treated with CAPOX (68.42 vs 54.35 %, p = 0.1268), and grade ≥ 2 toxicities were more frequent in CAPOX-treated pts (38.16 vs 15.22 % of patients, p = 0.0079). Survival analysis demonstrated trends towards improved median OS (9.86 vs 7.46 months, p = 0.1183) and median PFS (4.34 vs 3.33 months, p = 0.1674) with CAPOX. In multivariate analysis, CAPOX was associated with improved OS (p = 0.0156, hazard ratio (HR) 0.559) and disease-free survival (DFS) (p = 0.0094, HR 0.549).. Patients treated with CAPOX received lower doses of oxaliplatin and fluoropyrimidine compared to FOLFOX and had toxicities of higher grade but did not have worsened clinical outcomes.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Retrospective Studies; Survival Rate

The usefulness of oxaliplatin(L-OHP)as adjuvant chemotherapy for Stage III colon cancer has been shown in clinical trials, such as the MOSAIC trial. The Leucovorin, fluorouracil, and oxaliplatin(FOLFOX)regimen has been recommended as adjuvant chemotherapy for colorectal cancer in Japan. In the MOSAIC trial, 74.7% of patients completed all planned treatment cycles. Neurological toxicity caused byL -OHP is one of the factors for discontinuing treatment. Therefore, we planned to administer FOLFOX4 as postoperative adjuvant chemotherapy and evaluated the safety and feasibility of this regimen.. From November 2009, 13 patients with Stage III colon cancer who had undergone complete resection of a primary tumor were enrolled. Patients received 4 cycles of FOLFOX4, followed by 4 cycles of the simplified fluorouracil and Leucovorin (LV5FU2)regimen and 4 additional cycles of FOLFOX4(12 cycles in total).. Thirteen patients were treated with our FOLFOX4 regimen. In total, 11 patients(84.6%)completed all 12 planned treatment cycles. The median L-OHP dose per patient was 560mg/m / 2(compared with the per-protocol 12-cycle dose of 680 mg/m2). Grade 1 neurological toxicity during treatment was reported in 10 patients(76.9%). Neurological toxicity was reduced during the 4 cycles without L-OHP.. Our FOLFOX4 regimen showed reduced neurological toxicity compared to other trials and can be used safely.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Patient Compliance

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Phytogenic; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Middle Aged; Platelet Count; Thrombocytopenia

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

Chemotherapy can induce cognitive impairment in cancer patients. The main goal of this longitudinal study was to determine the incidence, characteristics, and duration of cognitive dysfunction in patients treated with adjuvant chemotherapy for colon cancer.. We assessed cognitive function, quality of life, anxiety and depression, fatigue, and hemoglobin levels in colon cancer patients at three assessment points: pre-chemotherapy (n=81), post-chemotherapy (n=73), and after 6-month follow-up (n=54). All patients were treated with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX4) for 6 months.. Thirty patients (37%) had cognitive impairment in the pre-chemotherapy evaluation, mainly in processing speed and psychomotor executive function (Trail Making Test A and B). At the end of treatment, the main domain affected was the verbal memory, with an acute decline detected in 56% of patients. Fifty-four percent of the patients improved their dysfunction after 6 months of follow-up, whereas 18 (33%) of them showed worsening in at least one test. Cognitive impairment was most common in older patients and in those with less years of education. Quality of life, anxiety, depression, fatigue, and hemoglobin did not influence the results of the cognitive tests.. Adjuvant FOLFOX4 in patients with colon cancer can have a negative effect on verbal memory. This deterioration is usually mild and transient.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cognition; Cognition Disorders; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Longitudinal Studies; Male; Memory; Middle Aged; Organoplatinum Compounds; Oxaliplatin

Adjuvant treatment of colon cancer relies on fluoropyrimidine-containing regimens as the intravenous formulation, 5-FU, or its oral prodrug, CA, combined with oxaliplatin (FOLFOX and CAPOX). There is currently no clinical trial comparing the 2 regimens; however, both are considered standard of care treatment options.. We performed a retrospective chart review comparing average relative dose intensity (ARDI), percentage of intended total dose (PITD), overall survival (OS), DFS, and toxicity profiles of these regimens. The patients (n = 176) received either modified FOLFOX6 (n = 93) or CAPOX (n = 83).. Oxaliplatin ARDI (80.72% vs. 87.11%; P = .0033) and PITD (70.09% vs. 88.11%; P = .0013) was significantly lower in those treated with CAPOX compared with FOLFOX. CA ARDI (87.10% vs. 93.60%; P < .0001) and PITD (77.19% vs. 88.11%; P = .0006) was significantly lower than 5-FU dosing. Patients treated with CAPOX had more ≥ Grade 2 toxicities and trended toward more dose-limiting toxicities. Survival analysis demonstrated a trend toward improved OS with CAPOX (hazard ratio [HR], 0.4741; 95% confidence interval [CI], 0.1660-1.354; P = .1663) and improved DFS with CAPOX (HR, 0.4949; 95% CI, 0.2512-0.9749; P = .0420). Multivariate analysis demonstrated similar results with CAPOX being associated with a trend toward improved OS (HR, 0.396; 95% CI, 0.110-1.429; P = .1571) and DFS (HR, 0.458; 95% CI, 0.210-1.001; P = .0504).. Patients receiving CAPOX had significantly lower ARDI and PITD compared with FOLFOX, but showed trends toward improved outcomes when treated with CAPOX in the adjuvant setting when compared with FOLFOX.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Survival Rate

Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice.. Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model.. There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439).. Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Colonic Neoplasms; Digestive System Diseases; Female; Fluorouracil; Follow-Up Studies; France; Hematologic Diseases; Humans; Incidence; Leucovorin; Male; Neoplasm Staging; Nervous System Diseases; Organoplatinum Compounds; Oxaliplatin; Prognosis; Survival Rate

Cancer patients not admissible for adjuvant chemotherapy are generally at high risk of considerably inferior prognosis. The aim of this retrospective study was to evaluate poorer survival without administration of oral adjuvant chemotherapy of stage III colon cancer patients in clinical settings.. Between April 2007 and September 2011, 259 patients with stage III colon cancer who underwent curative surgery were retrospectively assigned to the adjuvant chemotherapy group of 171 patients (66%) and the surgery alone group of 88 patients. Oral fluorouracil (5-FU) derivatives used in adjuvant chemotherapy, such as oral uracil and tegafur plus leucovorin (UFT/LV) or capecitabine, were the most commonly used.. The 3-year relapse-free survival (RFS) rates were 74.9% for all cases, 58.3% for the surgery alone group, and 83.4% for the adjuvant chemotherapy group (P=0.0001). The chemotherapy group was associated with a dramatic improvement in survival for stage IIIB (surgery alone 57.7% versus adjuvant chemotherapy 83.9%; P=0.0001) and stage IIIC (surgery alone 18.2% versus adjuvant chemotherapy 57.3%; P=0.006) patients. There was a significant difference in the overall recurrence rate between groups (surgery alone 35.2% versus adjuvant chemotherapy 18.1%; P=0.002). Multivariate analysis identified adjuvant therapy as an independent predictive factor of reduced recurrence (hazard ratio (HR): 3.231; P=0.004) and improved RFS (HR: 2.653; P=0.001).. In clinical settings, adjuvant therapy was the only significant prognostic factor of survival. Since many patients prefer not to receive chemotherapy, it is critical to inform stage III colon cancer patients that chemotherapy raises their chances of survival by three-fold compared with curative surgery alone.

Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Retrospective Studies; Survival Rate; Tegafur; Uracil; Young Adult

A 63-year-old woman underwent surgery for Stage IV cancer of the ascending colon with multiple lymph node metastases. The pathological diagnosis was neuroendocrine carcinoma. Following first-line chemotherapy, the patient presented clinically with progressive disease (PD). Second-line chemotherapy with bevacizumab/Leucovorin and 5-fluorouracil with oxaliplatin (FOLFOX4) was effective and a partial response (PR) was achieved after 7 courses of therapy, as determined by computed tomography (CT) examination. Neuroendocrine carcinoma is known to be extremely malignant; however, this case suggests that chemotherapy with bevacizumab may improve the prognosis of this disease.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Neuroendocrine; Colon, Ascending; Colonic Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds

Therapy comprising 5-fluorouracil, levofolinate, and oxaliplatin is currently the most common chemotherapy for colorectal cancer. We experienced a successful case of advanced colon cancer and recurrent breast cancer with 5-fluorouracil, levofolinate, and oxaliplatin therapy.. A 43-year-old Japanese woman who had already undergone surgery three times for bilateral breast cancer was admitted to our hospital for the treatment of advanced transverse colon cancer. Preoperative computed tomography demonstrated a swollen lymph node at her right upper clavicle, and fine-needle aspiration biopsy of the lymph node showed that it was a metastasis from the breast cancer. A laparoscopic-assisted colectomy was performed and the pathology demonstrated that the final stage was IIIC (T4aN2aM0, Union for International Cancer Control, 7th edition). The pathological findings and immunohistochemistry showed that the transverse colon tumor was not a metastatic lesion from the breast cancer, but was a de novo colon cancer. Chemotherapy was necessary for both the recurrent breast cancer and the Stage IIIC colon cancer. Therapy of 5-fluorouracil, levofolinate, and oxaliplatin was administered; the therapy included 5-fluorouracil, which is considered to be effective for both colon and breast cancer. After two courses of 5-fluorouracil, levofolinate, and oxaliplatin, the lymph node began to shrink and almost completely disappeared after eight courses of 5-fluorouracil, levofolinate, and oxaliplatin.. We surmise that 5-fluorouracil, levofolinate, and oxaliplatin have the potential to provide a good response for tumors that are sensitive to fluorinated pyrimidine and platinum-containing anticancer drugs such as breast cancer.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymph Nodes; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Organoplatinum Compounds; Treatment Outcome

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

Adjuvant folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Neutropenia, however, is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose-limiting toxicities and relative dose intensity of oxaliplatin and 5-FU, on relapse-free and overall survival in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer.. A chart review was conducted on patients treated at the British Columbia Cancer Agency receiving ≥1 cycle of mFOLFOX6 chemotherapy for resected stage II or III colon cancer between January 1, 2006, and December 31, 2007. Relapse-free survival (RFS) and overall survival (OS) were analyzed by the Kaplan-Meier method.. One hundred fourteen patients (median age 59 years, 44 % male, 98 % stage III, median follow-up 5.2 years) were included. Ninety percent of the patients experienced any dose-limiting toxicity (DLT), while 58 % of the patients had a neutropenia-related DLT. There were no documented episodes of FN. Granulocyte colony-stimulating factor (GCSF) was used in 10 % of the patients. Median relative dose intensity (RDI) was 81 and 85 % for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variables or categorically. Grade II or grade III/IV neutropenia compared to no neutropenia was not associated with RFS or OS.. DLTs affect the majority of patients on adjuvant FOLFOX for high-risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Prognosis; Retrospective Studies; 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

The pattern of adjuvant chemotherapy (AC) use, toxicity profile, and survival benefit in elderly patients with colon cancer (CC) is unclear. We sought to (1) determine whether patients ≥ 65 years with stage III CC were offered single-agent or combination AC, (2) evaluate the reason for selecting single-agent versus combination AC, (3) evaluate the toxicity profile of single-agent and combination AC in the elderly, and (4) determine whether a survival benefit exists for elderly patients receiving combination AC.. A retrospective analysis of records of patients ≥ 65 years diagnosed with stage III CC from 2004 to 2010 was performed to identify baseline characteristics, AC protocols, toxicity, dose intensity, and survival.. Two hundred sixty-eight patients ≥ 65 years were diagnosed and treated with AC from 2004 to 2010. Of these patients, 178 were treated with single-agent AC and 90 were treated with combination AC. The most common reasons for choosing single-agent AC were patient preference, comorbidities, and lack of drug coverage. For each year over 65 years, the odds of receiving combination over single-agent AC decreased by 22%. There were more dose delays, dose reductions, and early chemotherapy discontinuation in the combination AC group because of hematologic toxicity. The 5-year overall survival (OS) was 73% in patients who received single-agent AC compared with 84% in those who received combination AC. There was no difference in cancer-related deaths between the groups.. In elderly patients treated with AC for stage III CC, single-agent AC is used more frequently than combination AC, based on age, comorbidities, and patient choice. Toxicity with combination AC in elderly patients is high. No survival benefit was seen with combination AC over single-agent AC.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Canada; Capecitabine; Chemotherapy, Adjuvant; Choice Behavior; Colonic Neoplasms; Comorbidity; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Humans; Insurance Coverage; Insurance, Pharmaceutical Services; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Patient Preference; Retrospective Studies; Survival Rate; Vitamin B Complex

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

A case is presented of a 36-year-old male with primary sclerosing cholangitis-associated inflammatory bowel disease (PSC-IBD) and two synchronous stage 1 adenocarcinomata of the colon, who was initially treated with a subtotal colectomy with ileostomy. One year later, the patient presented with extensive intra-abdominal lymphadenopathy and peritoneal carcinomatosis, as well as a markedly elevated serum level of alpha-fetoprotein (AFP). Fine needle aspiration biopsy of a porta hepatis lymph node revealed a metastatic hepatoid adenocarcinoma. Subsequent review of the previous colectomy specimen showed that one of the previously identified adenocarcinomata had features suggestive of a hepatoid colonic adenocarcinoma. The patient was subsequently treated with a cytotoxic regimen of FOLFOX (oxaliplatin, leucovorin, 5-fluorouracil) and bevacizumab, with stable results being achieved after six months. This case presents the first known report of PSC-IBD associated with synchronous typical and hepatoid adenocarcinomata of the colon and highlights the importance of considering hepatoid adenocarcinoma as a differential diagnosis in patients with an increasing serum AFP level.

Topics: Adenocarcinoma; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Cholangitis, Sclerosing; Colectomy; Colitis, Ulcerative; Colonic Neoplasms; Fluorouracil; Humans; Ileostomy; Jejunostomy; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Risk Factors; Time Factors; Treatment Outcome

To analyze factors influencing survival of patients with stage II colon cancer treated at our cancer center (Sparrow Hospital) from February 1996 through December 2006.. Survival analyses on 197 patients' age 71.1±0.9 years (29 to 97) were done using SAS system (V9.3, Cary NC). Analysis included age, gender, stage, surgery type, number of examined lymph nodes, pathological grade, tumor size and the use of adjuvant chemotherapy.. Mean follow up length was 48.1±2.3 months (0.1-133) and 56±3.3 (0.2-133) for survivors. The average number of removed lymph nodes was 18±13 (1-103). Adjuvant chemotherapy treatment (5-FU± leucovorin) was given to 49 patients, while others (148) were followed expectantly. There were 90 deaths during follow up. Only age exhibits a statistically significant relationship to survival (Hazard Ratio (HR) =1.06, 95% CI=1.03-1.08, p<0.001). Adjuvant chemotherapy possibly reduced the risk of death by 42% approaching a borderline advantage for survival (HR=0.58, CI=0.33-1.03, p=0.06. The number of removed lymph nodes also showed a possible relationship to survival (HR=0.98, CI= 0.62-1.56, p=0.07). Other investigated factors (gender, type of surgery, etc.) were not significant correlates.. In this study we found that the most important factor for survival of patients with Stage II colon cancer is the patient's age. Adjuvant chemotherapy showed a borderline significance while the number of resected lymph nodes seemed to be an important survival factor. However, in our study statistical significance was not achieved.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Agents; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Lymph Nodes; Male; Middle Aged; Neoplasm Staging; Prognosis; Survival Analysis; Survivors

To compare XELOX and FOLFOX4 as colon cancer adjuvant chemotherapy based on MOSAIC and No. 16968 trails from Chinese cost-effectiveness perspective.. A decision-analytic Markov model was developed to compare the FOLFOX4 and XELOX regimens based MOSAIC and No. 16968 trial. Five states were included in our Markov model: well (state 1), minor toxicity (state 2), major toxicity (state 3), quitting adjuvant chemotherapy (state 4), and death due to adjuvant chemotherapy (state 5). Transitions among the 5 states were assumed to be Markovian. Costs were calculated from the perspective of the Chinese health-care payer. The utility data were taken from published studies. Sensitivity analyses were used to explore the impact of uncertainty factors in this cost-effectiveness analysis.. Total direct costs of FOLFOX4 and XELOX per patient were $19884.96 ± 4280.30 and $18113.25 ± 3122.20, respectively. The total fees related to adverse events per patient during the entire treatment were $204.75 ± 16.80 for the XELOX group, and $873.72 ± 27.60 for the FOLFOX4 group, and the costs for travel and absenteeism per patient were $18495.00 for the XELOX group and $21,352.68 for the FOLFOX4 group. The base-case analysis showed that FOLFOX4 was estimated to produce an additional 0.06 in quality adjusted life years (QALYs) at an additional cost of $3950.47 when compared to the XELOX regimen over the model time horizon. The cost per QALY gained was $8047.30 in the XELOX group, which was $900.98 less than in the FOLFOX4 group ($8948.28). The one way sensitivity analysis demonstrated that the utility for the well state and minor toxicity state greatly influenced the incremental cost-effectiveness ratio of FOLFOX4.. In term of cost-comparison, XELOX is expected to dominate FOLFOX4 regimes; Therefore, XELOX provides a more cost-effective adjuvant chemotherapy for colon cancer patients in China.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; China; Clinical Trials as Topic; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Drug Costs; Female; Fluorouracil; Humans; Leucovorin; Male; Markov Chains; Middle Aged; Models, Economic; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Quality-Adjusted Life Years; Time Factors; Treatment Outcome

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

Methylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and crucial in maintaining genomic stability and expression. Their prognostic impact on colon cancer patients receiving adjuvant chemotherapy has not been well established. We evaluated the association between LINE-1 methylation status and clinicopathologic features and postoperative oncological outcomes in stage III colon cancer patients.. 129 UICC stage III colon cancer patients who had received radical resection and FOLFOX adjuvant chemotherapy were enrolled. Global methylation was estimated by analyzing tumor LINE-1 methylation status using bisulfite-polymerase chain reaction (PCR) and pyrosequencing assay. Demographics, clinicopathological data, and postoperative outcomes were recorded by trained abstractors. Outcome measurements included postoperative recurrence and disease-free survival. Univariate, multivariate, and survival analyses were conducted to identify prognostic factors of oncological outcomes.. The LINE-1 methylation of all 129 patients was measured on a 0-100 scale (mean 63.3; median 63.7, standard deviation 7.1), LINE-1 hypomethylation was more common in patients aged 65 years and above (61.7%±7.6% vs. 64.6±6.4, p=0.019) and those with post-therapeutic recurrence (61.7±7.4 vs 64.3±6.7, p=0.041). Considering risk adjustment, LINE-1 hypomethylation was found to be an independent risk factor of post-therapeutic recurrence (Adjusted OR=14.1, p=0.012). Kaplan-Meier analysis indicated that patients in the low methylation group had shorter period of disease free survival (p=0.01). In a stratified analysis that included 48 patients with post-therapeutic recurrence, it was found that those who experienced shorter period of disease free survival (≦6 months) appeared to have lower LINE-1 methylation levels than patients who reported of recurrence after 6 months (56.68±15.75 vs. 63.55±7.57, p=0.041).. There was a significantly greater risk of early postoperative recurrence and a shorter period of disease-free survival in Stage III colon cancer patients exhibiting LINE-1 hypomethylation status after being treated with radical resection and FOLFOX chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; DNA Methylation; Epigenesis, Genetic; Female; Fluorouracil; Humans; Leucovorin; Long Interspersed Nucleotide Elements; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Analysis; Treatment Outcome

The objective of this study was to evaluate the real-world cost effectiveness of adjuvant stage III colon cancer chemotherapy regimens, given that previous analyses have been based on data from clinical trials. The study was designed using integrated decision tree and Markov model, which was developed to evaluate the cost effectiveness of 5-fluorouracil/leucovorin (5-FU/LV), capecitabine, and the combination of each with oxaliplatin. The analysis was performed from a US Veterans Affairs perspective via retrospectively collected data, over a 5-year model time horizon. Outcome and cost data were used to calculate cost per quality adjusted life year (QALY), and one-way and probabilistic sensitivity analyses were performed. In the base case analysis, capecitabine and capecitabine plus oxaliplatin both cost more and were less effective than other regimens, and 5-FU/LV plus oxaliplatin, compared to 5-FU/LV alone, resulted in a cost of $25,997 per QALY gained. Model results were generally robust to parameter variation. Capecitabine plus oxaliplatin could be economically reasonable if full dosing occurred ≥76% of the time (base case 42%). In a real-world setting, the addition of oxaliplatin to 5-FU/LV is more effective but also more costly than 5-FU/LV alone. If full dosing of capecitabine-containing regimens can be assured, they may also be cost-effective strategies.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Cost-Benefit Analysis; Female; Fluorouracil; Hospitals, Veterans; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Treatment Outcome; United States; United States Department of Veterans Affairs; Veterans

This study was aimed to detect post-chemotherapeutic circulating tumour cells (CTCs) in stage III colon cancer patients and identify those who were at high risk of relapse.. We used human telomerase reverse transcriptase, cytokeratin-19, cytokeratin-20, and carcinoembryonic antigen (CEA) as the biomarkers to detect CTCs in 90 stage III colon cancer patients undergoing curative resection followed by mFOLFOX chemotherapy.. Post-chemotherapeutic relapse occurred in 30 (33.3%) patients. By univariate analysis and multivariate proportional hazards regression analysis, perineural invasion (hazard ratio (HR): 2.752; 95% confidence interval (CI): 1.026-7.381), high post-chemotherapeutic serum CEA levels (HR: 2.895; 95% CI: 1.143-7.333) and persistent presence of post-chemotherapeutic CTCs (HR: 6.273; 95% CI: 2.442-16.117) were independent predictors of post-chemotherapeutic relapse. In addition, the persistent presence of post-chemotherapeutic CTCs strongly correlated with reduced disease-free survival and overall survival. Accuracy of detecting relapse in post-chemotherapeutic stage III colon cancer patients by analysing the persistent presence of post-chemotherapeutic CTCs was higher than that by post-chemotherapeutic CEA levels (odds ratio: 50.091 vs 5.211).. The persistent presence of post-chemotherapeutic CTCs is a potential powerful surrogate marker for determining clinical outcome in stage III colon cancer patients receiving adjuvant mFOLFOX chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplastic Cells, Circulating; Organoplatinum Compounds; Prognosis; Recurrence; Treatment Outcome

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

XELOX and FOLFOX4 have both been recommended as adjuvant therapy for stage III colon cancer. This study compared the two regimens in terms of monetary costs, assuming equal efficacy of the therapies.. A retrospective financial audit was conducted of the medical records of patients treated with XELOX or FOLFOX4. All itemized expenses were classified as direct (chemotherapy, hospitalization, venous access and tests), related to adverse effects due to the adjuvant therapy, or societal (travel and time costs). The cost of supportive care was not included.. XELOX involved less total cost to the patient than FOLFOX4 (a difference of US$2857.68), fewer costs related to adverse effects ($668.97), and less travel ($26.07) and time ($390.93) expenditure per patient.. The results indicate that, overall, XELOX is a more affordable option than FOLFOX4 in China.

Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; China; Colonic Neoplasms; Cost of Illness; Deoxycytidine; Female; Fluorouracil; Hospitalization; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaloacetates; Retrospective Studies; Treatment Outcome

Chemotherapy-induced thrombocytopenia (CIT) is an important cause of morbitity in patients with cancer.. To investigate the effect of the baseline plasma D-dimer level, an important marker for thrombotic activity, on chemotherapy-induced thrombocytopenia in patients with stage III colon cancer.. A total of 43 (28 men) eligible patients were divided into two groups according to whether they exhibited chemotherapy-induced thrombocytopenia: Group 1 (n=21) and Group 2 (n=22). Comparison was made using demographic, histopathologic, and laboratory variables. Additionally, baseline plasma D-dimer levels underwent receiver operation characteristics curve analysis, and areas under the curve were calculated. Sensitivity, specificity, and positive and negative likelihood rates were then determined.. The incidence of chemotherapy-induced thrombocytopenia had a significant correlation with baseline platelet count (r=0.568, P=0.031) and baseline plasma D-dimer levels (r=0.617, P=0.036). When the cut-off point for the latter was set as 498 ng/mL, the area under the curve was 0.89 (95%CI: 0.74-0.93), the sensitivity was 91.4%, the specificity was 89.7%, the positive likelihood rate was 3.64 and the negative likelihood rate was 0.24 for chemotherapy-induced thrombocytopenia diagnosis.. The baseline level of plasma D-dimer could help to differentiate high- risk patients for chemotherapy-induced thrombocytopenia.

Topics: Adult; Analysis of Variance; Anemia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Biomarkers; Colonic Neoplasms; Female; Fibrin Fibrinogen Degradation Products; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Pilot Projects; Platelet Count; Predictive Value of Tests; Retrospective Studies; ROC Curve; Statistics, Nonparametric; Thrombocytopenia

Surgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available.. PePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer.. PePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer.. 2009-011445-13 TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00994864.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Belgium; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Follow-Up Studies; Gene Rearrangement; Humans; Leucovorin; Lymphocytes, Tumor-Infiltrating; Neoplasm Staging; Neoplastic Cells, Circulating; Organoplatinum Compounds; Polymorphism, Single Nucleotide; Positron-Emission Tomography; Preoperative Care; Prognosis; Prospective Studies; Quality of Life; Survival Rate; Tomography, X-Ray Computed

This work presents a chemical and morphological analysis of samples of saliva taken from patients who were under treatment with intravenous chemotherapy with 5-fluorouracil and leucovorin calcium. Samples of saliva were extracted from fifteen patients during the three stages of the treatment: The initial stage (previous to the chemotherapy), the intermediate stage (during the chemotherapy), and the final stage (twenty-one days after finishing the treatment). An amount of 50 μl was collected in each visit. Chemical contrast images were taken by means of scanning electron microscopy, and X-ray characteristic spectra were obtained from all the studied samples by using an energy dispersive system from all the studied samples. Images that correspond to the intermediate stage showed important differences with respect to the initial and final stages. In addition, X-ray spectra provided information about the present elements in saliva and their relative abundance allowed us to determine variations in the chemical composition. The backscattered electron images and X-ray spectra from the intermediate stage showed clusters of crystals with fluorine content higher than those obtained in initial and final stages. This fact probably indicates the passage of metabolites of 5-fluorouracil and leucovorin calcium from the plasma to the oral cavity. This finding enhances the hypothesis proposed by other authors about the secondary effects of the drugs on the stomatognathic system such as oral mucositis, dysgeusia, and xerostomia with or without hyposalivation.

Topics: Administration, Intravenous; Adult; Antimetabolites, Antineoplastic; Calcium; Carcinoma; Colonic Neoplasms; Crystallography; Electron Probe Microanalysis; Female; Fluorine; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microscopy, Electron, Scanning; Middle Aged; Mouth Mucosa; Saliva; Spectrometry, X-Ray Emission; Stomatitis; Vitamin B Complex

Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy.. We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease.. Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease-free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437).. Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Retrospective Studies; Survival Analysis; Treatment Outcome

Many studies have demonstrated the impact of UGT1A1 on toxicity of irinotecan. In particular, patients bearing UGT1A1 28 (TA 7/7) have a higher risk of severe neutropenia and diarrhea. Based on this, prescribers of irinotecan are advised that patients with UGT1A1 28 (TA 7/7) should start with a reduced dose of irinotecan, although a particular dose is not specified. Research in Asian countries has shown a lower incidence of UGT1A1 28 (TA 7/7), while UGT1A1 6 (A/A) is more often found and is associated with severe irinotecan-related neutropenia. We report here a case of a metastatic colorectal cancer patient who is heterozygous for the UGT1A1 28 polymorphism (TA 6/7) as well as the UGT1A1 6 polymorphism (G/A). The patient was treated with FOLFIRI for 9 cycles and underwent two irinotecan dose reductions according to pharmacokinetic data regarding exposure to the active metabolite, SN-38. Simultaneous heterozygous UGT1A1 28 and UGT1A1 6 polymorphisms may produce higher exposure to SN-38 and a higher risk of adverse effects related to irinotecan. Additional studies will be necessary to determine the optimal starting dose of irinotecan for patients with both UGT1A1 28 and UGT1A1 6 polymorphisms.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Fluorouracil; Glucuronosyltransferase; Heterozygote; Humans; Irinotecan; Leucovorin; Male; Neutropenia; Polymorphism, Genetic; Severity of Illness Index; Treatment Outcome

A 48-year-old man was administered bevacizumab+FOLFOX for lymph node recurrence of colon cancer in the abdominal cavity, and developed serious thrombosis of the portal system after 6 courses of the chemotherapy. We discontinued it promptly and anticoagulant therapy with urokinase was started immediately, but a complete dissolution was not achieved. Preservation therapy using anticoagulants for a long duration was effective for controling the of clinical symptom of thrombosis. The result of 6 courses of chemotherapy was CR, and the effect continues today, without further treatment 2 years later.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Fibrinolytic Agents; Fluorouracil; Humans; Leucovorin; Male; Mesenteric Veins; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Recurrence; Urokinase-Type Plasminogen Activator; Venous Thrombosis

To perform a retrospective analysis of UFT and oral leucovorin combination adjuvant chemotherapy for Stage III colon cancer patients over 76 years old, in order to evaluate both treatment efficacy and toxicity.. Between 2002 and 2011, 333 Stage III colon cancer patients had surgery performed in our institute, and we studied 25 of them on our chemotherapy regimen.. Patients'median age was 78 years old, with 12 men and 13 women. Of all the patients, 19 had Stage IIIa and 6 had Stage IIIb. The 3-year disease-free survival rates for Stage III and Stage IIIa patients were 65. 1% and 83. 1%, respectively, and the 3-year overall survival rate for Stage III was 79. 9%. With regard to toxicity, liver function disorder was observed in 8% of the patients, being the adverse event that occurred the most, but there was no Grade 3 or 4 toxicity.. UFT and oral leucovorin combination adjuvant chemotherapy for Stage III colon cancer patients over 76 years showed a good response, especially for Stage III a.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Female; Humans; Leucovorin; Male; Neoplasm Staging; Retrospective Studies; Tegafur; Uracil

The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer.. This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used.. The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2 %) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9 %; log-rank, P = 0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95 % confidence interval 1.03-3.23, P = 0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P = 0.732).. Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.

Topics: Adenocarcinoma, Mucinous; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Prognosis; Retrospective Studies; Survival Rate; 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

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

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 18; Colonic Neoplasms; Colonoscopy; Deoxycytidine; Early Detection of Cancer; Europe; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Mucosa; Leucovorin; Lymphatic Metastasis; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Occult Blood; Organoplatinum Compounds; Oxaloacetates; Risk; Risk Assessment; Risk Factors; Sigmoidoscopy; Treatment Outcome

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colonoscopy; Combined Modality Therapy; Electroretinography; Evoked Potentials, Visual; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Optic Nerve Diseases; Organoplatinum Compounds; Paraneoplastic Syndromes, Ocular; Radiotherapy; Retinal Diseases; Vision Disorders; Visual Acuity; Visual Field Tests; Visual Fields

Findings from multiple clinical trials established AC as a standard of care for stage III colon cancer. However, there is no recommended standard time for delivery of AC. We explored the timeliness of AC with FOLFOX as a predictor of recurrence and its role as a quality indicator in patients with stage III colon cancer.. We conducted a retrospective analysis of patients with colon cancer who received AC at Los Angeles County Hospital and Norris Cancer Center between 2003 and 2011. Time to recurrence (TTR) was the primary end point of the study, Kaplan-Meier curves and log-rank tests were used to assess the association between timing of the AC and TTR.. We identified 102 patients with stage III colon cancer who had received AC. With a median follow-up of 3.2 years, time from surgery to AC was not a predictor of recurrence (P = .19). However, there was a nonsignificant trend toward higher risk of systemic recurrence when the delay of AC was more than 12 weeks (P = .068). Additionally, a significant association was found between age, race, type of hospital, and timeliness of AC.. To date, our study is the largest data set to assess the timeliness of FOLFOX as a predictor of outcome in stage III colon cancer. Because FOLFOX is the current standard for AC for colon cancer, we report a trend toward worse outcome when FOLFOX is delayed more than 12 weeks. This result, thus supports quality measures to assess the timeliness of AC in stage III colon cancer and might have a meaningful effect on the care of patients with colon cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Recurrence; Retrospective Studies; Risk Factors; Time Factors

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

Accurate assessments of recurrence risk and absolute treatment benefit are needed to inform colon cancer adjuvant therapy. The 12-gene Recurrence Score assay has been validated in patients with stage II colon cancer from the Cancer and Leukemia Group B 9581 and Quick and Simple and Reliable (QUASAR) trials. We conducted an independent, prospectively designed clinical validation study of Recurrence Score, with prespecified end points and analysis plan, in archival specimens from patients with stage II and III colon cancer randomly assigned to fluorouracil (FU) or FU plus oxaliplatin in National Surgical Adjuvant Breast and Bowel Project C-07.. Recurrence Score was assessed in 892 fixed, paraffin-embedded tumor specimens (randomly selected 50% of patients with tissue). Data were analyzed by Cox regression adjusting for stage and treatment.. Continuous Recurrence Score predicted recurrence (hazard ratio for a 25-unit increase in score, 1.96; 95% CI, 1.50 to 2.55; P < .001), as well as disease-free and overall survival (both P < .001). Recurrence Score predicted recurrence risk (P = .001) after adjustment for stage, mismatch repair, nodes examined, grade, and treatment. Recurrence Score did not have significant interaction with stage (P = .90) or age (P = .76). Relative benefit of oxaliplatin was similar across the range of Recurrence Score (interaction P = .48); accordingly, absolute benefit of oxaliplatin increased with higher scores, most notably in patients with stage II and IIIA/B disease.. The 12-gene Recurrence Score predicts recurrence risk in stage II and stage III colon cancer and provides additional information beyond conventional clinical and pathologic factors. Incorporating Recurrence Score into the clinical context may better inform adjuvant therapy decisions in stage III as well as stage II colon cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Survival Analysis

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

A 74-year-old woman was diagnosed with advanced rectal cancer and stenosis. To resolve the rectal stenosis, we successfully placed an expandable metallic stent across the stenosis. After stent placement, food intake improved, and a good quality of life was maintained. Subsequently, the patient received systemic chemotherapy with modified FOLFOX6 (mFOLFOX6). The tumor responded remarkably to chemotherapy, and the patient did not experience any complications. After 2 courses of mFOLFOX6, the patient underwent high anterior resection. The postoperative course was satisfactory, and she has now been disease-free for 6 months after surgery.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Intestinal Obstruction; Leucovorin; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Stents

A 65-year-old woman was referred to our hospital for examination of anemia. Colonoscopy showed a type 1 tumor in the ascending colon with nearly complete stenosis that was diagnosed as a tubular adenocarcinoma. Computed tomography (CT) revealed swelling of the regional, periaortic, and celiac lymph nodes and lymphangitis carcinomatosa. The patient was diagnosed as having Stage IV ascending colon cancer, and neoadjuvant chemotherapy was administered to avoid non-curative resection. The patient was treated with cetuximab and oxaliplatin, Leucovorin, and 5-fluorouracil( mFOLFOX6) combination chemotherapy. After 6 courses of chemotherapy, the primary lesion and multiple lymph node swellings greatly reduced in size and lymphangitis carcinomatosa improved. Accordingly, right colectomy with D3 nodal dissection was performed. The patient was recurrence free at her 8-month follow-up examination. Neoadjuvant chemotherapy with molecular targeted drugs is useful in the treatment of patients with unresectable primary cancer.

Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds

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

Recent studies indicate that auraptene (7-geranyloxycoumarin, AUR), a geranyloxycoumarin extracted from fruits of edible plants belonging to the Rutaceae family, may represent a novel lead compound for dietary colon cancer chemoprevention in rodents. As a continuation of studies aimed to better depict the pharmacological effects and mechanism of action of the title natural compound, the current investigation was undertaken to determine whether AUR would be able to prevent the growth and sphere (surrogate tumors) formation of FOLFOX-resistant colon cancer cells that are highly enriched in cancer stem cells (CSCs). Our results demonstrate that AUR at a concentration of 10 μM was able to inhibit the growth and formation of colonospheres of FOLFOX-resistant colon cancer HT-29 cells in vitro. The corresponding parental cells were also similarly affected by AUR at the same concentration level. The reduction in the growth and colonospheres formation in FOLFOX-resistant HT-29 was also associated with a concomitant decrease in phospho-epidermal growth factor receptor. These findings suggest that AUR could prevent the re-emergence of CSCs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemoprevention; Colonic Neoplasms; Coumarins; Drug Resistance, Neoplasm; Fluorouracil; HT29 Cells; Humans; Leucovorin; Neoplastic Stem Cells; Organoplatinum Compounds; Spheroids, Cellular

Lung disease associated with FOLFOX (oxaliplatin/5-fluorouracil/leucovorin) chemotherapy is uncommon. We describe a case of cryptogenic organizing pneumonia (COP) occurring in a 78-year-old woman after receiving 2 cycles of modified FOLFOX6 as adjuvant chemotherapy for treatment of resected nonmetastatic colon cancer. This patient presented with respiratory symptoms including cough with scant clear sputum and wheezing on day 10 of the second cycle of mFOLFOX6. Despite therapy with systemic antibiotics and supplemental oxygen, she had a steady and relentless progression of her respiratory symptoms and status, with chest radiographs revealing progressive bilateral pulmonary infiltrates. Further chest radiograph evaluation demonstrated findings consistent with COP. Antibiotics were discontinued and methylprednisolone sodium succinate initiated as the mainstay of management for COP. The patient required a higher dose of methylprednisolone sodium succinate than typical for initial response with doses up to 3 mg/kg per d leading to prompt improvement in her respiratory symptoms and function and declining need for supplemental oxygen therapy. Chest radiographs also showed improvement. The Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's COP and the FOLFOX chemotherapy. Clinicians should be aware of the potential for this uncommon, yet severe adverse reaction associated with the FOLFOX chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Cryptogenic Organizing Pneumonia; Female; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds

Chemotherapy improves the survival rate of stage III colon cancer patients. The combination of oxaliplatin, 5-fluorouracil, and leucovorin (the FOLFOX4 regimen) has emerged as the standard of care. This prospective study evaluates potential alterations in cognitive function in FOLFOX4-treated patients.. We evaluated 57 consecutive colorectal cancer patients who received adjuvant chemotherapy with FOLFOX4. Patients underwent a complete battery of neuropsychological tests at three different times: before (T0), at the end (T1), and 6 months after treatment (T2).. We have analyzed cognitive impairment (Mini Mental State Examination, MMSE), visuo-spatial memory (Clock Drawing Test, CDT, Rey Complex Figure, copy and recall), information processing speed (Trial Making Test-A, TMT-A, and Trial Making Test-B, TMT-B), verbal memory (Rey Auditory Verbal Learning Test, call and recall), emotional distress (Psychological Distress Inventory, PDI), anxiety (State and Trait Anxiety Inventory, STAI-Y1 and Y2), and depression (Beck Depression Inventory, BDI). Then we have calculated, for each test and for each interval of time, mean ± standard deviation for the mean. In a subsequent phase, we tested the significance of different results through the ANOVA analysis for repeated measures. In this case, we could not find any statistically significant modification in cognitive function, but we could notice an improvement in emotional performance, anxiety and depression a short time after chemotherapy administration.. We found no effect on cognitive function related to chemotherapy, the only little modification is about some emotional performance during chemotherapy. These findings may be explained by the central role of the psychological adaptation process, which occurs during the period from diagnosis to completion of treatment and is characterized by anxiety and adjustment depression. Our results seem to rule out any significant cognitive impairment due to adjuvant FOLFOX4 chemotherapy in colon cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cognition; Cognition Disorders; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neuropsychological Tests; Organoplatinum Compounds; Pilot Projects; Prospective Studies

Surgical resection of asymptomatic primary colorectal cancer in patients presenting with synchronous unresectable metastatic disease is controversial. Concerns and controversies remain over combining cytotoxic chemotherapy with bevacizumab in this patient population.. We identified medical records of 99 patients with synchronous metastatic primary colorectal cancer who received chemotherapy with bevacizumab as their initial treatment. The incidence of subsequent use of surgery and surgical outcomes were recorded. Patients were also assessed for overall survival.. Patients who received bevacizumab-containing chemotherapy for synchronous metastatic primary colorectal cancer were divided into the non-surgery and surgery groups according to the resection status of their asymptomatic primary tumor. In the non-surgery group, two patients (4.4%) underwent additional surgery, while three patients (5.7%) required surgery for rectovesical fistula in the surgery group. The median overall survival was 17 months for the non-surgery group (95% CI: 10.6-23.3 months) and 23 months for the surgery group (95% CI: 21.3-24.6 months; P = 0.322).. This study utilizing chemotherapy with bevacizumab did not result in an increased rate of morbidity related to the unresected primary tumor. Survival is not compromised by leaving the primary colon tumor intact.

Topics: Adenocarcinoma; Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neoplasms, Multiple Primary; Organoplatinum Compounds; Oxaliplatin; Prognosis; Rectal Neoplasms; Retrospective Studies; Survival Rate; Young Adult

This study examined the geographic variation and sociodemographic disparities in the use of oxaliplatin chemotherapy, which has not been widely studied in the past. Our results suggest that chemotherapy use varies across geographic regions. Patterns of use that relate specifically to oxaliplatin-containing chemotherapy can inform providers and researchers how newer regimens are being used as standard chemotherapy in a real-world setting.. According to the National Cancer Comprehensive Network (NCCN), oxaliplatin with 5-fluorouracil and leucovorin (5-FU/LV) is the recommended adjuvant chemotherapy for patients with resected stage III colon cancer. Age and race are considered strong predictors of chemotherapy receipt, whereas geographic disparity has received minimal attention. The purpose of this study was to examine geographic variation and sociodemographic disparity in the use of chemotherapy in patients with stage III colon cancer, focusing specifically on oxaliplatin.. A retrospective cohort of 4106 Medicare patients was identified from the Surveillance, Epidemiology and End Results (SEER)/Medicare linked database. Descriptive statistics show how oxaliplatin-containing chemotherapy was used in various geographic regions among different age and racial groups. Multiple logistic regression analysis was performed to examine the relationship between receipt of oxaliplatin-containing chemotherapy and geographic region while adjusting for other sociodemographic and tumor characteristics.. Only 49% of the patients with stage III disease received adjuvant chemotherapy within 3 to 6 months of colon cancer-specific surgery. Patients aged 66 to 70 years were 78% more likely to receive chemotherapy than were those aged 80 years and older (P<.001). Patients in less urban regions were approximately 42% less likely to receive oxaliplatin chemotherapy than those residing in a big metro region (odds ratio [OR], 0.58; P=.008).. Chemotherapy use varies across geographic regions, especially for new chemotherapy drugs like oxaliplatin. Further research is needed to identify the causes of this geographic disparity and ways to provide high-quality cancer care to all patients according to their preferences and needs.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Female; Fluorouracil; Health Services Needs and Demand; Healthcare Disparities; Humans; Leucovorin; Logistic Models; Male; Medicare; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; SEER Program; Socioeconomic Factors; United States; Urban Population

Elderly patients derive similar benefits from 5-fluorouracil-based adjuvant chemotherapy in Stage III colon cancer; however, conflicting data exist regarding additional benefit from oxaliplatin, fluorouracil and leucovorin (FOLFOX) chemotherapy.. Single-center, retrospective analysis was performed to compare the safety and efficacy of adjuvant oxaliplatin, fluorouracil and leucovorin-4 chemotherapy in older patients (age ≥65 years) with younger patients with Stage III colon cancer after surgical resection.. Among 391 patients with Stage III colon cancer, 229 patients received adjuvant oxaliplatin, fluorouracil and leucovorin chemotherapy (87 (43.5%) ≥65 years old versus 142 (74.3%) <65 years old). Older patients had similar clinico-pathological characteristics as younger patients except for higher Charlson-Age comorbidity score (median 3.44 versus 2.85, P < 0.01). The estimated 3-year disease-free survival (76.5 versus 80.0%, P = 0.88) and 3-year overall survival (90.9 versus 92.7%, P = 0.98) were similar. Grade 3-4 neutropenia was the only toxicity with higher frequency in the elderly patients (62.1 versus 46.5%, P = 0.02). Elderly patients received a lower relative dose intensity of oxaliplatin (0.76 versus 0.79) and 5-fluorouracil (0.75 versus 0.80, P = 0.009).. Adjuvant oxaliplatin, fluorouracil and leucovorin chemotherapy resulted in similar efficacy without significant increase in toxicity in older patients aged ≥65 when compared with younger patients with curatively resected Stage III colon cancer. Therefore, for colon cancer patients aged ≥65, oxaliplatin, fluorouracil and leucovorin chemotherapy can be recommended as safe and effective adjuvant chemotherapy after curative surgery in Asia.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intravenous; Injections, Intravenous; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Republic of Korea; Retrospective Studies; Treatment Outcome

The study characterizes the long-term pharmacokinetics (PK) following last dose of bevacizumab as adjuvant therapy in patients with resected stage II and III colon carcinoma in a Phase III clinical study (AVF3077s).. Patients in AVF3077s received bevacizumab (5 mg/kg every 2 weeks) as adjuvant therapy for 1 year. Following the last dose bevacizumab concentration, data at 3 and 6 months were used to characterize long-term bevacizumab PK based on the population-modeling approach.. The long-term bevacizumab PK were consistent with previously reported results based on short-term bevacizumab PK. The clearance (CL), central volume of distribution (V(1)), intercompartmental clearance (Q), and the peripheral volume of distribution (V(2)) were 214 mL/day, 2,830 mL, 636 mL/day, and 2,490 mL, which correspond to a disposition and elimination half-life of 1.33 and 19.1 days, respectively. The empirical Bayes estimates of median post-treatment bevacizumab drug levels at 3 and 6 months were 6.14 and 0.23 μg/mL, respectively. For test covariates, the change in CL and V(1) of bevacizumab was less than 20% of the typical value. Body weight is the important covariate explaining the inter-individual variability on CL and V(1).. Long-term bevacizumab PK in this study was predictable based on short-term PK data from metastatic settings in other tumor types. An exploratory analysis demonstrated no apparent association of the tested covariates with bevacizumab PK. Further, the extended serum persistence of bevacizumab following last dose should be considered in clinical study designs and post-treatment evaluations that may be affected by bevacizumab.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Enzyme-Linked Immunosorbent Assay; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Vascular Endothelial Growth Factor A; Young Adult

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

We evaluated the cost-effectiveness of adjuvant chemotherapy using 5-fluorouracil, leucovorin (5FU/LV), and oxaliplatin (FOLFOX) compared with 5FU/LV alone and 5FU/LV compared with observation alone for patients who had resected stage II colon cancer.. We developed 2 Markov models to represent the adjuvant chemotherapy and follow-up periods and a single Markov model to represent the observation group. We used calibration to estimate the transition probabilities among different toxicity levels. The base case considered 60-year-old patients who had undergone an uncomplicated hemicolectomy for stage II colon cancer and were medically fit to receive 6 months of adjuvant chemotherapy. We measured health outcomes in quality-adjusted life-years (QALYs) and estimated costs using 2007 US dollars.. In the base case, adjuvant chemotherapy of the FOLFOX regimen had an incremental cost-effectiveness ratio (ICER) of $54,359/QALY compared with the 5FU/LV regimen, and the 5FU/LV regimen had an ICER of $14,584/QALY compared with the observation group from the third-party payer perspective. The ICER values were most sensitive to 5-year relapse probability, cost of adjuvant chemotherapy, and the discount rate for the FOLFOX arm, whereas the ICER value of 5FU/LV was most sensitive to the 5-year relapse probability, 5-year survival probability, and the relapse cost. The probabilistic sensitivity analysis indicates that the ICER of 5FU/LV is less than $50,000/QALY with a probability of 99.62%, and the ICER of FOLFOX as compared with 5FU/LV is less than $50,000/QALY and $100,000/QALY with a probability of 44.48% and 97.24%, respectively.. Although adjuvant chemotherapy with 5FU/LV is cost-effective at all ages for patients who have undergone an uncomplicated hemicolectomy for stage II colon cancer, FOLFOX is not likely to be cost-effective as compared with 5FU/LV.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Cost-Benefit Analysis; Fluorouracil; Humans; Leucovorin; Markov Chains; Organoplatinum Compounds; Probability; Quality-Adjusted Life Years; Survival Rate

Ethnic diversity of genetic polymorphism can result in individual differences in the efficacy and toxicity of cancer chemotherapy.. We analyzed 20 germline polymorphisms in 10 genes (TS, MTHFR, ERCC1, XPD, XRCC1, ABCC2, AGXT, GSTP1, GSTT1 and GSTM1) from prospectively enrolled 292 Korean patients treated with adjuvant oxaliplatin plus leucovorin plus 5-fluorouracil (FOLFOX) for colon cancer.. In contrast to previous studies in Caucasians, neutropenia (grade 3-4, 60.5 %) was frequently observed, whereas only 16.4 % experienced grade 2 or more sensory neuropathy. Neutropenia was more frequent in MTHFR 677TT [adjusted odds ratio (OR) 2.32, 95 % confidence interval (CI) 1.19-4.55] and ERCC1 19007TT (adjusted OR 4.58, 95 % CI 1.20-17.40) genotypes. Patients harboring XRCC1 23885GG experienced less grade 2-4 neuropathy [adjusted OR 0.52, 95 % CI 0.27-0.99]. MTHFR 677TT (p = 0.002) and XRCC1 23885GG (p = 0.146) genotypes were also more prevalent in Koreans compared to Caucasians. TS 'low' genotype (adjusted HR 1.83, 95 % CI 1.003-3.34) was significantly related to shorter disease-free survival. Overall survival was not significantly different according to the polymorphisms.. Polymorphisms in MTHFR, XRCC1 and TS are related to toxicities and disease-free survival in patients with colon cancer. The ethnic differences in frequencies of genotypes may explain the ethnic difference in toxicity profile following adjuvant FOLFOX chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; DNA-Binding Proteins; Female; Fluorouracil; Genotype; Humans; Korea; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Multidrug Resistance-Associated Protein 2; Organoplatinum Compounds; Pharmacogenetics; Polymorphism, Single Nucleotide; Proportional Hazards Models; X-ray Repair Cross Complementing Protein 1

Leucovorin is a reduced form of folic acid, which has multiple uses.(1) In this case report, it is used in combination with fluorouracil in the treatment of colon cancer. We describe a 53-year-old male, who was started on FOLFOX 6 + bevacizumab who experienced a hypersensitivity reaction to leucovorin. There have been very few cases of leucovorin hypersensitivity reactions reported in the literature. In this case, symptoms include flushing, hives, body pain, headaches, elevated blood pressures, and general discomfort. Although leucovorin reactions are considered rare, one should be aware of the types of reactions that can occur with leucovorin.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Drug Hypersensitivity; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds

To validate established cutoff levels of thymidylate synthase (TS) and excision repair cross-complementing (ERCC-1) intratumoral mRNA expressions in tumor samples from metastatic colorectal cancer (mCRC) patients treated with PTK787/ZK222584 (PTK/ZK). From 122 samples of patients with mCRC enrolled in CONFIRM-1 (Colorectal Oral Novel Therapy for the Inhibition of Angiogenesis and Retarding of Metastases) or CONFIRM-2, mRNA was isolated of microdissected formalin-fixed paraffin-embedded samples and quantitated using TaqMan-based technology. Existing TS and ERCC-1 cutoff levels were tested for their prognostic value in first-line and second-line therapy. TS expression was associated with overall survival (OS) in first-line, but not second-line therapy. ERCC-1 was associated with OS in patients treated with first-line and second-line FOLFOX4. In first-line FOLFOX4, combination of high TS and/or high ERCC-1 was associated with shorter OS. A correlation was observed between ERCC-1 expression and benefit from PTK/ZK+FOLFOX4 treatment. TS and ERCC-1 expression is associated with clinical outcome in mCRC. Baseline TS and ERCC-1 levels may allow the selection of patients who benefit from FOLFOX4 chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA-Binding Proteins; Endonucleases; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; RNA, Messenger; Survival Analysis; Thymidylate Synthase; Treatment Outcome

Clinical trials have shown a statistically significant disease-free survival benefit of oxaliplatin-based or irinotecan-based combination regimens for stage IV colon cancer. Less is known regarding the comparative effectiveness and cost-effectiveness of these agents among elderly patients. Whether the benefits of these agents justify the additional costs for elderly Medicare recipients is particularly policy relevant after US health care reform.. A cost-effectiveness analysis of oxaliplatin-based or irinotecan-based combination therapy versus 5-fluorouracil/leucovorin alone in elderly stage IV colon cancer patients was performed from a US Medicare perspective. Survival and direct medical costs were estimated using Surveillance, Epidemiology, and End Results-Medicare data sets for patients diagnosed from 2002 to 2005 with follow-up through 2007. Incremental cost-effectiveness ratios (ICERs) were calculated as costs per life-year gained, with sensitivity analysis estimating the cost per quality-adjusted life-year (QALY).. Median improved overall survival with 5-fluorouracil/leucovorin alone, or irinotecan-based or oxaliplatin-based combination therapy was 0.99, 1.07, and 1.47 life-years, respectively. Costs per life-year gained for oxaliplatin-based or irinotecan-based combination regimens compared with 5-fluorouracil/leucovorin alone were $78,181 and $267,938, respectively. ICERs comparing oxaliplatin-based to irinotecan-based regimens were $40,230 per life-year gained or $160,920 per QALY.. Oxaliplatin-based or irinotecan-based combination therapy improves overall survival but also substantially increases direct medical costs compared with 5-fluorouracil/leucovorin alone when used in elderly US patients with stage IV colon cancer. Oxaliplatin-based regimens are more cost-effective than irinotecan-based regimens for treatment of elderly stage IV colon cancer patients in terms of cost per life-year gained, but not in terms of cost per QALY.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Cost-Benefit Analysis; Disease-Free Survival; Female; Fluorouracil; Health Care Costs; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Quality-Adjusted Life Years; Survival Analysis

Both acute and chronic neurotoxicities are well-described with the use of oxaliplatin. We describe the case of a 50-year-old man with Dukes C colon carcinoma being treated with an adjuvant FOLFOX4 (5-fluorouracil, leucovorin and oxaliplatin (85 mg/m(2) per cycle)) who developed a widespread acute pain 5 min after commencing his twelfth cycle of chemotherapy. The pain was disabling and distressing, and remained for 16 h despite multimodality analgesia. The patient was not rechallenged with oxaliplatin. We believe this presentation represents an acute neurological phenomenon relating to oxaliplatin. Of note, this acute reaction occurred after 11 cycles of treatment, significantly later in the treatment course than other reports of atypical acute reactions.

Topics: Acute Pain; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

Little is known about how well guidelines about adjuvant chemotherapy in colon cancer are followed in daily practice. We evaluated the current guideline, which is based on the MOSAIC trial, by examining implementation, treatment patterns and disease-free survival.. We analysed a population-based cohort of 391 patients treated with adjuvant chemotherapy for stage III colon cancer in 2005-2006. Data were gathered from the Dutch Cancer Registry and medical records of 19 hospitals. Patients were classified according to whether or not they fulfilled MOSAIC trial eligibility criteria.. The administered regimens were: fluorouracil-leucovorin (17 patients), capecitabine (93), fluorouracil-leucovorin plus oxaliplatin (145), and capecitabine plus oxaliplatin (136). After its inclusion in national guidelines, oxaliplatin was prescribed in 16 hospitals within six months. Patients receiving oxaliplatin were younger and had less comorbidity than other patients. Dose schedules corresponded well with guidelines. Two-year disease-free survival probability of oxaliplatin patients meeting MOSAIC eligibility criteria was 78.4% (95% CI 72.5-84.3), which was comparable to MOSAIC trial results.. Guidelines for adjuvant chemotherapy in stage III colon cancer are generally well followed in daily practice. However, uncertainty remains regarding the optimal treatment of elderly patients and patients with comorbidities, which underscores the need for practical clinical trials including these patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Guideline Adherence; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Netherlands; Organoplatinum Compounds; Oxaliplatin; Practice Guidelines as Topic; Registries; Treatment Outcome; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; DNA-Binding Proteins; Fluorouracil; Hispanic or Latino; Humans; Leucovorin; Male; Microsatellite Instability; Organoplatinum Compounds; Risk Factors; Treatment Outcome

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Dihydropyrimidine Dehydrogenase Deficiency; Female; Fluorouracil; Humans; Leucovorin; Leukoencephalopathies; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds

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

Oxaliplatin is effective in advanced colorectal cancer and is known to have relatively few side effects, such as hemolysis and renal toxicity. We report a case of acute kidney injury (AKI) after treatment with a combination of oxaliplatin, folinic acid and 5-fluorouracil or capecitabine. The patient developed acute renal failure, hemolytic anemia and thrombocytopenia after the 34th course of chemotherapy including oxaliplatin. A positive direct antiglobulin test and detection of immunoglobulin G and complement C3b and C3d on erythrocytes suggested the diagnosis of immune-related severe intravascular hemolytic anemia. She was successfully treated and recovered using plasma exchange, corticosteroids and hemodialysis therapy. Only seven other cases of AKI associated with oxaliplatin use have been reported to date. As in this case, acute hemolysis due to autoimmune mechanisms and subsequent AKI occurred suddenly after frequent use of oxaliplatin in four of those cases. We should be aware that oxaliplatin may cause sudden life-threatening hemolysis by drug-induced antibodies and subsequent AKI, even though oxaliplatin is frequently administered without side effects. This represents the first case report of AKI-related hemolysis due to oxaliplatin in Japan.

Topics: Acute Kidney Injury; Anemia, Hemolytic, Autoimmune; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prednisone; Thrombocytopenia

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Young Adult

To investigate the relationship between serum concentration of fluorouracil and therapeutic efficacy as well as adverse reactions in patients with unresectable locally advanced or measurable metastatic colorectal cancer, and to analyze its role in further improving therapeutic efficacy and reducing adverse reactions of fluorouracil-based chemotherapy.. Eighty-six patients were randomly assigned into three groups according to the average plasma concentration of fluorouracil after three cycles of chemotherapy with the initial regimen of two weeks FOLFOX-4 (oxaliplatin + leucovorin + fluorouracil) or FOLFIRI (irinotecan + leucovorin + fluorouracil): group 1 (plasma concentration of fluorouracil < 25 ng/ml), group 2 (25 - 35 ng/ml) and group 3 (> 35 ng/ml). The blood samples were taken at 12 h after continuous infusion of fluorouracil in each cycle and the plasma concentration of fluorouracil was detected by high performance liquid chromatography (HPLC) (about 5 am ± 1 h). The relationship between the drug plasma concentration, therapeutic efficacy and adverse reactions in different fluorouracil plasma concentration arms was analyzed retrospectively.. The average plasma concentrations of fluorouracil of the three groups were (23.48 ± 1.95) ng/ml, (31.47 ± 2.33) ng/ml and (39.89 ± 3.87) ng/ml, respectively (P < 0.01). As for therapeutic efficacy, the median OS of the groups 2 and 3 were 18.0 and 17.5 months, significantly higher than that in the group 1 (13.0 months, P < 0.01). The PFS were 4.5, 7.5 and 8.0 months, respectively (P < 0.01). In terms of adverse reactions, the incidences of bone marrow suppression, mucositis and diarrhea in the group 3 were significantly higher than that in the first two groups (P = 0.02, P = 0.04 and P = 0.02).. The patients with local advanced and metastatic colorectal cancer, receiving fluorouracil-based chemotherapy, and with an average plasma concentration of fluorouracil between 25 - 35 mg/L have a better prognosis, and lower incidence of adverse reactions such as bone marrow suppression, mucositis and diarrhea.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Diseases; Colonic Neoplasms; Diarrhea; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Neoplasm Staging; Organoplatinum Compounds; Random Allocation; Rectal Neoplasms; Remission Induction; Survival Rate

To perform a retrospective analysis of UFT and oral leucovorin plus PSK combination adjuvant chemotherapy for stage III colon cancer in order to evaluate both treatment efficacy and toxicity.. Between 2003 and 2009, 273 stage III colon cancer patients underwent surgery in our institute, and we studied 156 of them.. Patients' median age was 72 years old; 87 men and 69 women. Of all patients, 119 had stage IIIa and 37 had stage IIIb. The 3-year disease, free survival rates for stage III, stage IIIa and stage IIIb patients were 73. 9%and 80. 6%and 51. 4%, respectively, and the 3-year overall survival rates for stage III was 97. 6%. With regard to toxicity, liver function disorder was observed in 9. 6%of the patients as the most frequent adverse event, but there was no grade 3 or 4 toxicity.. UFT and oral leucovorin plus PSK combination adjuvant chemotherapy for stage III colon cancer showed a good response especially for stage III a.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Leucovorin; Neoplasm Staging; Polysaccharides; Recurrence; Retrospective Studies; Tegafur; Uracil

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 50-year-old woman was diagnosed with ascending colon cancer with bilateral ovarian metastases, carcinomatous peritonitis, and carcinomatous pleurisy. Nine courses of mFOLFOX6 treatment resulted in the disappearance of her ascites and pleural effusion and a marked decrease in her serum CEA and CA19-9 levels. Additionally, the primary tumor and ovarian metastases became smaller. Therefore, a right hemicolectomy with D3 lymph node dissection, total hysterectomy, and bilateral salpingo-oophorectomy were performed. Postoperatively, we changed the chemotherapy from mFOLFOX6 to bevacizumab+FOLFIRI because the patient had an allergic reaction to oxaliplatin, and we suspected lung metastasis. Because the lung metastasis grew after ten courses of bevacizumab+FOLFIRI, we changed to cetuximab+FOLFIRI. Unfortunately, 28 months after her diagnosis, the patient died of carcinomatous pleurisy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Grading; Organoplatinum Compounds; Ovarian Neoplasms; Peritoneal Neoplasms

The patient was a 72-year-old woman, admitted to our hospital due to appetite loss. We performed gastroscopy, colonoscopy and abdominal CT. She had both advanced ascending colon cancer with multiple liver metastasis(cStage IV: cT3N1H3)and early gastric cancer(cStage 0: cTisN0M0). She received chemotherapy with modified FOLFOX6(mFOLFOX6), and the chemotherapy was judged effective for her gastric cancer. During the next 6 months, a total of 10 courses had been performed. The tumor marker scores(CEA, CA19-9)decreased significantly. Gastric cancer was diagnosed as CR(complete response)in gastroscopy after 6 courses of chemotherapy. In this case, chemotherapy with mFOLFOX6 was effective for gastric cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Neoplasms, Second Primary; Organoplatinum Compounds; Stomach Neoplasms; Tomography, X-Ray Computed

A 63-year-old woman with chief complaints of abdominal distention and vomiting was brought to our hospital in May, 2010. Her radiological examination revealed that she was suffering from perforative peritonitis. The patient underwent emergency open laparotomy. Perioperatively, we made a diagnosis of unresectable transverse colon cancer accompanied with tough peritoneal dissemination, and therefore performed intraperitoneal irrigation drainage, transverse loop colostomy and biopsy of omental dissemination. A pathological examination of omental dissemination demonstrated mucinous adenocarcinoma with the wild-type Kras gene, and the cytology of ascites was negative. FOLFOX4 combined with panitumumab therapy was initiated 1 month after the operation. Seventeen courses of this chemotherapy regimen were performed, although adverse events including grade 3 neutropenia and grade 2 skin symptoms were noted. Consequently, serum CEA levels decreased to 5. 5 ng/mL, although the size of the primary lesion of transverse colon cancer was unchanged on abdominal computed tomography(CT). Chemotherapy has been continued without marked side effects, although 1 year has passed since we started medical treatment for this difficult case. We found that a multidisciplinary approach with a focus on FOLFOX4 therapy combined with panitumumab is useful for patients with highly advanced mucinous adenocarcinoma of the colon that develops into peritoneal dissemination.

Topics: Adenocarcinoma, Mucinous; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Panitumumab; Peritoneal Neoplasms; Tomography, X-Ray Computed

A 61-year-old man on hemodialysis due to chronic renal failure caused by diabetes mellitus was diagnosed as having ascending colon cancer with multiple liver metastases. Colonoscopy revealed a Type 2 tumor located in the ascending colon. Abdominal CT showed hepatic tumors in S8 measuring 8×7 cm and in S6 measuring 5×4 cm, with a number of small tumors in the other sites. In order to prevent a hemorrhage from the colonic tumor, laparoscope-assisted right colectomy was performed. Seventeen days after the operation, oral administration of tegafur uracil(300mg/body/day)and calcium folinate(75mg/body/day)was initiated for the treatment of hepatic metastases. After three courses of treatment, size reduction of the hepatic metastases(the S8 4×3. 5 cm and the S6 2. 5×2. 5 cm)was obtained. Although nine months with seven courses of chemotherapy had passed without significant side effects, the size of hepatic metastases increased. Currently, therefore, CPT-11 and cetuximab are being administered as second-line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Humans; Kidney Failure, Chronic; Leucovorin; Male; Middle Aged; Neoplasm Staging; Renal Dialysis; Tegafur; Tomography, X-Ray Computed; Uracil

Colorectal carcinoma is an extremely rare tumor in childhood. Therefore, the role of adjuvant chemotherapy has not been adequately evaluated in children leading to limited data on safety profile and treatment response after application of novel drugs and novel targeted agents. In this report, we describe a case of colon adenocarcinoma in a 13-year-old girl treated with standard adult treatment as well as novel targeted therapy. This case report illustrates initial good disease control with FOLFOX therapy. On the other hand, targeted therapy revealed no improvement in disease control and good safety profile without significant adverse effects.

Topics: Adenocarcinoma; Adolescent; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colonic Neoplasms; Deoxycytidine; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Metastasis; Organoplatinum Compounds

A 76-year-old man with renal dysfunction received FOLFIRI due to a relapse in his pelvis after surgery for sigmoid colon cancer. FOLFIRI was continued for approximately 21 months with stabilization of disease observed on CT scans, but his tumor marker levels increased and tumors showed progression. He then began treatment with cetuximab/CPT-11, but disease progression was observed. XELOX in a low-dose was then administered, but this therapy was discontinued because of progression. He could not receive the other antitumor agents, due to mutations of the KRAS gene and renal dysfunction. Therefore, FOLFIRI was restarted, because it can be continued for long periods of time. Consequently, his tumor marker levels decreased with stabilization of disease on CT scans, and he continued the therapy for 7 months while maintaining quality of life. Ultimately, this case suggested that if there was effectiveness from a previous treatment, retreatment would be successful as chemotherapy for colon cancer in the difficult situation of selecting the other effective antitumor agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Male; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Salvage Therapy; Tomography, X-Ray Computed

Oxaliplatin combined with fluoropyrimidine improves survival in patients with stage III colon cancer. However, adjuvant chemotherapy with oxaliplatin is controversial in stage II and elderly patients.. We performed subgroup analyses of stage II and elderly patients randomly assigned fluorouracil with leucovorin (FL) ± oxaliplatin (FOLFOX4) in the Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer study. Comorbidities, severe adverse events, second cancers, management of relapse and death as a result of causes than other colon cancer were studied.. Two thousand two hundred forty-six patients were enrolled. Overall, 899 patients had stage II disease, including 330 low-risk and 569 high-risk patients. A total of 315 patients were ages 70 to 75 years. For stage II patients, the hazard ratio (HR) for comparing FOLFOX4 with FL was 0.84 (95% CI, 0.62 to 01.14) for disease-free survival (DFS), 0.70 (95% CI, 0.49 to 0.99) for time to recurrence (TTR), and 1.00 (95% CI, 0.70 to 1.41) for overall survival (OS). There was no interaction between treatment and stage or age. Low-risk stage II patients did not benefit from oxaliplatin. In high-risk stage II patients, the HR comparing FOLFOX4 with FL was 0.72 (95% CI, 0.51 to 1.01) for DFS, 0.62 (95% CI, 0.41 to 0.92) for TTR, and 0.91 (95% CI, 0.61 to 1.36) for OS. In elderly patients, the HR comparing FOLFOX4 with FL was 0.93 (95% CI, 0.64 to 1.35) for DFS, 0.72 (95% CI, 0.47 to 1.11) for TTR, and 1.10 (95% CI, 0.73 to 1.65) for OS.. The results of these subset analyses show no statistically significant benefit (OS and DFS) for the addition of oxaliplatin to FL as adjuvant treatment for either stage II and elderly patients.

Topics: Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Survival Analysis

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Survival Analysis

Cardiotoxicity associated with 5-fluorouracil (FU) is an uncommon, but potentially lethal, condition. The case of an 83-year-old man with colon cancer who developed chest pain during 5-FU infusion is presented. The electrocardiogram (ECG) showed pronounced ST elevation in the lateral leads, and the chest pain was resolved after infusion of nitroglycerin. A coronary angiogram (CAG) revealed that the patient had significant atherosclerosis in the proximal left circumflex artery. Coronary artery spasm with fixed stenosis was considered, and a drug-eluting stent was implanted. After 8 hours, the patient complained of recurring chest pain, paralleled by ST elevation on the ECG. The chest pain subsided after administration of intravenous nitroglycerin followed by sublingual nifedipine. Repeated CAG showed patency of the previous stent. This case supports the vasospastic hypothesis of 5-FU cardiac toxicity, indicating that a calcium channel blocker may be effective in the prevention or treatment of 5-FU cardiotoxicity.

Topics: Aged, 80 and over; Angina Pectoris; Antineoplastic Combined Chemotherapy Protocols; Calcium Channel Blockers; Colonic Neoplasms; Coronary Angiography; Coronary Vasospasm; Drug-Eluting Stents; Electrocardiography; Fluorouracil; Humans; Leucovorin; Male; Nifedipine; Nitroglycerin; Organoplatinum Compounds; Percutaneous Coronary Intervention; Recurrence; Severity of Illness Index; Treatment Outcome; Vasodilator Agents

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

Topics: Adjuvants, Immunologic; Administration, Metronomic; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Interleukin-2; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Maintenance Chemotherapy; Organoplatinum Compounds; Remission Induction; Sjogren's Syndrome; Treatment Outcome

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

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

To evaluate whether neutrophil-lymphocyte ratio(NLR) predicts risk of recurrence in patients with advanced colon cancer undergoing curative resection followed by adjuvant chemotherapy.. A total of 149 patients with advanced colon cancer undergoing curative resection followed by adjuvant chemotherapy(FOLFOX6 protocol) were included. NLR was calculated preoperatively and before chemotherapy. The changes in NLR and the predictive value of NLR for prognosis were analyzed.. The NLR of 149 patients was 2.8±1.5. NLR of 3.5 was identified according to the ROC curve. NLR<3.5 and NLR≥3.5 were classified as low and high NLR group, respectively. The 5-year recurrence-free survival(RFS) of patients with high preoperative NLR(n=22) was significantly worse than that of those with low preoperative NLR(n=127)(50.9% vs. 76.4%, P=0.025). The difference of 5-year RFS between high pre-chemotherapy NLR group(n=34) and low pre-chemotherapy NLR group(n=115) was statistically significant(50.1% vs. 71.4%, P=0.032). The 5-year RFS was 79.5% in patients with low preoperative NLR converting to high pre-chemotherapy NLR(n=16), similar to the group with high pre-chemotherapy group(P=0.077). The 5-year RFS was 17.7% in patients with high preoperative NLR reverting to low pre-chemotherapy NLR(n=12), similar to the group with low pre-chemotherapy group(P=0.978). There was significant difference in 5-year RFS between the postoperatively elevated group and postoperatively decreased group(P=0.036).. An elevated blood NLR may be a biomarker of poor RFS in patients with advanced colon cancer after curative resection and chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Lymphocytes; Male; Middle Aged; Neutrophils; Organoplatinum Compounds; Prognosis

This retrospective study evaluated the outcome of adjuvant chemotherapy comprising modified FOLFOX6 (mFOLFOX6) after potentially curative metastasectomy from colorectal cancer.. The subjects were 40 patients with colorectal cancer who underwent potentially curative metastatectomy without any prior chemotherapy between December 2003 and November 2011. Patient background, type of adjuvant chemotherapy, and prognosis were examined.. Adjuvant chemotherapy was given in 30 patients (mFOLFOX6, n=26; oral fluoropyrimidines, n=4). The median relapse-free survival tended to be longer in patients treated with mFOLFOX6 compared to those treated with fluoropyrimidines (28.5 months vs 14.8 months; p=0.11). The median overall survival did not differ significantly between the 2 groups (37.9 months vs 31.3 months, p=0.56). When the analysis was restricted to patients treated with mFOLFOX6, no significant differences were found in relapse-free survival (p=0.46), overall survival (p=0.29), and frequency of adverse events during chemotherapy(Grade 3, p=0.32) between patients with synchronous metastasis(n=11) and those with metachronous metastasis (n=15).. These results suggest that mFOLFOX6 might contribute to prolonging the time to relapse and that the timing of developing metastasis(synchronously or metachronously) may not have any effect on the outcome of adjuvant mFOLFOX6.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Prognosis; Retrospective Studies

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

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

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Pyrazines; Treatment Failure

Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. To better elucidate the molecular mechanisms involved in resistance to irinotecan (and its active metabolite SN38), we established SN38-resistant clones derived from HCT-116 and SW48 cell lines. These clones show various levels (6- to 60-fold) of resistance to SN-38 and display enhanced levels of activated MAPK p38 as compared with the corresponding parental cells. Because four different isoforms of p38 have been described, we then studied the effect of p38 overexpression or downregulation of each isoform on cell sensivity to SN38 and found that both α and β isoforms are involved in the development of resistance to SN38. In this line, we show that cell treatment with SB202190, which inhibits p38α and p38β, enhanced the cytotoxic activity of SN38. Moreover, p38 inhibition sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Finally, we detected less phosphorylated p38 in primary colon cancer of patients sensitive to irinotecan-based treatment, compared with nonresponder patients. This indicates that enhanced level of phosphorylated p38 could predict the absence of clinical response to irinotecan. Altogether, our results show that the p38 MAPK pathway is involved in irinotecan sensitivity and suggest that phosphorylated p38 expression level could be used as a marker of clinical resistance to irinotecan. They further suggest that targeting the p38 pathway may be a potential strategy to overcome resistance to irinotecan-based chemotherapies in colorectal cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Female; Fluorouracil; HCT116 Cells; Humans; Imidazoles; Immunohistochemistry; Irinotecan; Isoenzymes; Leucovorin; MAP Kinase Signaling System; Mice; Mice, Nude; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Xenograft Model Antitumor Assays

A 61-year-old man undergoes a sigmoid colectomy for a T3N1 (two of 18 nodes) adenocarcinoma of the sigmoid colon. He recovers well and receives 6 months of adjuvant FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) uneventfully. At his first follow-up visit, the oncologist recommended every 3 month visits for a physical, liver function tests, and carcinoembryonic antigen (CEA) measurement; every 6 month chest, abdomen, and pelvic computed tomography (CT) scans for 3 years; and aspirin, vitamin D supplementation, and exercise. Is CT scanning appropriate in the follow-up of colon cancer patients? (This case was presented at Massachusetts General Hospital Cancer Center.).

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colectomy; Colon, Sigmoid; Colonic Neoplasms; Exercise; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Organoplatinum Compounds; Oxaliplatin; Quality of Life; Tomography, X-Ray Computed

A woman in her late sixties had an operation for ascending colon cancer 15 months before her current admission. The pathological finding was T3(mod. SE), N0, H0, P3, M0, Stage IV. She had received chemotherapy after her operation. The first-line therapy comprised 15 courses of FOLFOX6 (from 14 to 5 months before admission). Her second-line chemotherapy comprised 6 courses of FOLFOX6+bevacizumab (BV) (from 3 to 2 months before admission). The third-line chemotherapy comprised 3 courses of FOLFIRI+BV (from 40 to 11 days before admission). She developed a high fever and respiratory failure 3 days before admission. On admission to our hospital, her chest X-ray and CT showed ground-grass opacities in bilateral lung fields. Bronchoalveolar lavage showed a predominance of lymphocytes without any evidence of infection. We diagnosed the patient as a case of lung injury caused by anticancer drugs. Steroid therapy was implemented, and her fever, respiratory failure, and chest X-ray abnormalities disappeared. Steroid therapy was stopped 6 months later and subsequently lung injury did not recur. Judging by the progress seen in this case, we concluded that her lung injury was due to irinotecan. We continued the chemotherapy for her colon cancer by prescribing S-1, it proved ineffective. The patient died from the colon cancer 27 months after her operation.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fatal Outcome; Female; Fluorouracil; Humans; Leucovorin; Lung Injury; Neoplasm Staging; Organoplatinum Compounds; Tomography, X-Ray Computed

Pelvic schwannomas are rare; it is even more rare for a pelvic schwannoma to occur concurrently with a colon cancer. The authors report the case of a 62-year-old woman with a cecal mass that was surgically removed and the histopathologic diagnosis was adenocarcinoma of the colon. Meanwhile, aretroperitonealpelvic nodalmasswas detected as questionable metastasis of the primary tumor. A subsequent computed tomography-guided fine-needle biopsy was carried out to establish the tumor stage. Surprisingly, the fine-needle biopsy revealed a benign schwannoma. This unusual case posed a dilemma in postoperative staging of the colon cancer.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Fine-Needle; Carcinoembryonic Antigen; Cecum; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms, Multiple Primary; Neurilemmoma; Organoplatinum Compounds; Oxaliplatin; Pelvic Neoplasms; Peripheral Nervous System Neoplasms; Tomography, X-Ray Computed

FOLFOX4 has been proven to be effective for metastatic colorectal cancer and is now used as a postoperative adjuvant therapy. However, adverse effects such as cold-sensitive paresthesia and bone marrow suppression are common, and this may necessitate a change of chemotherapy regimen even though FOLFOX is effective. PSK, a polysaccharide derived from mushrooms, has been developed in Japan as an immune-enhancing agent, and is widely used in patients with gastric, colorectal and pulmonary cancer. PSK has also been reported to decrease some adverse effects of chemotherapy. FOLFOX4 combined with PSK was administered to patients with metastatic colorectal cancer and the results were evaluated. Eight cycles of FOLFOX4 and PSK (3.0 g/day, po) were given to 25 patients with metastatic (19 hepatic, 3 pulmonary and 3 peritoneal) colorectal cancer. There was no CR (0%), while PR, SD and PD were 48, 36 and 16%, respectively. The response rate was 48%, and the disease control rate was 84%. There were significantly lower frequencies of adverse effects in comparison with published data. Grades 1 and 3 neutropenia occurred in 48 and 24%, respectively, of the patients; grades 1 and 3 nausea in 48 and 4%; and grades 1, 2 and 3 sensory neurotoxicity in 52, 4 and 0%. No patient dropped out due to adverse effect in this study. PSK plus FOLFOX4 seemed to be as effective as FOLFOX4 monotherapy as has been published, and significantly less toxic. These results suggest that this combination therapy may be more effective than FOLFOX4 monotherapy when given over a longer period, with a lower incidence of adverse effects.

Topics: Agaricales; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Peripheral Nervous System Diseases; Polysaccharides; Recurrence

We have previously demonstrated that expression of the novel gene schlafen-3 (Slfn-3) correlates with intestinal epithelial cell differentiation (Patel VB, Yu Y, Das JK, Patel BB, Majumdar AP. Biochem Biophys Res Commun 388: 752-756, 2009). The present investigation was undertaken to examine whether Slfn-3 plays a role in regulating differentiation of FOLFOX-resistant (5-fluorouracil + oxaliplatin) colon cancer cells that are highly enriched in cancer stem cells (CSCs). Transfection of Slfn-3 in FOLFOX-resistant colon cancer HCT-116 cells resulted in increase of alkaline phosphatase activity, a marker of intestinal differentiation. Additionally, Slfn-3 transfection resulted in reduction of mRNA and protein levels of the CSC markers CD44, CD133, CD166, and aldehyde dehydrogenase 1 in both FOLFOX-resistant HCT-116 and HT-29 cells. This was accompanied by decreased formation of tumorosphere/colonosphere (an in vitro model of tumor growth) in stem cell medium and inhibition of expression of the chemotherapeutic drug transporter protein ABCG2. Additionally, Slfn-3 transfection of FOLFOX-resistant HCT-116 and HT-29 cells reduced Hoechst 33342 dye exclusion. Finally, Slfn-3 transfection inhibited the expression of transforming growth factor-α in both FOLFOX-resistant colon cancer cells, but stimulated apoptosis in response to additional FOLFOX treatment. In summary, our data demonstrate that Slfn-3 expression inhibits multiple characteristics of CSC-enriched, FOLFOX-resistant colon cancer cells, including induction of differentiation and reduction in tumorosphere/colonosphere formation, drug transporter activity, and autocrine stimulation of proliferation. Thus Slfn-3 expression may render colon CSCs more susceptible to cancer chemotherapeutics.

Topics: AC133 Antigen; Aldehyde Dehydrogenase 1 Family; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Autocrine Communication; Cell Adhesion Molecules, Neuronal; Cell Cycle Proteins; Cell Differentiation; Colonic Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Fetal Proteins; Fluorouracil; Glycoproteins; HCT116 Cells; HT29 Cells; Humans; Hyaluronan Receptors; Isoenzymes; Leucovorin; Neoplasm Proteins; Neoplastic Stem Cells; Organoplatinum Compounds; Peptides; Proteins; Retinal Dehydrogenase; RNA, Messenger; Signal Transduction; Transfection; Transforming Growth Factor alpha

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

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

To compare the effectiveness and utilization trends of irinotecan (IRI)-based and oxaliplatin (OX)-based regimens with those of 5-fluorouracil and leucovorin (5FU/LV) alone in people aged 66 and older with Stage III colon cancer.. Retrospective cohort study.. Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare data.. People with Stage III surgically resected colon cancer who received adjuvant chemotherapy were categorized into 5FU/LV-alone (n = 3,581), OX-based regimen (n = 814), and IRI-based regimen (n = 219) subgroups.. Multivariable Cox proportional hazards models examined the effect of chemotherapies on overall survival, colon cancer-specific survival, and non-colon cancer-specific survival.. Use of the OX-based regimen increased, and use of the 5FU/LV-alone and IRI-based regimens decreased over time. OX was statistically significantly associated with longer overall survival (hazard ratio (HR) = 0.73, 95% confidence interval (CI) = 0.62-0.86, P < .001) and colorectal cancer-specific survival (HR = 0.39, 95% CI, 0.28-0.55, P < .001) than 5FU/LV alone. There was a greater risk of overall mortality (HR = 1.38, 95% CI = 1.14-1.67, P<.001) and cancer-specific mortality (HR = 1.92, 95% CI=1.49-2.47, P < .001) associated with IRI than with 5FU/LV. The superiority of OX on survival was found in participants aged 66 to 79 but not in those aged 80 and older.. This "real world" comparative effectiveness research extends randomized controlled trial results by documenting the relative survival benefit of OX in older adults with Stage III colon cancer. The associated shift in treatment away from 5FU/LV alone or IRI toward OX is consistent with evidence-based medicine from real-world outcomes research.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Comparative Effectiveness Research; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Proportional Hazards Models; Retrospective Studies; SEER Program; Survival Analysis; Treatment Outcome; United States

Oxaliplatin-based chemotherapy regimens are currently a standard of care for the treatment of colorectal cancer in both the adjuvant and metastatic disease settings. Significant improvements in survival have resulted from the use of oxaliplatin-based combinations. This article describes the use of oxaliplatin-based chemotherapy in a patient with stage III colon cancer who developed fatal diffuse alveolar damage during his adjuvant therapy. Other cases of pulmonary toxicity associated with oxaliplatin use are presented and the proposed pathophysiology of this rare occurrence is discussed.

Topics: Acute Lung Injury; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Pulmonary Alveoli; Respiratory Insufficiency

We report a case of undifferentiated colon cancer treated with FOLFIRI therapy. A 69-year-old male had suffered from descending colon cancer. He underwent a left hemicolectomy with D3 dissection. Histopathologically, the tumor was undifferentiated carcinoma, and the cytology of ascites was positive. Peritoneal disseminations occurred soon after surgery, and these tumors did not respond to FOLFOX4 therapy. FOLFIRI therapy was employed, and it reduced the size of these tumors once. However, the therapy failed to control the tumor progression 2 months later. Although we started bevacizumab and S-1, the patient died 11 months after the operation. The present case demonstrates the efficacy of FOLFIRI therapy for undifferentiated colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Male; Tomography, X-Ray Computed

A 69-year-old man was referred to our hospital with the chief complaint of a palpable abdominal mass. Computed tomography and colonofiberscopy revealed that a large type 2 ascending colon cancer had invaded the duodenum and pancreas. To down-size the tumor, chemotherapy was planned and a FOLFOX regimen was effective; we therefore decided to perform a radical operation. The patient is still alive and disease-free 1 year and 8 months after the surgery.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Combinations; Fluorouracil; Humans; Leucovorin; Male; Neoadjuvant Therapy; Organoplatinum Compounds; Oxonic Acid; Pancreaticoduodenectomy; Tegafur; Tomography, X-Ray Computed

The use of uridine triacetate for the management of fluorouracil toxicity is reported.. A 55-year-old man with malignant neoplasm of the sigmoid colon (stage IIIC) was seen in an outpatient chemotherapy center for his first six-month regimen of leucovorin calcium, fluorouracil, and oxaliplatin. Fluorouracil 2400 mg/m(2) i.v. was prescribed to be given over the next 46 hours at a home infusion center. Due to a medication error, a home infusion pharmacist incorrectly programmed the 46-hour infusion of fluorouracil to be administered over 4 hours. To manage the fluorouracil overdose, the physician decided to start the patient on uridine triacetate. The patient received his first dose of uridine triacetate 18 hours after the fluorouracil overdose. He was admitted to the hospital for observation and daily laboratory tests during treatment with uridine triacetate. He received ondansetron (as the hydrochloride salt) 8 mg orally 20 minutes before each dose of uridine triacetate to prevent nausea and vomiting. Uridine triacetate 11 g every 6 hours was administered orally for a total of 20 doses. It was mixed with applesauce at the time of administration and followed with 8 oz of water. The patient's laboratory values remained stable. The patient did not experience any nausea or vomiting during treatment. He was discharged from the hospital on day 5, with no clinical complications and an Eastern Cooperative Oncology Group Performance score of 0.. A patient with colon cancer who had received an overdose of fluorouracil was successfully treated with a five-day course of oral uridine triacetate.

Topics: Antiemetics; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Overdose; Fluorouracil; Home Infusion Therapy; Humans; Leucovorin; Male; Medication Errors; Middle Aged; Ondansetron; Organoplatinum Compounds; Uridine

A 45-year-old man was admitted to our hospital because of disseminated intravascular coagulation syndrome (DIC) and severe pain in his back and lumbar. Abdominal CT scan demonstrated lymph node enlargement in the whole body. FDG-PET revealed abnormal uptake of FDG in the thickening wall of the descending colon and the entire skeleton. Colonoscopy was performed continuously and revealed a poorly-differentiated adenocarcinoma of the descending colon. He was treated with the systemic chemotherapy of modified FOLFOX6 (mFOLFOX6). After one course of the treatment, DIC was resolved and severe back pain and lumbargo were improved.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Colonic Neoplasms; Disseminated Intravascular Coagulation; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds

Adding oxaliplatin to adjuvant 5-fluorouracil (5-FU) chemotherapy improves 3-year disease-free survival (DFS) after resection of stage III colon cancer. Several studies suggest that patients with tumors exhibiting defective mismatch repair (MMR) do not benefit from adjuvant 5-FU chemotherapy, but there are few data on 5-FU-oxaliplatin (FOLFOX) adjuvant chemotherapy in this setting. The aim of this study was to evaluate the prognostic value of MMR status for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy.. MMR status was determined by microsatellite instability testing or immunohistochemistry in 303 unselected patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy in 9 centers. Cox proportional hazards models were used to examine the association between MMR status and 3-year DFS.. The 3-year DFS rate was significantly higher in the 34 patients (11.2% of the study population) with defective MMR tumors (90.5%) than in patients with proficient MMR tumors (73.8%; log-rank test; HR = 2.16; 95% CI, 1.09-4.27; P = 0.027). In multivariate analysis, MMR status remained an independent significant prognostic factor for DFS (HR = 4.48; 95% CI, 1.34-14.99; P = 0.015).. MMR status is an independent prognostic biomarker for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; DNA Mismatch Repair; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Proportional Hazards Models

Adjuvant chemotherapy is the current standard in the management of patients with localised colon cancer (CC) following curative resection. The use of oxaliplatin plus 5 fluorouracil/leucovorin (FOLFOX) or oxaliplatin plus capecitabine-based (XELOX) regimens, both approved in Europe as adjuvant treatment for stage III CC, has improved prognosis in this stage, but questions on their usefulness in high-risk stage II or elderly CC patients and on the role of some prognostic biomarkers are still pending. In April 2010, a consensus meeting on adjuvant CC treatment based on a revision of the most recent literature was held in Spain. The panel considered the use of adjuvant chemotherapy for high-risk stage II CC patients to be justified. Additionally, the more convenient administration of oral fluoropyrimidines vs. IV continuous infusion 5-FU would make XELOX a more suitable alternative for the patient. A more cautious decision should be taken when prescribing oxaliplatin treatment in patients aged ≥70.

Topics: Adjuvants, Immunologic; Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Oxaloacetates; Practice Guidelines as Topic; Spain

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

A 58-year-old woman, who was undergoing peritoneal dialysis( PD) for chronic kidney disease (CKD) and had been operated by sigmoidectomy for early colonic cancer, was diagnosed as peritoneal recurrence of the colonic cancer. Her treatment for CKD was switched from PD to hemodialysis. She was administered mFOLFOX6 therapy(reducing the dose to 70%). Hemodialysis was performed 1 hour after administration of oxaliplatin on day 1 and repeated two days later after the completion of drug administration. No serious adverse events were observed. After 10 courses of mFOLFOX6, an ovarian metastasis was appeared. We then changed the regimen to FOLFIRI (70% dose)/bevacizumab (BV). Neutropenia (grade 4) was observed after the second treatment. After some rest, 21 courses of FOLFIRI/BV therapy were performed safely by reducing the dose to 60%. We thought that a reduced dose of FOLFIRI/BV therapy appeared to be safe for a patient with chronic kidney disease who is on hemodialysis.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Middle Aged; Organoplatinum Compounds; Peritoneal Dialysis; Peritoneal Neoplasms

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

A 54-year-old female with cecal cancer underwent Rt. hemicolectomy in December 2000. The lesion was mod, ss, p1(+), n1, stage IV. The level of CEA increased around August 2002. Abdominal CT revealed a recurrent tumor in the RLQ in July 2003, peritoneal dissemination was suspected. In December 2003, we performed a partial resection of the ileum and transverse colon including initial anastomosis. Lung metastases were found by chest CT in right S4, S5, S9 and S3, S8 in February 2004. Because of experience of severe side effect of intravenous chemotherapy, UFT/LV was administered from February 2004. Chest CT revealed the disappearance of tumor in September 2004, and no signs of recurrence were observed for 65 months.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Humans; Leucovorin; Lung Neoplasms; Middle Aged; Neoplasm Staging; Recurrence; Remission Induction; Tegafur; Time Factors; Tomography, X-Ray Computed; Uracil

Oxaliplatin is an effective chemotherapeutic agent frequently used in the treatment of colorectal carcinoma. Rare cases of renal failure and hemolytic reactions have been reported as separate side effects of oxaliplatin. Here we present a clinical picture of immune-related intravascular hemolysis and acute tubular necrosis in a patient receiving this drug. This case suggests a mechanistic explanation of renal failure in patients treated with oxaliplatin.

Topics: Acute Kidney Injury; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Fluorouracil; Hemolysis; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Prognosis

The aim was to determine the values of p53 tumour expression and microsatellite instability (MSI) phenotype to predict benefit from adjuvant chemotherapy of colon cancer by 5-fluorouracil and leucovorin (FL) alone or with oxaliplatin (FOLFOX).. This retrospective study included 233 unselected patients with stage III colon cancer treated by FL (n = 124) or FOLFOX (n = 109). The impact of p53 expression and MSI on disease-free survival (DFS) was defined using univariate and multivariate analyses. A Cox proportional hazards model was specifically designed to evaluate the interaction between chemotherapy and these genetic alterations.. In univariate analyses, addition of oxaliplatin significantly improved DFS provided that tumour overexpressed p53 [hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.19-0.82; P = 0.01] or displayed MSI phenotype (HR 0.17; 95% CI 0.04-0.68; P = 0.01). In multivariate analyses, p53 was confirmed as an independent factor predictive of benefit from FOLFOX (P = 0.03), while the interaction of MSI with chemotherapy could not be determined in the absence of relapse in the MSI group treated with FOLFOX.. Our observations indicate that MSI status and p53 expression may influence the impact of oxaliplatin on adjuvant treatment of stage III colon cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Microsatellite Instability; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Retrospective Studies; Tumor Suppressor Protein p53

We report a male patient with double advanced tumors in the jejunum and descending colon and multiple lung tumors. The intestinal cancers were surgically resected. Immunoprofiling of the specimens revealed a rare phenotype: the jejunal cancer was positive for cytokeratin (CK) 7, partially positive for CK20, and Cdx-2-negative, whereas the colon cancer was CK7(+), CK20(-), and Cdx-2(-). Biopsied lung tumor was diagnosed as tubular adenocarcinoma, and CK7(+)/CK20(+)/Cdx-2(-). Together with clinical information, we deduced that the jejunal adenocarcinoma had presumably metastasized to the lung. Moreover, postoperative oxaliplatin, including chemotherapy, significantly reduced the lung metastases, suggesting that this regimen is a promising treatment option for advanced small bowel adenocarcinoma.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Biopsy; CDX2 Transcription Factor; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Fatal Outcome; Fluorouracil; Homeodomain Proteins; Humans; Immunohistochemistry; Jejunal Neoplasms; Keratin-20; Keratin-7; Leucovorin; Lung Neoplasms; Lymph Node Excision; Male; Middle Aged; Neoplasms, Multiple Primary; Organoplatinum Compounds; Oxaliplatin; Phenotype; Tomography, X-Ray Computed; Treatment Outcome

Colon cancer with DNA mismatch repair (MMR) defects reveals indistinguishable clinical and pathologic aspects, including better prognosis and reduced response to 5-fluorouracil (5-FU)-based chemotherapy. There has been no consensus for p53 as a prognostic marker in colorectal cancer. This study investigated the clinical implication of MSI-H/MMR-D and p53 expression in R0-resected colon cancer patients who received adjuvant oxaliplatin/5-FU/leucovorin (FOLFOX) therapy.. We analyzed 135 patients, who had been treated by adjuvant chemotherapy containing 5-FU and oxaliplatin (FOLFOX) after curative resection (R0) for colon adenocarcinoma between May 2004 and November 2007. Tumor expression of the MMR proteins, MLH1 and MSH2, was detected by immunohistochemistry (IHC) in surgically resected tumor specimens. MSI was analyzed by polymerase chain reaction (PCR) amplification using fluorescent dye-labeled primers specific for microsatellite loci. Tumors with MMR defects were defined as those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Expression patterns of p53 were determined in a semiquantitative manner by light microscopy.. There were 13 (9.6%) patients with stage II, 108 (80%) with stage III, and 14 (10.4%) with stage IV. Fourteen patients with stage IV (10.3%) had metastases to liver only, all of whom underwent complete metastasectomy for liver metastases. In total, 134 tumor specimens were genotyped, 115 specimens were tested by IHC and 113 cases had both genotyping and IHC results available for analysis. Genotyping results demonstrated that 12 (9.0%) cases were MSI-H and 122 (91.0%) were MSI-L/S. By IHC, 11 (9.6%) patients were MMR-D and 104 (90.4%) were MMR-I. The methods were in agreement in 108 patients (94.7%). We assessed 114 patients for p53 expression by immunostaining. MMR status was not significantly associated with DFS (P = 0.56) or OS (P = 0.61) in patients with colon cancer (n = 135) receiving adjuvant FOLFOX. According to p53 status, there was also no significant difference for DFS (P = 0.11) and OS (P = 0.94). For patients with genotyping/IHC agreement (n = 108), there was no difference in DFS (P = 0.57) and OS (P = 0.98) between patients with MSI-H/MMR-D and MSI-L/S/MMR-I tumors.. The MMR status or p53 positivity was not significantly associated with outcomes to FOLFOX as adjuvant chemotherapy in colon cancer patients with R0 resection. Adding oxaliplatin in adjuvant chemotherapy may overcome negative impact of 5-FU on colon cancers with MSI-H/MMR-D.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; DNA Mismatch Repair; Female; Fluorouracil; Genetic Markers; Genotype; Humans; Immunohistochemistry; Leucovorin; Male; Microsatellite Instability; Middle Aged; Organoplatinum Compounds; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Tumor Suppressor Protein p53

FOLFOX 4 chemotherapy (5-fluorouracil, leucovorin and oxaliplatin) is the standard adjuvant treatment for stage III colon cancer. The principal secondary effects described are haematological, gastro-intestinal or neurological. A single case of obliterative bronchiolitis with organising pneumonia has been described recently.. We report the case of a female patient aged 74 years who, after 12 courses of FOLFOX 4 chemotherapy, developed acute onset of severe shortness of breath and a dry cough but remained afebrile. A thoracic CT-scan showed symmetrical bilateral interstitial infiltration that was reticular in appearance, and predominantly basal and peripheral in distribution. Broncho-alveolar lavage revealed an alveolitis with 9% eosinophils and 4% neutrophils. Transbronchial biopsies showed the appearances of obliterative bronchiolitis with organising pneumonia. Systemic corticosteroid treatment led to a remarkable clinical and functional improvement.. To our knowledge, this is the second case of obliterative bronchiolitis with organising pneumonia that has been described following adjuvant treatment based on FOLFOX 4.

Topics: Acute Disease; Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Adjuvant; Colonic Neoplasms; Cryptogenic Organizing Pneumonia; Diagnosis, Differential; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Pulmonary Alveoli; Tomography, X-Ray Computed

Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been suggested to be a valuable marker in colorectal cancer (CRC), but the effects of chemotherapy on TIMP-1 levels are unknown. The present study evaluated the effect of chemotherapy on TIMP-1 levels in comparison with carcinoembryonic antigen (CEA) levels in patients with stage III colon cancer.. Thirty patients who had been curatively resected for stage III colon cancer were included. The patients received 10-12 cycles of modified FOLFOX6 regimen. Blood samples were collected before and after the first and the second cycle and three months later.. No significant change could be detected in CEA levels while TIMP-1 raised significantly after the second cycle but returned to normal 3 months later.. Plasma CEA levels are stable during adjuvant chemotherapy while the plasma level of TIMP-1 might be directly affected by chemotherapy represented by a transient rise about 2 weeks following the initiation of treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Tissue Inhibitor of Metalloproteinase-1

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

Two Web-based prognostic calculators (Adjuvant! and Numeracy) are widely used to individualize decisions regarding adjuvant therapy among patients with resected stage II and III colon cancer. However, these tools have not been directly compared. Hypothetical scenarios were formulated for the Numeracy calculator based on all potential combinations of age, lymph nodes status, tumor stage, and grade of tumor. These were then applied to three postsurgical therapy choices: observation, 5-fluorouracil (5-FU), or FOLFOX (5-FU, leucovorin, and oxaliplatin chemotherapy) to obtain the predicted 5-year disease-free survival (DFS) and overall survival (OS). Wilcoxon signed rank tests were used to compare the numerical predictions between the Adjuvant! and Numeracy calculators for each combination. A total of 192 hypothetical patient scenarios were obtained. For these patients, DFS and OS predictions from Adjuvant! were statistically significantly different than Numeracy (P <.05), except for four of 144 categories. While the estimated benefit in DFS and OS for 5-FU compared to surgery obtained from Adjuvant! and Numeracy were similar, the benefit in DFS and OS for FOLFOX over 5-FU, obtained from the Adjuvant! tool was slightly lower than that estimated from Numeracy. Among patients with resected stage II and III colon cancer, the DFS and OS estimates obtained from Numeracy and Adjuvant!, regarding the benefit of 5-FU over surgery, are similar, but the benefits of FOLFOX over 5-FU differ. Validation studies are needed to clarify the discrepancy and to assess the accuracy of these tools for predicting actual patient outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Prognosis; SEER Program

Angiogenesis plays an important role in tumor progression. The vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. In the present study we evaluated single nucleotide polymorphisms (SNPs) -2578C > A, -1154G > A, and +936C > T in the VEGF gene, and their prognostic value for patients operated on for colorectal cancer (CRC).. VEGF polymorphisms have been analyzed in 177 patients who had undergone surgical resection at Hospital Clínico San Carlos. The analysis of these polymorphisms was performed with specific probes for each nucleotide in a multiplex reaction using real-time PCR.. We only found a statistically significant relationship for one of these three polymorphisms, +936C > T, with gender and tumor location; 10.7% of patients heterozygotes for this SNP had tumors located in proximal colon, 35.2% in distal segment and 54.1% in rectum (p = 0.03). Patients with the +936T/T genotype had 100% overall survival (OS).. Patients with a +936T/T genotype showed increased survival, therefore the +936C > T SNP could be a useful marker in the follow-up and clinical management of patients with colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Genetic Predisposition to Disease; Genotype; Humans; Leucovorin; Male; Middle Aged; Neoplasm Proteins; Neovascularization, Pathologic; Polymorphism, Single Nucleotide; Prospective Studies; Rectal Neoplasms; Survival Analysis; Vascular Endothelial Growth Factor A

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

The aim of this study was to determine the antimetastatic efficacy of the combination of 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (CPT-11) (FOLFIRI) in an orthotopic nude mouse model of GFP-HCT-116 human colon cancer-expressing green fluorescent protein (GFP). The mice were randomly divided into four groups: Group 1: saline control; Group 2: 30 mg/kg 5-FU + 90 mg/kg LV; Group 3: 5-FU + LV + 16 mg/kg CPT-11 (FOLFIRI); and Group 4: 5-FU + LV + 24 mg/kg CPT-11. 5-FU and LV were administered on days 11, 16 and 21, and CPT-11 on days 12, 18 and 22. Survival in Groups 3 and 4 was significantly longer than that in Groups 1 and 2, although no dose-dependency on CPT-11 was observed. Analysis of the primary and metastatic tumors by GFP imaging, as well as that of oncogene expression in mesentery lymph nodes, demonstrated that tumor growth and metastasis were significantly inhibited or even prevented by FOLFIRI. Pathological evaluation also demonstrated that metastasis was also inhibited by FOLFIRI. The results of the present study suggest FOLFIRI prolongs survival by inhibiting metastasis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Disease Progression; Fluorouracil; Green Fluorescent Proteins; Humans; Leucovorin; Lymphatic Metastasis; Mice; Mice, Nude; Survival Rate; Treatment Outcome; Whole Body Imaging; Xenograft Model Antitumor Assays

Fundamental research identified new therapy targets implicated in tumor proliferation and angiogenesis which lead to the development of several targeted therapies. Currently, three drugs are used in the treatment of advanced colorectal cancer, cetuximab and panitumumab, two anti epidermal growth factor receptor, and bevacizumab, an anti vascular endothelial growth factor.. We evaluated a treatment with oxaliplatin-based chemotherapy (Folfox7 regimen) and bevacizumab in patients with locally advanced and/or metastatic colorectal cancer. Objectives of the study are the evaluation of the efficacy, toxicity, progression free survival, overall survival and tumor cell expression of the vascular endothelial growth factor by immunochemistry.. 47 patients are included in the study during the period between April 2005 and June 2007; 28 men and 19 women. After six cycles of treatment, we achieved 67.3% of objectives responses and 76% of tumor control. The median progression free survival evaluated was 12 months (9.3-14.6 months) and median overall survival 18 months (9-26.9 months). The immunochemistry study of 46 tumours of the study achieved the following results: 13% (0), 17.4% (1+), 23.9% (2+) and 45.7% (3+). A correlation between the vascular endothelial growth factor expression, therapeutic responses and survival has been demonstrated but the difference was not significant in term of survival. Both chemotherapy toxicity and bevacizumab related toxicity are acceptable in our study.. The fact that vascular endothelial growth factor expression is common in more than 80% of colorectal cancers, lead to recommend the systematic use of bevacizumab with chemotherapy in the treatment of advanced colorectal cancer.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Proteins; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Vascular Endothelial Growth Factors; Young Adult

A portable infusion pump is essential to sustain the 46-hour continuous administration of 5-fluorouracil in the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and folinic acid, fluorouracil, and irinotecan (FOLFIRI) protocols in colorectal cancer chemotherapy. However,the accuracy of the 5-fluorouracil dose administered via the infusion pump and patient compliance varies because the infusion rate changes depending on the viscosity of the drug, temperature, etc. In addition, the termination of administration based on the patient's judgment may influence these factors. In the present study, the amount of 5-fluorouracil remaining in the infusion pump and the administration time were investigated. As a result, the median amount that was found to remain in the pump was 49 mg, which was 2.0% of the average dosage, and an median administration time delay of 70 min was obtained. A questionnaire survey revealed that a majority of the patients felt insecurity about in adequate administration and administration time delays. These results indicate that customizing capacity modulation in the infusion pump corresponding to the patient's usage or seasonal variability of air temperature, and patient education may be important to improve patient compliance.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Infusion Pumps; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Seasons; Surveys and Questionnaires

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

Topics: Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease Progression; ErbB Receptors; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds

We have previously reported that by inducing calcium sensing receptor (CaSR), calcitriol, the active form of vitamin D, promoted the sensitivity of the human colon carcinoma cells to anticancer drugs. In the current study we tested several other potential CaSR modulators, calcipotriol and the effective components of Chinese herbal medicine lentinan, for their functions in inducing CaSR expression in human colon carcinoma cell line CBS, Moser, Fet, and SW480 cells and subsequently promoting sensitivity of the cells to anticancer drugs. Calcipotriol and lentinan suppressed invasion of the colon carcinoma cells and enhanced the cytotoxicity of anticancer regimen FOLFIRI to cells in culture or in anchorage-independent growth. In the mechanism study we found that calcipotriol and lentinan suppressed protein expression and gene transcriptional activities of survivin and thymidylate synthase, increased E-cadherin cell membrane localization and complex formation of E-cadherin and beta-catenin, and repressed TCF4 transcriptional activation. These effects were attenuated, however, in CaSR knocked-down cells, indicating that CaSR was required in the pathway. We concluded that calcipotriol and lentinan are efficient in promoting chemosensitivity in colon carcinoma cells. Since both compounds have much less side effects than calcitriol in clinic, they have greater potential to be applied as supplements of colon cancer therapy.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Calcitriol; Camptothecin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colonic Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression; Humans; Immunoprecipitation; Lentinan; Leucovorin; Receptors, Calcium-Sensing; Transcription, Genetic; Transfection

Although lymph node metastasis (LNM) is the most critical prognostic factor in colorectal cancer patients, the anti-LNM efficacy of chemotherapeutic agents is largely unknown because of the limitations of reproducible human colorectal cancer LNM models. Here, we developed a new LNM model from a recently established colorectal cancer cell line (COLM-5) and compared the anti-LNM efficacy of two oral formulations of 5-fluorouracil (5-FU) derivatives, S-1 and UFT/leucovorin (LV). COLM-5 cells is a poorly differentiated adenocarcinoma cell line with unique features such as left-sided, beta-catenin cytoplasmic localization, and microsatellite stable phenotype. COLM-5 cells expressed vascular endothelial growth factor (VEGF-C) and exhibited peritumoral lymphangiogenesis. Consequently, they showed high LNM potential at an incidence of approximately 90% when subcutaneously injected into nude mice, allowing use for preclinical study. When chemotherapy with S-1 or UFT/LV started from the micrometastasis stage, not the advanced macroscopic metastasis stage, anti-LNM efficacy of S-1 was significantly higher than that of UFT/LV at the dosage in which antitumor activity of the two drugs against primary subcutaneous tumor was comparable. COLM-5 cells showed expression pattern of 5-FU metabolizing enzymes such as high dihydropyrimidine dehydrogenase (DPD) and low thymidylate synthase (TS)/orotate phosphoribosyltransferase (OPRT) both in vitro and in vivo. These results suggest that the preferential anti-LNM activity of S-1 compared with UFT/LV against high-DPD COLM-5 tumors is due to the higher DPD inhibitory activity of 5-chloro-2, 4-dihydroxypyrimidine (CDHP) present in S-1 than uracil in UFT. The COLM-5 model would be an excellent tool for understanding the basic mechanism of LNM and for preclinical study on the anti-LNM efficacy of the drugs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Colonic Neoplasms; Drug Combinations; Drug Evaluation, Preclinical; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Mice; Middle Aged; Oxonic Acid; Tegafur; Uracil; Xenograft Model Antitumor Assays

In colorectal cancers, the local cytokine network and the levels of nitric oxide (NO) and reactive oxygen species (ROS) are known to be closely related to cancer progression and metastasis, but the influence of the currently administered therapies on the cancer microenvironment is not completely understood. We analyzed the levels of reactive oxygen species (ROS), nitric oxide (NO), and cachexia-mediated cytokines (IL-1beta, IL-6, TNF-alpha) in cocultures of human colon carcinoma spheroids prepared with cells derived from tumors of different grades with human normal colon epithelial and myofibroblast cells and normal endothelial cells. We also analyzed the influence of standard chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) combined with camptothecin (CPT-11) (IFL regimen with drug concentrations adjusted to in vitro conditions) on these parameters. The results indicated that adhesion of colon carcinoma spheroids to colon epithelium and myofibroblast monolayers induced O2- anion production but decreased NO levels compared to the sum of the radicals released by monocultures of the two types of cells. Coculture of colon carcinoma spheroids with endothelium was an exception to this rule, as only HT29 cells decreased NO production. In cocultures, anticancer drugs additionally, though only slightly and insignificantly, increased the production of the radicals compared to a nontreated coculture, but in monocultures, the drugs, and especially CPT-11, were ROS inducers and simultaneously NO production inhibitors. However, the levels of released ROS and NO were dependent on the stage of colon carcinoma that the cells were derived from. LS180 cells (grade B) grown in monocultures produced the lowest ROS levels but were the best producers of NO. Adhesion of tumor spheroids to normal cells influenced the microenvironmental cytokine network compared to monocultures, decreasing IL-1beta and TNF-alpha secretion but significantly enhancing L-6 levels. The addition of the drugs had no effect on IL-1beta levels but increased TNF-alpha production and lowered the amounts of IL-6. In conclusion, cytotoxic drugs may, dependent on the stage of tumor growth or the type of chemotherapy regimen administered, significantly influence the proinflammatory cytokine network and local ROS and NO levels. Moreover, in cocultures of tumor cells with normal epithelial, myofibroblast, and endothelial cells, ROS production seems to be involved in local cell injury, which was detect

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Coculture Techniques; Colon; Colonic Neoplasms; Cytokines; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Fluorouracil; Humans; Leucovorin; Neoplasm Metastasis; Nitric Oxide; Reactive Oxygen Species; Spheroids, Cellular

We report a case of acute interstitial pneumonitis and respiratory failure occurring in a 69-year-old, previously healthy patient receiving FOLFOX regimen plus cetuximab for colon cancer. Association between this chemotherapy regimen and interstitial pneumonitis is rarely reported in the literature. We treated the patient with pulse steroid therapy, and improvement in respiratory function and decreased pulmonary infiltrations demonstrated good response to steroids use. However, the patient ultimately expired from respiratory complications after 98 days from admission, possibly due to secondary infection. Both oxaliplatin and cetuximab have rarely been associated with interstitial pneumonitis, and our case may serve as an important reference for physicians notice in patients receiving these chemotherapeutic agents.

Topics: Acute Disease; Adenocarcinoma; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lung Diseases, Interstitial; Organoplatinum Compounds

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

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

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

These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients.. We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06.. A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV.. RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study.

Topics: Algorithms; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Recurrence; Reverse Transcriptase Polymerase Chain Reaction

We report a rare case of metastatic colorectal cancer who suffered from hyperammonemic encephalopathy induced by 5- FU and was continuously treated with FOLFOX therapy. A 50-year-old man with ileus was diagnosed with ascending colon cancer Stage IV, and a right hemicolectomy was performed. Postoperative chemotherapy with modified FOLFOX6 was performed. Complications of nausea and vomiting were seen on day 2 , with confusion and cognitive disturbances on day 3 . None of the other radiographic examinations provided an explanation for his symptoms. Laboratory examination revealed hyperammonemia, so branched-chain amino acid solutions and high-volume drip infusion were started for its treatment. His symptoms entirely disappeared on day 4. We changed to chemotherapy for FOLFOX4 using branched-chain amino acid solutions and drip infusion. The tumor marker level normalized following two courses, and CT following ten courses showed that the size of the lung metastasis and abdominal lymph node had reduced significantly. The patient is currently receiving FOLFOX4.

Topics: Amino Acids, Branched-Chain; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Tomography, X-Ray Computed

A 74-year-old man was administered FOLFIRI therapy, followed by modified FOLFOX therapy and FOLFIRI therapy due to ascending colon carcinoma with multiple lung metastases. After 19 months, the tumor marker became normal, and CT and PET-CT revealed the multiple lung metastases had disappeared. He was operated due to stenosis of the ascending colon carcinoma, and is now being treated with chemotherapy due to liver metastasis. There has been no regrowth of lung metastases for 21 months since the disappearance of multiple lung metastases.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Organoplatinum Compounds; Positron-Emission Tomography; Tomography, X-Ray Computed

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 report a case of high CEA advanced colon cancer, which we were able to down stage after treatment with FOLFIRI-1. The patient was a 56-year-old woman who had advanced sigmoid colon cancer with high CEA. It was suspected that the tumor had directly invaded the ovary by CT scan. For curative operation, hysterectomy was considered necessary. Neoadjuvant therapy was performed to avoid an extensive operation. After the fourth course, according to colonoscopy and CT findings, a significant tumor reduction was obtained. Sigmoid colorectomy with D3 nodal dissection was then performed. The histological diagnosis was pT1, pN0, PStage I. The histological effect was observed in lymph node metastasis. The patient was recurrence free at her 3-year follow-up examination.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoembryonic Antigen; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Remission Induction

Fluoropyrimidine-based chemotherapy is the most common treatment for unresectable metastatic colorectal cancer (m-CRC). Therapy with 5-FU/folinic acid (FA) continues to be a standard treatment in developing countries. Pharmacogenomics allows the tailoring of cancer therapy to the patient. The polymorphism 677C>T of the methylenetetrahydrofolate reductase (MTHFR) gene seems to influence the effectiveness of treatment with 5-FU. We undertook this study to evaluate the frequency of MTHFR 677C>T polymorphism and its relationship to the time to progression (TTP) and overall survival (OS) in m-CRC treated with 5-FU/FA.. The MTHFR 677C>T polymorphism was determined using PCR and allele-specific digestion. The clinical variables, TTP and OS, were analyzed in each case and compared between wild-type and variant polymorphic groups.. Among 34 patients (12 males and 22 females), we detected eight wild-type homozygous patients (CC; 24%), nine variant homozygous (TT; 26%), and 17 heterozygous (CT; 50%) individuals. The median TTP in patients with the MTHFR 677 CC, CT, and TT genotypes was 3.43, 4.77, and 4.80 months, respectively (p = 0.047, log rank). A longer TTP was observed in patients with polymorphic variant (CT and TT) compared with the wild-type homozygous patients (4.80 vs. 3.43 months; p = 0.031, log rank).. In this study, the frequency of the MTHFR 677C>T polymorphism is 50% among m-CRC Mexican patients. The results of this study appear to show that the presence of the MTHFR 677C>T polymorphism is associated with longer TTP and OS in m-CRC treated with 5-FU/FA.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Single Nucleotide; Time Factors

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pain; Palliative Care; Pancreatic Neoplasms; Radiotherapy, Adjuvant; Treatment Outcome

Goblet cell carcinoid of the large intestine is a rare neoplasm, usually located in ascending colon and rectum. A 60-year-old male patient underwent surgery after the diagnosis of acute abdomen. Exploratory laparotomy revealed perforation with a diameter of 1 cm at the site of the previously performed gastroenterostomy and dilatation of the right colic flexure, secondary to a solid obstructive mass located in the mid-portion of transverse colon. Histopathological investigation of the biopsies, taken from the gastroenterostomy site and the tumor, revealed mixed carcinoid-adenocarcinoma with carcinoid component, predominantly composed of goblet cells. Three cycles of FOLFOX-4 protocol was administered. Following respiratory distress secondary to pulmonary metastasis, the patient's condition deteriorated and subsequently died in the fourth postoperative month. Our aim with this paper is to point out that more cases should be reported for more effective diagnosis, histopathological study, clinical investigation, treatment and prognosis of this specific neoplasm.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Colon, Transverse; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Gastroenterostomy; Humans; Intestinal Perforation; Laparotomy; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Prognosis

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

Clinical path for executing mFOLFOX6 in an outpatient chemotherapy room was settled on for the aim of standardization and common information with medical staffs about mFOLFOX6. The feature of this clinical path is described doses of drugs, results of laboratory examination, criteria for deciding adverse effects, common adverse effects and management, criteria for reduction and suspension of oxaliplatin and 5-fluorouracil. Patients before induction of the clinical path were compared with patients after that about relative dose intensity (RDI), reasons why treatments were suspended and progression-free survival (PFS). Fifty eight patients after induction were significantly higher RDI of oxaliplatin than 108 patients before induction (p=0.04). There were no significant differences about a frequency of suspension due to adverse effects (p=0.18) and PFS (p=0.74). The clinical path that we settled on was considered useful not only for common information with medical staffs but also for standardization.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Critical Pathways; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cholangitis, Sclerosing; Colectomy; Colonic Neoplasms; Crohn Disease; Cytoprotection; Edetic Acid; Fluorouracil; Humans; Leucovorin; Male; Palliative Care; Pyridoxal Phosphate; Young Adult

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Colonoscopy; Female; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Organoplatinum Compounds; Polymerase Chain Reaction

Several studies have shown how cytostatics may cause hypofunction of salivary glands but failed to elucidate any potentially related side effects. Keeping in mind the sialochemical assistance and the role of saliva on the homeostasis of the stomatognathic system, the aim of this study was to establish potential gland disorders in patients submitted to 5- Fluorouracil (5-Fu) and Leucovorin calcium (LV) as well as their correlation with certain oral health disorders that diminish the quality of life.. the focus of this research was observational and longitudinal. Twenty-five patients diagnosed with colon cancer at an initial, intermediate and late phase submitted to specifically devised therapy were assessed. Clinical history, oral health indexes and basal or stimulated saliva samples were recorded.. Basal and stimulated flow dropped in the intermediate stage. Stimulated saliva pH decreased during treatment. On basal saliva, urea, sodium and potassium rose during the intermediate phase. Löe and Silness rates as well as simplified bleeding increased during therapy but reverted by the end of the treatment. Depth index of the vestibular gingival sulcus rose during the intermediate phase but did not return.. This treatment caused functional salivary gland disorders as evidenced by basal and stimulated hyposialia, and acidification of stimulated saliva pH during the intermediate phase. Increase in basal urea may be due to proteic catabolism arising from plasma or glands. Variation in Na+ and K+ of basal saliva concentrates might be assumed as a possible duct disorder. Recovery of bleeding and Löe and Silness rates may point to a transient inflammatory effect associated to a decrease in salivary flow. Increase in the depth rates of the periodontal vestibular sulcus could be correlated with a higher risk of periodontal disease.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Colonic Neoplasms; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Longitudinal Studies; Male; Middle Aged; Salivary Gland Diseases; Vitamin B Complex; Young Adult

A 58-year-old woman underwent right hemicolectomy with lymph node dissection(D2)for advanced ascending colon cancer which pathological examinations revealed to be moderately-differentiated adenocarcinoma. CEA and CA19-9 levels increased 6 months after the operation. She started adjuvant chemotherapy with oral administration of UFT-E(400 mg/day), but CEA and CA19-9 levels continued to elevate. However, a recurrent tumor was not detected by computed tomography(CT)and endoscopic examinations. A local recurrence in the right lateral abdominal wall was confirmed by PET-CT examination. We then conducted modified-FOLFOX6/FOLFIRI alternating regimen(modified- FIREFOX regimen). After this therapy, repeated PET-CT showed that the abnormal FDG-uptake concentration had disappeared, leading to a complete response(CR). The adverse event was grade 3 in leucopenia and grade 2 in gastrointestinal toxicity. She had maintained CR for the 12 months since undergoing chemotherapy. CEA and CA19-9 levels reduced to the normal range. We report this case with some review of the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Positron-Emission Tomography; Recurrence; Remission Induction; Tomography, X-Ray Computed

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Female; Fluorouracil; Health Services for the Aged; Humans; Leucovorin; Male; Organoplatinum Compounds

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Erythema; Fluorouracil; Foot; Hand; Humans; Leucovorin; Lymphatic Metastasis; Male; Organoplatinum Compounds; Oxaliplatin; Pain; Penis; Scrotum; Skin Diseases; Stomatitis; Syndrome

Topics: Adenocarcinoma; Adrenal Cortex Hormones; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lung Diseases, Interstitial; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

FOLFOX therapy is a commonly used chemotherapeutic regimen against recurrent and unresectable colon cancer. However, its acute neurotoxicity is rare and not well recognized. We herein report a case of mFOLFOX6-induced hyperammonemic encephalopathy in a patient having recurrent colon cancer. A 74-year-old female with a history of sigmoid colon cancer was diagnosed as liver, lung, and peritoneal recurrences by surveillance CT and PET/CT. She was initially treated with modified FOLFOX6 therapy. After completing treatment, she presented with sudden onset of confusion, cognitive disturbances, and repeated seizures. None of the other radiographic examinations and laboratory tests provided an explanation for her symptoms except hyperammonemia. She was treated with branched-chain amino acid solutions and high-volume drip infusion, 6 hours after which the encephalopathy resolved. Clinicians should be aware of the adverse hyperammonemia induced by mFOLFOX6 when patients treated with mFOLFOX6 present with neurological disorders.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Diseases, Metabolic; Colonic Neoplasms; Female; Fluorouracil; Humans; Hyperammonemia; Leucovorin; Organoplatinum Compounds; Positron-Emission Tomography; Recurrence; Tomography, X-Ray Computed

To estimate the modifying effect of age on the survival benefit associated with adjuvant chemotherapy receipt in elderly patients with a diagnosis of Stage III colon cancer.. Observational, retrospective cohort study using two samples: an overall sample of 7,182 patients to provide externally valid analyses and a propensity score-matched sample of 3,016 patients to provide more internally valid analyses by reducing the presence of treatment endogeneity. An interval-censored survival model with a complementary log-log link was used. Hazard ratios and 95% confidence intervals were obtained for all regressions.. Data from the National Cancer Institute's Surveillance, Epidemiology and End Results database and the linked Medicare enrollment and claims database were used.. Selected patients were aged 66 and older and had a diagnosis of Stage III colon cancer. Patients were followed from surgery to time of death or censorship.. The outcome was colon cancer-specific death during the follow-up period. Receipt of adjuvant chemotherapy was measured according to the presence of a claim for 5-fluorouracil or leucovorin within 6 months after surgery.. All elderly patients had a significant survival benefit associated with adjuvant chemotherapy receipt, although the survival benefit of adjuvant chemotherapy was not uniform across all age groups.. These findings have important clinical and policy implications for the risk-benefit calculation induced by treatment in older patients with Stage III colon cancer. The results suggest that there is a benefit from chemotherapy, but the benefit is lower with older age.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Logistic Models; Male; Medicare; Neoplasm Staging; Proportional Hazards Models; Retrospective Studies; SEER Program; Survival Analysis; Treatment Outcome; United States

5-Fluorouracil (5-FU) is the most commonly used chemotherapeutic agent for colorectal cancer (CRC). However, resistance to this drug is a major obstacle in CRC chemotherapy. Accurate prediction of response to 5-FU would avoid unnecessary chemotherapy and allow the selection of other effective drugs. To identify a candidate predictor of 5-FU resistance, we isolated secreted proteins that were up- or downregulated in a 5-FU-resistant cancer cell line, compared with the parent cell line (SNU-C4), using a stable isotope-coded labeling protocol. For validating the clinical applicability of this method, levels of the identified proteins were determined in the sera of 46 patients treated with 5-FU. In total, 238 proteins with molecular weights ranging from 50 to 75 kDa were identified. Among these, 45 and 35 secreted proteins were up- and downregulated in the 5-FU-resistant cell line, respectively. We observed significant upregulation of glycolytic enzymes, including glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase M2 (PK-M2), transketolase, and NADP(+)-dependent malic enzyme 1. In particular, the level of PK-M2, a key enzyme in the glycolytic pathway, showed an increasing tendency in both sera and tissues from CRC patients displaying no response to 5-FU-based chemotherapy (progressive and stable disease cases), compared with that in complete or partial responders to 5-FU-based chemotherapy; however, it did not reach the statistical significance. In conclusion, increasing pattern of PK-M2 observed with 5-FU resistance induced in vitro and in sera and tissues from CRC patients displaying poor response to 5-FU-based chemotherapy suggest the relevance of dysregulated glycolysis and 5-FU-resistant CRC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cell Line, Tumor; Colonic Neoplasms; Down-Regulation; Drug Resistance, Neoplasm; Female; Fluorouracil; Glycolysis; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoplasm Proteins; Proteome; Pyruvate Kinase; Reproducibility of Results; Up-Regulation

A 50-year-old man undergoing operations for sigmoid colon cancer, small intestine invasion, and liver metastasis was given adjuvant chemotherapy postoperatively. During the course, lung, brain and bone metastasis were found, FOLFIRI therapy was started. Fifth FOLFIRI therapy was performed, but on the night of the next day, he was transported on an emergency basis to our hospital because of a coma. Laboratory examination revealed hyperammonemia, so aminoleban was started for its treatment. After 3 days in the hospital, consciousness and serum ammonia were improved. Cases of hyperammonemia caused by 5-FU have been reported in the literature, and this case was diagnosed with the same. Hyperammonemia should be taken into account as a differential diagnosis in the disturbance of consciousness in chemotherapy.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Consciousness Disorders; Fluorouracil; Humans; Hyperammonemia; Irinotecan; Leucovorin; Male; Middle Aged

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Genes, Neoplasm; Humans; Leucovorin; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Radiotherapy, Adjuvant

Reversible posterior leukoencephalopathy (RPLS), also known as posterior reversible encephalopathy syndrome, is characterized by magnetic resonance imaging (MRI) findings of reversible vasogenic subcortical edema without infarction. The clinical presentation is usually nonspecific and typically involves global encephalopathy, seizures, headache, or visual symptoms. MRI of the brain is essential to the diagnosis of RPLS. Typical findings of RPLS include high-intensity signal on T2-weighted images predominantly in the posterior lobes of the brain that is caused by subcortical white matter vasogenic edema. Fluid-attenuated inversion recovery (FLAIR) sequences on MRI improve sensitivity and detect subtle peripheral lesions. This clinical radiographic syndrome has been described in a number of medical conditions, with hypertensive encephalopathy, eclampsia, and the use of immunosuppressant drugs (most notably calcineurin inhibitors) being the most common. It has occasionally been reported with cisplatin and rarely with carboplatin. Its occurrence with oxaliplatin is very unusual. An extensive literature search including PUBMED and direct contact with the drug manufacturer yielded only 2 known case reports. Herein, we describe a case that had classic clinical and radiologic features of RPLS. We also briefly describe 2 other patients who have been described to have RPLS with oxaliplatin in the literature.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Posterior Leukoencephalopathy Syndrome; Prognosis; 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

A cost-effectiveness analysis of oral capecitabine versus intravenous bolus 5-fluorouracil/l-leucovorin (FU/LV) as adjuvant therapy in patients with stage 3 colon cancer was performed from a Japanese healthcare payer perspective.. Adjuvant therapy comprised 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily on days 1-14 of a 21-day cycle or intravenous bolus FU 500 mg/m(2) and LV 250 mg/m(2) weekly for 6 weeks of an 8-week cycle (Roswell Park regimen). The analysis comprised short-term (1 year after initiation of adjuvant therapy) and long-term (up to 15 years) components. The long-term analysis involved a three-state (disease-free, recurrence and death) Markov model. Estimates for transition probabilities, costs and utilities were derived from the X-ACT trial, a Japanese phase II trial, and other published sources. Cost estimates were considered from the perspective of a healthcare payer. Costs were expressed in Japanese Yen (yen), year 2007 values. A discount rate of 3% was applied to costs and outcomes. Cost effectiveness was expressed as a cost per QALY. The effects of uncertainty were explored through one-way and probabilistic sensitivity analyses.. In the 1-year analysis, direct costs were yen440,000 ($US4000) less per patient with capecitabine than with FU/LV. In the long-term analysis, differences between treatments in direct medical costs ranged from yen470,000 ($US4300) to yen580,000 ($US5300) depending on the time horizon used. Capecitabine was also projected to increase the number of QALYs compared with FU/LV. The sensitivity analysis suggested that the model outcome was robust. The probabilistic sensitivity analysis estimate of capecitabine being the dominant regimen was 96.6% at a zero willingness to pay. Direct costs remained lower with capecitabine if the price of generic LV was >OR=50% of the branded product.. This analysis suggests that capecitabine improves health outcomes and lowers direct costs compared with bolus FU/LV (i.e. dominant treatment strategy) when used as adjuvant therapy in patients with stage 3 colon cancer in Japan.

Topics: Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Markov Chains; Middle Aged

Prognosis of stage II colorectal cancer varies. Whether or not to perform adjuvant chemotherapy on patients with stage II colorectal cancer is controversial. This study was to explore the prognostic factors for the patients with stage II colorectal cancer and evaluate the effect and the necessity of adjuvant chemotherapy.. Between January 2000 and January 2005, 443 patients with stage II colorectal cancer receiving radical surgery at Sun Yat-sen University Cancer Center were retrospectively analyzed. The overall survival rate and survival curve were analyzed using the Kaplan-Meier method and the log-rank test. The univariate and multivariate prognostic analyses were performed by the Cox regression model. Patients with or without chemotherapy (Xelox/Folfox regimen) with high-risk factors were analyzed respectively.. The median follow-up time was 59 months, and the 3-and 5-year survival rates were 88.4% and 82.5%, respectively. Univariate analysis showed that intestinal obstruction or perforation, diabetes mellitus, inadequate surgical margin, and the number of sampled nodes < 9 were poor prognostic factors. Patients with intestinal obstruction or perforation, the number of sampled nodes < 9 achieved higher 5-year survival (80% and 86%) undergoing adjuvant chemotherapy than those receiving surgery alone (67% and 64%).. The prognosis of colorectal cancer patients with intestinal obstruction or perforation, diabetes mellitus, inadequate surgical margin, and the number of sampled nodes < 9 are relatively poor. Adjuvant chemotherapy is recommended to patients with intestinal obstruction, perforation or sampled nodes < 9.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Child; Colonic Neoplasms; Deoxycytidine; Female; Fluorouracil; Follow-Up Studies; Humans; Intestinal Obstruction; Intestinal Perforation; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaloacetates; Proportional Hazards Models; Rectal Neoplasms; Retrospective Studies; Survival Rate; Young Adult

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

The patient was a 41-year-old female, who underwent histectomy and sdnexopexy due to perforated ovarian tumor. One month later, she was diagnosed with simultaneous bilateral metastatic ovarian tumor of colon cancer, and right hemicolectomy (D3) was performed. After surgery, the patient was treated with 10 courses of therapy with the FOLFOX4 regimen. No recurrence was recognized, and the patient was treated with 12 courses of therapy with oral tegafur/ uracil (UFT)+oral Leucovorin (LV). The patient evidenced no tumor recurrence 2 years after the initial treatment. We consider oral UFT+oral LV therapy was useful for post FOLFOX4 therapy after R0 surgery.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Ovarian Neoplasms; Tegafur; Uracil; Vitamin B Complex

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

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome

A 77-year-old woman was admitted to our hospital because of para-aortic lymph node swelling pointed out by abdominal CT scan. She had a previous history of colectomy with a diagnosis of ascending colonic cancer 8 years later. Pathological examination was a moderately-differentiated adenocarcinoma with lymph node metastasis (Stage IIIa). PET scan demonstrated hot spots of para-aortic and left supra-clavicular lesions. The serum CEA and CA19-9 levels regained the normal value. No malignancy was recognized by endoscopic examinations of upper and lower gastrointestinal tract. We supported that swelling of lymph nodes were due to lymphoma. Laparotomic biopsy of para-aortic lymph node was done after 6 months. Histologically metastatic adenocarcinoma was recognized. We performed systemic chemotherapy of UFT and LV on recurrent colonic cancer. After 9 courses, spots of para-aortic and left supra-clavicular lesions disappeared on the PET scan. Lymph node metastasis was not found by CT scan 20 months after beginning chemotherapy. Thus, we consider that this therapy was recommendable for the treatment of an older adult patient with recurrent colonic cancer.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aorta, Abdominal; Colectomy; Colonic Neoplasms; Female; Humans; Leucovorin; Lymphatic Metastasis; Positron-Emission Tomography; Tegafur; Time Factors; Uracil

We report a case of ascending colon cancer successfully treated for synchronous liver metastases with mFOLFOX6 after a resection of the primary tumor. A 79-year-old woman was diagnosed as having an ascending colon cancer with synchronous liver metastases. After right hemicolectomy, she was treated with mFOLFOX6. A partial response was observed after the fifth course and CEA decreased to a normal range (8 ng/mL). A complete response was observed after the ninth course and the treatment finished at the twelfth course. Sequentially, she was treated with UFT/LV/PSK after three courses of FOLFIRI regimen. The patient is alive without recurrence.

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

A 45-year-old male patient with right colonic cancer, of which clinical finding was SIM1 (No.216), Stage IV, underwent extended right hemicolectomy with paraaortic lymph node resection as surgical treatment. However, CY1 was detected and a final finding was SIM1 (No.216) H0CY1, Stage IV. After the operation, we administered 3-course of FOLFOX4 plus bevacizumab protocol, 3-course of FOLFOX4, 6-course of FOLFIRI, and 6-course of IRIS for one year. The patient is presently alive with no sign of recurrence after 22 months.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Combined Modality Therapy; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Oxonic Acid; Postoperative Period; Tegafur

We report a case of transverse colon cancer with gastric regional lymph node metastasis. A 50-year-old man was admitted to our hospital for abdominal distension and abnormal evacuation. He was diagnosed with advanced transverse colon cancer with regional lymph node metastasis by a barium enema examination and computed tomography. In operative findings, the main tumor at splenic flexure had invaded greater omentum. Therefore, left hemicolectomy with D3 lymph node dissection including gastroepiploic lymph node (classified to No. 204) was performed. Histopathological examination revealed the metastasis to gastroepiploic lymph node. Six months after initial surgery, mediastinal and hilar lymph node swelling was detected by follow-up CT scan, although mFOLFOX6 was administered as postoperative adjuvant chemotherapy. We therefore performed FOLFIRI as second-line chemotherapy. He had a stable disease during FOLFIRI. Extensive lymph node dissection of gastric region may be useful for advanced transverse cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colon, Transverse; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Stomach

We report a case of ovarian metastasis after complete response of colon cancer. A 55-year-old woman underwent a sigmoidectomy for sigmoid colon cancer with hepatic metastasis and para-aorta lymph node metastasis. After the operation, the patient was given chemotherapy with bevacizumab+mFOLFOX6. Nine months after the operation, the patient was judged to have achieved complete response. Thirteen months after the operation, right ovarian tumor was found and bilateral oophrectomy, hysterectomy and omentectomy were performed. Histopathologically the ovarian tumor was metastasized from colonic cancer. After the second operation, the patient was given chemotherapy with bevacizumab+FOLFIRI. At present, the patient remains disease-free for 6 months after the ovarian operation.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Hysterectomy; Leucovorin; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Ovariectomy

The standard chemotherapy regimen for esophageal cancer is cisplatin and 5-fluorouracil (5-FU). We herein report a case of esophageal cancer associated with colon cancer, which was treated with combination chemotherapy of FOLFOX. The patient received chemotherapy of modified FOLFOX6 (mFOLFOX6) at dosages of 80% of standard regimen (oxaliplatin 68 mg/m2, levofolinate calcium 160 mg/m2, bolus 5-FU 320 mg/m2, and followed by continuous 5-FU 1,920 mg/m2/ 46 hr) in combination with radiotherapy (total 61.6 Gy). He developed grade 3 leukopenia after 2 courses of mFOLFOX6 and the 3rd course was started at dosages of 70% of standard regimen with 1 week delay. After that, no other adverse event without grade 2 esophagitis was appeared. Esophagogram revealed a partial response in primary tumor of the esophagus after 3 courses of chemotherapy with radiotherapy and blood chemistry examination showed negative squamous cell carcinoma antigen. One month after chemoradiotherapy, esophagogram revealed tracheoesophageal fistula, but tumor of the esophagus was well controlled. FOLFOX regimen combined with radiotherapy is well tolerated and effective for inoperable esophageal cancer. FOLFOX cannot be used for esophageal cancer in Japan, so clinical trial of FOLFOX for esophageal cancer should be conducted in the near future in Japan.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Esophageal Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms, Multiple Primary; Organoplatinum Compounds

We undertook this study to analyze clinical features and surgical outcome of en bloc resections of the right side colon cancer directly invading duodenum and/or pancreatic head.. The records of all patients who underwent en bloc resection of duodenum and/or pancreas for right colon cancers were analyzed retrospectively. From September 1994 to September 2006, 1,016 patients underwent curative right hemicolectomy. Nine patients (0.9%) had en bloc resection of a right side colon cancer with duodenum or pancreatic head invasion.. The median operative time was 320 minutes (range, 200-420) and the median blood loss was 700 mL (range, 100-2,000). The mean size of tumor was 6.6 cm (range, 3.2-10.7). The mean preoperative carcinoembryonic antigen (CEA) was 10.6 ng/mL (range, 0.2-50.8). There was no 30 day perioperative mortality. The median disease-free survival was 23.5 months [95% confidence interval (CI) 5.2-41.8] and the median overall survival was 28.1 months (95% CI 9.7-46.5).. In patients with locally advanced right side colon cancer that directly invades the duodenum or pancreas can be safely resected with curative potential with minimum morbidity and mortality. Long term disease free survival can occur in a significant number of patients undergoing curative en bloc resection in this particular subset of patients.

Topics: Adult; Aged; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Duodenal Neoplasms; Duodenum; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreas; Pancreatic Neoplasms; Retrospective Studies; Treatment Outcome

The efficacy of adjuvant chemotherapy in colon cancer has been well established in clinical trials, yet data on its routinely clinical practice are few. Two hundred forty-one patients were treated with fluorouracil-based adjuvant therapy from 1996 to 2001 and 147 out of 241 patients consecutively treated was aged 65 years or more at the time of diagnosis. Kaplan-Meyer progression-free survival and overall survival of stage II and III patients were calculated, the same statistic analyses were done for elderly population. Three- and 5-year overall survivals were respectively 94.4% and 90.4%. The survival observed in our retrospective study reflects that reported in the chemotherapy arm of randomized clinical trials. As expected, stage II patients survival was better than that of stage III patients (p = 0.0019, log-rank test). The treatment was generally well tolerated and there was no therapy related death and no clinical immonotoxicological effects was observed also in elderly patients.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Randomized Controlled Trials as Topic; Retrospective Studies; Survival Rate; Vitamin B Complex

Five-fluorouracil (FU), mainly associated with leucovorin (L), plays an essential role in chemotherapy of colorectal carcinoma. Moreover, FU +/- L has been found to increase the expression of tumor-associated carcinoembryonic antigen (CEA), that may be an important target in therapeutic protocols of active specific immunotherapy. FU + L (FUL) are frequently combined with oxaliplatin (OXA) in advanced colon cancer patients. Thus, we investigated whether FUL in combination with OXA according to 2 different schedules may influence CEA expression in human colon cancer cells in vitro.. CEA protein expression was evaluated by cytofluorimetric and western blot analysis. Relative quantification of CEA mRNA was assessed by real time RT-PCR analysis.. Levels of CEA protein and transcript were found to be higher in FUL-treated cells than in controls. However, when target cells were exposed to OXA before but not after FUL treatment, the up-regulation of CEA was partially inhibited.. These results suggest that target cells must be exposed to OXA after but not before treatment with the fluoropyrimidine in order to exploit drug-induced up-regulation of CEA. This finding appears to provide useful information to design chemo-immunotherapy protocols based on FUL + OXA, combined with host's immunity against CEA directed cancer vaccines.

Topics: Antineoplastic Agents; Carcinoembryonic Antigen; Cell Line, Tumor; Colonic Neoplasms; Flow Cytometry; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; RNA, Messenger

A 78-year-old male with sigmoid colon cancer underwent sigmoidectomy. The lesion was se, p1(+), n1, and Stage IV. Oral UFT therapy was performed, but was replaced with oral S-1 therapy 1 year and 6 months after surgery. Three months later, lung metastases 2.0 x 1.5 cm and 0.6 x 0.6 cm were found by chest CT in right S10a and S5b, respectively. Since the patient did not wish surgery, the treatment was changed to oral UFT/Leucovorin(LV)therapy(UFT 300 mg/ LV 75 mg, 4-week administration and 1-week no-administration periods). After 2 courses, chest CT showed disappearance of both lung metastases, indicating complete remission. Oral UFT/LV therapy is convenient because of the oral route. Adverse reactions are few, and the therapeutic effect has been reported to be comparable to that of intravenous 5-FU/LV therapy. Also, in this patient, no adverse reaction was noted, and complete remission was maintained until the patient died of another disease 31 months after the beginning of oral UFT/LV therapy.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Humans; Leucovorin; Lung Neoplasms; Male; Radiography; Tegafur; Uracil

An 81-year-old woman, who suffered from ascending colon cancer with liver metastases, underwent right hemicolectomy. She did not undergo liver resection due to her age and her family's decision, and was treated with UFT plus oral Leucovorin therapy. The metastases were remarkably reduced in the early phase and disappeared completely on SPIO-MRI 2 years 9 months later. Adverse effects of this therapy are relatively few, and it can serve as first-line chemotherapy for advanced colorectal cancer.

Topics: Administration, Oral; Aged, 80 and over; Colonic Neoplasms; Female; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Tegafur; Uracil

Thymidylate synthase (TS) is a potentially valuable marker for therapy response since it is the molecular target of 5-fluorouracil (5-FU). TS can be analyzed at the DNA (gene polymorphisms and amplification) and protein level (immunohistochemistry). This study investigated the predictive role of TS at the DNA and protein levels in patients with N(+) colon cancer (n = 38). Tumor and normal tissues were genotyped using PCR for variable number of tandem repeats (VNTR), a single nucleotide polymorphism (SNP) in the 3R allele and a 6 bp deletion (1494del6) in the TS gene. Tumor tissues were additionally analyzed for loss of heterozygosity (VNTR polymorphism). A newly developed real time PCR assay was used to detect the presence of TS gene amplifications in tumor tissues. VNTR analysis in normal tissue was significantly associated with distant tumor recurrence (8% for 2R/2R vs. 52% for patients carrying a 3R allele, p = 0.038) and cancer-specific survival (p = 0.021). IHC was not found to be significantly associated with patients' outcome. No correlations between TS gene polymorphisms and IHC were found. However, TS gene amplification was correlated with a strong IHC staining intensity. In conclusion, this study indicates that DNA based analysis is more predictive for patients' outcome than TS IHC.

Topics: Adenocarcinoma; Adult; Aged; Colonic Neoplasms; Combined Modality Therapy; DNA, Neoplasm; Female; Fluorouracil; Gene Amplification; Genotype; Humans; Immunohistochemistry; Leucovorin; Loss of Heterozygosity; Male; Middle Aged; Minisatellite Repeats; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Retrospective Studies; Thymidylate Synthase

Some patients with initially unresectable hepatic colorectal cancer metastases can be effectively treated with neoadjuvant chemotherapy to allow operative resection in curative intent. Here, we report on a patient with unresectable locoregional recurrence of colon cancer, which was down-staged using combination chemotherapy with infusional 5-fluorouracil, folinic acid, oxaliplatin and cetuximab. After 12 weeks of therapy a partial response was documented and 3 weeks later the tumor was completely resected without increased perioperative morbidity. Therefore, neoadjuvant treatment with molecular targeted agents in combination with chemotherapy can also be an option to enable selected patients with locoregional recurrence to undergo surgical resection in curative intent.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cetuximab; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Invasiveness; Neoplasm Staging; Neoplastic Cells, Circulating; Reoperation; Retroperitoneal Neoplasms

In the recent X-ACT (Xeloda in Adjuvant Colon cancer Therapy) trial, oral capecitabine (Xeloda) demonstrated superior efficacy and an improved safety profile compared with infused fluorouracil + leucovorin (folinic acid) [FU+LV] in patients with Dukes' C colorectal cancer. We used the X-ACT results to determine the cost effectiveness of capecitabine compared with FU+LV from the perspective of the Italian National Health Service (NHS).. Medical resource use data were collected throughout the treatment period. Unit costs for drug administration, hospitalization, emergency room visits and concomitant medications were obtained using Italian published sources. A health-state transition model was used to estimate the incremental cost-effectiveness ratio per quality-adjusted life-month (QALM) gains in the intent-to-treat population (1004 and 983 patients in the capecitabine and FU+LV arms, respectively). Costs and effectiveness were discounted at 3.5%. Costs were calculated in euros (2005 values).. Administration of capecitabine required fewer clinic visits per patient than FU+LV (7.35 vs 28.0, respectively). Mean acquisition costs per patient for capecitabine were higher than for FU+LV (euro 2533 vs euro 231, respectively), but this difference was offset by the difference in mean chemotherapy administration costs per patient for FU+LV (euro 4338, compared with euro 152 for capecitabine). Mean total hospital days and medication costs for treatment-related adverse events were higher for FU+LV than for capecitabine (euro 352 vs euro 78, respectively). The cost of emergency room visits for the treatment of adverse events did not differ between the treatment groups. With respect to the lifetime horizon, compared with FU+LV, capecitabine is projected to increase QALMs by a mean 6.5 months, with overall cost savings of euro 2234 over the treatment period. These findings show that capecitabine is an economically dominant treatment in this setting.. Adjuvant capecitabine for patients with Dukes' C colon cancer has the same activity in terms of outcome when compared with FU+LV but is a lower cost option from the economic perspective of the Italian NHS.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Cost-Benefit Analysis; Deoxycytidine; Female; Fluorouracil; Health Care Costs; Humans; Infusions, Parenteral; Italy; Leucovorin; Male; Middle Aged; National Health Programs; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Young Adult

Topics: Adaptor Proteins, Signal Transducing; Adenosine Triphosphatases; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Repair Enzymes; DNA-Binding Proteins; Fluorouracil; Humans; Leucovorin; Microsatellite Instability; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; MutS Homolog 2 Protein; Nuclear Proteins; Organoplatinum Compounds

To understand the mechanism by which (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, exerts its anti-inflammatory action.. To check our hypothesis that the anti-inflammatory properties of EGCG could be related to its antifolate action and whether adenosine and its receptors are involved in EGCG action, we investigated the EGCG-induced suppression of NF-kappaB in Caco-2 cell monolayer, which acted as a model of the human intestinal epithelium.. We demonstrate that the anti-inflammatory properties of EGCG are associated with its antifolate activity. By using a natural stable folate we were able to reverse the EGCG suppression of TNF-alpha-induced NF-kappaB activation, the phosphorylation and degradation of IkappaBalpha and the phosphorylation of Akt in this human colon carcinoma cell line. These suppressions were mediated by the release of adenosine following disruption of the folate cycle by EGCG. By binding to its specific receptors, adenosine can modulate the Akt and NF-kappaB pathway. Moreover, EGCG produces a significant increase in a specific adenosine receptor, which could explain the suppression of the constitutive activation of NF-kappaB in colon cancer cells.. The data suggest that by modulating NF-kappaB activation, EGCG might not only combat inflammation, but also cancer.

Topics: Adenosine; Anticarcinogenic Agents; Antioxidants; Caco-2 Cells; Catechin; Colonic Neoplasms; Folic Acid; Humans; I-kappa B Proteins; Leucovorin; NF-kappa B; NF-KappaB Inhibitor alpha; Proto-Oncogene Proteins c-akt; Tumor Necrosis Factor-alpha; Vitamin B Complex

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Paresthesia

Oxaliplatin (L-OHP) is one of the key drugs against advanced, recurrent colorectal cancer, and FOLFOX4 regimen combination of l-leucovorin (l-LV)and 5-fluorouracil (5-FU)with oxaliplatin is a standard therapy in colorectal cancer. We performed a retrospective study that researched adverse events and relative dose intensity(RDI)to evaluate safety and feasibility of FOLFOX4 regimen.. We administered 188 patients a FOLFOX4 regimen. To evaluate RDI, this study research dose modification and delay treatment procedure was done for 1 to 13 cycles.. RDI of oxaliplatin is 89.1% (1-4 cycles), 81.4% (4-7 cycles), 78.2% (7-10 cycles), 69.0% (10-13 cycles). The factors of RDI decrease were hematologic toxicity(leucopenia, neutropenia, thrombocytopenia), peripheral neuropathy and allergic reaction. Moreover, peripheral neuropathy and allergic reaction often require therapy to be discontinued (peripheral neuropathy: 15.2%, allergic reaction: 20.3%).. Feasibility of FOLFOX4 regimen is related to incidents of hematologic toxicity, peripheral neuropathy and allergic reaction. We should pay sufficient attention to these adverse events of FOLFOX4.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

We reported a case of super-elderly colon cancer with peritoneal dissemination effectively treated with modified FOLFOX6 chemotherapy. A 80-year-old woman was referred to our hospital for abdominal distension in January 2007. Abdominal CT showed peritoneal dissemination and colonoscopy revealed transverse colon cancer. The patient's performance status (PS) score was 3. She had pleural effusion on the left side and massive acsites. After the general condition was improved, operation was performed for sub-ileus in March, but it became a probe laparotomy for severe peritoneal dissemination. We tried modified FOLFOX6 chemotherapy from April. The patient's pleural effusion decreased after 3 courses of chemotherapy and we could remove the thoracic tube. Massive acsites observed in abdominal CT disappeared after 5 courses of chemotherapy. The patient did not suffer from sub-ileus after around 8 courses of chemotherapy and she could then take food. The patient's PS score became 1, and she was discharged in September. Two more courses of chemotherapy were given on as an outpatient basis. The chemotherapy was changed to S-1 on the patient's request in November. As of February 2008, the patient's PS score was 0, and she has been under treatment as an outpatient.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Peritoneal Neoplasms; Tomography, X-Ray Computed

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Hepatic Veno-Occlusive Disease; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds

A 62-year-old male presents with colon cancer that has metastasized to both lobes of the liver. Resection was performed; chemotherapy initially consisted of combination treatment with FOLFIRI or XELIRI plus bevacizumab, with the possibility of changing treatment to either FU/LV or capecitabine, combined with bevacizumab. Although reported data would allow the consideration of a strategy of sequential treatment in this patient, the consulting oncologists treating him have acknowledged the benefit of a strategy employing "inductive" combination chemotherapy plus monoclonal antibodies. Combination chemotherapy offers the potential for longer treatment holidays than is possible with sequential therapy. One of the enduring concepts informing treatment decisions for mCRC is that patients who receive the three mainstays of drug treatment fluorouracil, irinotecan, and oxaliplatin fare better than those who do not.

Topics: Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male

Oral tegafur/uracil (UFT)/Leucovorin (LV) therapy has been used for chemotherapy for advanced colorectal cancer with anti-cancer effects the same as conventional 5-fluorouracil and Leucovorin (5-FU/LV). However, the effectiveness and safety of UFT/LV in the treatment of elderly patients with advanced colorectal cancer is not evaluated. We report a case of multiple lymph node metastases from colon cancer successfully treated with UFT/LV. An 81-year-old man had been admitted to our hospital because of left neck and axillary mass, which was diagnosed as transverse colon cancer with multiple lymph node metastases. After a laparoscopic partial resection of transverse colon, UFT/LV (UFT 300 mg/m2/day and LV 75 mg/day) was administered for 4-week-on and 1-week-off. After the administration of the chemotherapy, a good partial response of these metastatic lymph nodes was achieved. No grade 3 or more severe adverse reactions have been observed. He has now survived for 14 months without a recurrence after the administration of the chemotherapy. This case suggests the effectiveness and safety of UFT/LV in elderly patients with colorectal cancer.

Topics: Administration, Oral; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colon, Transverse; Colonic Neoplasms; Humans; Leucovorin; Lymphatic Metastasis; Male; Tegafur; Tomography, X-Ray Computed

Bevacizumab (Avastin) is a monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that has demonstrated increased overall survival when added to standard chemotherapy regimens in patients with metastatic colorectal cancer. Gastrointestinal perforation is a known risk factor of unknown etiology associated with the use of bevacizumab.. We report a 61-year-old woman with adenocarcinoma of the colon ascendens who underwent hemicolectomy and adjuvant chemotherapy with oxaliplatin, 5-fluorouracil, and leucovorin. Eight months after the operation, we started therapy with bevacizumab combined with irinotecan, 5-fluorouracil, and leucovorin due to disease progression. Two months after completion of this therapy, ischemic anastomotic bowel perforation occurred and a resection of the anastomosis was performed. Because of anastomotic insufficiency 8 days later, a further revision had to be done and the terminal ileum and the colon were brought out through a stoma.. This case is unusual because the time interval between the primary operation and the application of bevacizumab is regarded as safe with regard to the risk of perforation. An ischemic genesis of the perforation was considered on the basis of the histopathological workup. In case of perforations during therapy with bevacizumab, a safe surgical approach should be preferred, i.e., a transient stoma instead of a primary reconstruction of the bowel passage.

Topics: Anastomosis, Surgical; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colectomy; Colitis, Ischemic; Colonic Neoplasms; Female; Fluorouracil; Humans; Ileostomy; Ileum; Intestinal Perforation; Ischemia; Leucovorin; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Reoperation; Surgical Wound Dehiscence; Tomography, X-Ray Computed

Although 5-fluorouracil (5-FU) plus leucovorin (LV) is a standard chemotherapy regimen for colorectal cancer, the factors that determine the LV-mediated enhancement of the antitumor activity of 5-FU have remained unknown. We investigated the roles of folylpolyglutamate synthase (FPGS) and gamma-glutamyl hydrolase (GGH), which are the main enzymes involved in folate metabolism, in the effect of LV. LV enhanced the anticancer activity of 5-FU and the level of reduced folate in human colon cancer cells. Small-interfering RNA (siRNA) transfected into DLD-1 cells to downregulate FPGS reduced the basal level of reduced folate, the folate level after LV treatment, and the enhancement of 5-fluoro-2'-deoxyuridine (FdUrd)-induced cytotoxicity elicited by LV. By contrast, the downregulation of GGH by siRNA increased cellular sensitivity to FdUrd combined with LV. These results suggest that FPGS and GGH expression levels in tumors are determinants of the efficacy of LV in enhancing the antitumor activity of 5-FU.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; gamma-Glutamyl Hydrolase; Humans; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Peptide Synthases; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Calcium Compounds; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Magnesium Compounds; Male; Organoplatinum Compounds; Oxaliplatin; Priapism

The current standard adjuvant chemotherapy for suitable patients with stage III colon cancer is the combination of oxaliplatin and 5-fluorouracil plus folinic acid (5-FU/LV). However, until recently and for many years prior to this, the accepted standard adjuvant chemotherapy was 6-8 months of bolus 5-FU/LV. However, bolus treatment was associated with significant toxicity, namely stomatitis, diarrhea and neutropenia, in addition to multiple hospital visits for drug administration for patients. The X-ACT trial (Xeloda in Adjuvant Colon Cancer Therapy) compared traditional bolus 5-FU/LV (as per the Mayo Clinic regimen) with capecitabine, in the adjuvant treatment of 1987 stage III colon cancer patients. The main safety, efficacy and pharmacoeconomic results have all been published, and the updated 5-year efficacy results have also recently been presented. This trial demonstrated that capecitabine was at least as effective as bolus 5-FU/LV in terms of disease-free and overall survival, with trends towards superiority for both. Moreover, there was much less toxicity associated with capecitabine, apart from hand-foot syndrome which was significantly more prevalent. On the basis of the X-ACT trial, capecitabine was approved by the US FDA, the National Institute for Clinical Excellence and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Costs and Cost Analysis; Deoxycytidine; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Male; Middle Aged; Multivariate Analysis; Neoplasm Staging; Survival Rate

GOLFIG-1 chemo-immunotherapy is a new translational anticancer regimen based on the combined use of gemcitabine, oxalipatin, levofolinic acid and infusional 5-fluorouracil together with the subcutaneous administration immunoadjuvant cytokines (GM-CSF and ultra low dose IL-2). This regimen, tested in a phase II trial, was safe and very active in patients with metastatic colorectal carcinoma and it has been shown to have powerful immunobiological activity. Treatment with the GOLFIG regimen resulted in the induction of a colon cancer specific cell mediated immune response associated with a significant reduction in the percentage of peripheral regulatory T (T(reg)) cells, a very immunosuppressive lymphocyte subset which is commonly over-represented in cancer patients. These cells are able to prevent the occurrence of autoimmunity in response to immunological stimuli, thus their malfunctioning has been associated with the occurrence of auto-immune diseases but may also be responsible for more efficient anticancer immune reaction. In this manuscript we describe a clinical case concerning a patient with metastatic colon carcinoma who responded to the GOLFIG regimen, showed symptoms of autoimmunity [Discoid Lupus Erythematosus (DLE)] and had a very long survival.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Autoimmunity; Colonic Neoplasms; Deoxycytidine; Female; Flow Cytometry; Fluorouracil; Gemcitabine; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunotherapy; Interleukin-2; Leucovorin; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin

Two recent North American studies have shown that completion of 5-fluorouracil (5FU)-based adjuvant chemotherapy is a major prognostic factor for the survival of elderly stage III colon cancer patients. The aim of the present study was to confirm this finding in a population-based series from Australia. The study cohort comprised 851 stage III colon cancer patients treated by surgery alone and 461 who initiated the Mayo chemotherapy regime. One-third of patients who initiated chemotherapy failed to complete more than three cycles of treatment. Independent predictors for failure to complete were treatment in district or rural hospitals, low socioeconomic index and treatment by a low-volume surgeon. Patients who failed to complete chemotherapy showed worse cancer-specific survival compared not only to those who completed treatment (HR=2.24; 95% confidence interval (CI) (1.66-3.03), P<0.001) but also to those treated by surgery alone (HR=1.37; 95% CI (1.09-1.72), P=0.008). The current and previous studies demonstrate the importance of completing adjuvant 5-FU-based chemotherapy for colon cancer. Further prospective studies are required to identify better the physiological and socioeconomic factors responsible for failure to complete chemotherapy so that appropriate improvements in health service delivery can be made.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Survival Analysis

We evaluated the efficacy and safety of modified FOLFIRI for patients with refractory advanced or recurrent colorectal cancer. Modified FOLFIRI was given 29 patients (21 men and 8 women, with a median age of 61.0 years) from 2 to 16 times (median 10.0). 19 out of 29 patients were colon cancer, and the other 10 were rectal cancer. 18 patients were administered as first-line chemotherapy, and 11 were more than second line. CPT-11 was administered at a dose of under 150 mg/m(2), to remain within the limits in Japan. The response to treatment was CR in 3 patients, PR in 8, and SD in 12. The response rate was 37.9%. Grade 4 hematologic toxicities included leukocytopenia in 2 patients, neutropenia in 7 and anemia in 1. Grade 3/4 non-hematologic toxicities included febrile neutropenia in 4 patients, anorexia in 3, fatigue in 3, and nausea, diarrhea and interstitial pneumonia in 1. Except in 2 patients, all reactions could be controlled with the use of G-CSF or by setting drug holiday. In summary, modified FOLFIRI is a safe and effective regimen even at a dose of under 150 mg/m(2), of CPT-11. It can be given with good tolerance for patients with refractory advanced or recurrent colorectal cancer on an outpatient basis with due care especially for neutropenia.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intravenous; Irinotecan; Leucovorin; Leukopenia; Male; Middle Aged; Neutropenia; Quality of Life; Rectal Neoplasms

Patients aged > or = 70 years with colon cancer benefit from chemotherapy, with no major added toxicities compared with a younger population. However, the safety and efficacy of chemotherapy or chemoradiation therapy in octogenarians and nonagenarians with colorectal cancer (CRC) has not been previously reported.. We conducted a retrospective study of the safety and efficacy of chemotherapy or chemoradiation therapy in patients with CRC treated between January 2002 and June 2006 at Roswell Park Cancer Institute.. Thirty-three patients were identified, 24 of whom had colon cancer and 9 of whom had rectal cancer. Twenty-two patients with metastatic colon cancer and 8 patients with rectal cancer were evaluable for toxicity. All patients were started on an attenuated regimen of chemotherapy. A high rate of severe diarrhea (46%) and treatment-related hospitalizations (73%) were noted among patients with metastatic colon cancer. Toxicities were managed by treatment interruptions. The median overall survival among the metastatic colon cancer cohort was 20.6 months (95% confidence interval, 11.1-26.4 months). Among the patients with rectal cancer, 5 had locally advanced disease and were treated with chemoradiation therapy. Chemotherapy was interrupted in 3 of 5 patients because of toxicity. Radiation therapy was discontinued because of toxicity in 1 of 5 patients.. Our results suggest the susceptibility of patients with CRC aged > or = 80 years to chemotherapy toxicity. This age group should receive an attenuated dose of chemotherapy and be evaluated for dedicated clinical trials. Despite the high rate of treatment toxicity, selected octogenarians and nonagenarians with advanced CRC could benefit from chemotherapy, with overall survival neighboring that seen in younger populations.

Topics: Age Factors; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Colonic Neoplasms; Combined Modality Therapy; Deoxycytidine; Female; Fluorouracil; Humans; Leucovorin; Male; Rectal Neoplasms; Retrospective Studies; Survival; Treatment Outcome

We have treated 14 advanced and metastatic colorectal cancers with irinotecan (CPT-11) plus fluorouracil (5-FU) and l-leucovorin (l-LV) combination chemotherapy. The 14 patients consisted of 8 males and 6 females with a mean age of 65 years. We diagnosed adenocarcinoma of the colon in 10 patients and of the rectum in 4 patients. Four patients had liver metastases, five had lung metastases, and one had both, while one had lung and lymph node metastases, two had lymph node metastases and one had a local recurrence. The chemotherapy consisted of CPT-11 100 mg/m(2) div, as a 150-minute infusion, simultaneously l-LV 10 mg/m(2) div, as a 30-minute infusion, followed by 5-FU 500 mg/m(2) iv, as a bolus injection. This treatment was administered weekly for 2 weeks followed by a 2-week rest period and repeated every 4 weeks. All patients received this regimen as first-line chemotherapy. All patients were evaluated for efficacy 1 CR, 2 PR, 9 SD, and 2 PD. The overall response rate was 21.4% with a median time to progression of 8.1 months and a median survival time of 18.6 months. Grade 3 nausea, diarrhea and the suppression of white blood cells were seen in 3 patients, respectively. All other adverse reactions were mild (grade 1 or 2). Except for one patient,residual patients were able to receive the systemic chemotherapy on schedule. CPT-11/5-FU/l-LV combination chemotherapy appears to be effective first-line chemotherapy for advanced and metastatic colorectal cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Rectal Neoplasms; Retrospective Studies

Considerable progress has been made in improving disease-free survival in stage III colon cancer with the use of adjuvant chemotherapy. In recent years, it has been shown that infusional 5-fluorouracil regimens maintain the efficacy and reduce toxicity associated with bolus 5-fluorouracil, that improved tolerability can be achieved with use of the oral fluoropyrimidine capecitabine, and that improved efficacy can be achieved by combining 5-fluorouracil/leucovorin with other cytotoxic agents (eg, oxaliplatin and irinotecan). Studies are ongoing to identify optimal adjuvant regimens in stage II or III disease and to identify the potential benefits of adding bevacizumab or cetuximab to adjuvant therapy.

Topics: Antibodies, Monoclonal; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Colonic Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prodrugs; Rectal Neoplasms; Vitamin B Complex

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Topics: Adenocarcinoma; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Receptors, Cell Surface; Treatment Outcome

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Epidermal Growth Factor; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Panitumumab

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds

Irinotecan-induced gastrointestinal toxicities are common and typically present in the form of diarrhea or nausea and vomiting. However, severe hyperbilirubinemia (grade 3/4) has not been previously reported in association with this chemotherapeutic agent. We report a case of prolonged grade 4 hyperbilirubinemia after a single dose of irinotecan at 125 mg/m(2). This severe toxicity was attributed to a UGT1A1 7/7 genotype and resolved to grade 2 after 8 weeks of supportive care. This case outlines the possibility of severe hepatic toxicity with moderate doses of irinotecan in patients with a UGT1A1 7/7 genotype. Despite the severity and prolonged duration of the associated irinotecan-induced hepatic toxicity, the management of similar cases should focus on intensive supportive measures because the toxicity is likely to resolve eventually.

Topics: Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cetuximab; Colonic Neoplasms; Fluorouracil; Genotype; Glucuronosyltransferase; Humans; Hyperbilirubinemia; Irinotecan; Leucovorin; Liver Neoplasms; Male; Organoplatinum Compounds; Polymorphism, Genetic

There are a few clinical trials of combination chemotherapy of oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX-4) in Japan, and its efficacy and safety have not been confirmed yet, especially clinical experience in patients with prior chemotherapy.. To analyze the efficacy and safety of FOLFOX-4 in patients with colorectal cancer who received prior chemotherapy.. Twenty patients were treated with FOLFOX-4 beginning in April 2005. Three patients were entered into the safety study, and seventeen patients were treated on a reduced dose, because they had already received heavy doses of prior chemotherapy.. Number of prior chemotherapy was 1 regimen in 7 patients, more than two regimens in 13 patients. The median course of FOLFOX-4 was 10 (4-12), which gave an overall response rate of 20.0% and a median time to progression of 5.0 months. The median survival time was 15.6 months from initiation of the FOLFOX-4, and 28.5 months from the first-line treatment. Grade 3/4 neutropenia was seen in 12 patients (60%), and neuropathy was observed in 11 patients (55%). No response was seen in irinotecan based regimens after FOLFOX-4.. FOLFOX-4 in patients with pretreated colorectal cancer was effective, and contributed to prolonged life with the TTP of 5 months. However, hematological toxicity was high despite the reduced dose. Further extension of prolonged life is anticipated by administering incorporating molecular targeting agents.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Fatigue; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Rectal Neoplasms; Salvage Therapy; Survival Rate

A 62-year-old female had been operated for sigmoid colon cancer and liver metastasis. We showed our original guideline of adjuvant chemotherapy for colorectal cancer to the patient. She selected UFT/LV 3 months after operation. Six months after operation,follow-up CT showed a paraaortic lymph node growing to 1.8 cm. We used FOLFIRI regimen for 3 series, but the nodule size did not change. Twelve months after operation, a new metastatic lesion measuring 2.0 cm appeared in the liver and the paraaortic nodule grew to 3.0 cm in size. We used FOLFOX 4 regimen, which had decreased the size of liver metastasis after only 2 series. After 6 series, liver metastasis disappeared completely and the paraaortic nodule was reduced to 1.2 cm. Making a detailed guideline of adjuvant chemotherapy at each hospital is helpful not only for doctors to have more clinical discretion but for patients to have better-informed consent.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Informed Consent; Leucovorin; Liver Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Practice Guidelines as Topic

This analysis assesses the efficacy and safety of a modified FOLFOX (oxaliplatin/leucovorin [LV]/5-fluorouracil [5-FU]) regimen given with a low dose of LV.. Forty patients with previously untreated metastatic colorectal cancer were enrolled to receive every-2-week cycles of oxaliplatin 100 mg/m(2) intravenously administered over 2 hours concurrently with LV 20 mg/m(2) bolus and 5-FU 400 mg/m(2) bolus, followed by a 46-hour infusion of 5-FU 2.4 g/m(2).. Thirty-nine patients received > or = 1 oxaliplatin dose and a median of 10 treatment cycles (range, 1-13 cycles). Thirteen patients (34%) experienced grade 3/4 neutropenia, whereas 21% of patients experienced grade 3 neurotoxicity. Of 37 eligible patients, complete or partial responses were observed in 18 patients (49% [95% confidence interval (CI), 32%-66%]). The median progression-free survival was 6.2 months (95% CI, 5.5-8.7 months) with a median overall survival of 14.2 months (95% CI, 10-20.5 months).. A modified schedule of FOLFOX using a lower than standard dose of LV provides good response and survival results with excellent safety. A comparison with a previous study undertaken in the same centers using identical inclusion/exclusion criteria but using higher doses of LV suggests that reducing the dose of LV improves safety without compromising efficacy.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Staging; Organoplatinum Compounds; Rectal Neoplasms; Survival Rate

Topics: Adenocarcinoma; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Ethics, Medical; Fluorouracil; Humans; Irinotecan; Leucovorin; Leukemia; Randomized Controlled Trials as Topic; Recurrence; Treatment Outcome; Uncertainty

A 68-year-old woman underwent right colectomy for cancer of the ascending colon, followed by a local recurrence 26 months after surgery. She presented with fever and right lower abdominal pain, and was admitted to the hospital for locally recurrent colorectal cancer and tumor rupture. The patient was treated with a modified (reduced-dose) FOLFOX 4 regimen (mFOLFOX 4). In the four course of this regimen, the serum level of CEA decreased from 268 to 2.3 ng/mL. Even after 8 course, the serum CEA level remained within the normal range (4.7 ng/mL). Our case suggests that the mFOLFOX 4 regimen is effective for advanced or recurrent colorectal cancer with less toxicities including neuropathy,thus enabling patients to undergo long-term therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Neoplasm Recurrence, Local; Organoplatinum Compounds

In performing FOLFOX (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, neurotoxicity of oxaliplatin (L-OHP) is the serious dose limiting factor. On the other hand, goshajinkigan is recently considered as an effective agent for the neurotoxicity of taxanes in Japan. We have applied goshajinkigan (TJ 107) for a case of advanced colon cancer with mFOLFOX 6, and experienced a reduction in numbness, the adverse effect of LOHP. A 57-year-old woman with descending colon cancer (H 1, P 3, Stage IV) underwent hemicolectomy D 2, rt.colectomy, bilateral oophorectomy, cholecystectomy and transverse colonostomy. After operation, mFOLFOX 6 was applied. In order to reduce the neurotoxicity of L-OHP, TJ 107 was used together from the third course. The severities of neurotoxicity before and after administration of TJ 107 were grade 2 and 1,respectively. TJ 107 could reduce or prevent the neurotoxicity of L-OHP.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neurotoxicity Syndromes; Organoplatinum Compounds

Combination therapy of irinotecan, leucovorin (LV), and 5-fluorouracil (5-FU)(FOLFIRI regimen) has certain effect on advanced colorectal cancer. However, data of this regimen as first-line chemotherapy for Chinese patients with advanced colorectal cancer is still lacking, and its efficacy and safety still needs to be defined. This study was to explore the efficacy of FOLFIRI regimen as first-line chemotherapy on advanced colorectal cancer in Chinese patients, and observe its safety.. Clinical data of 54 chemotherapy-naive patients with advanced colorectal cancer, treated with FOLFIRI regimen from Jan. 2002 to Sep. 2005 in Cancer Center of Sun Yat-sen University, were analyzed.. Of the 54 patients, 52 were evaluable for response. The overall response rate was 42.6%, the time to progression (TTP) was 6 months, and the overall survival time was 15.2 months. The most common drug-related adverse events were neutropenia (38.9%), diarrhea (37.1%) and nausea and vomiting (50.0%). The occurrence rates of these grade 3-4 events were 5.6%, 9.3%, and 9.3%, respectively. All adverse events were tolerable.. FOLFIRI regimen is effective and well-tolerated as first-line treatment for Chinese patients with advanced colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neoplasm Staging; Neutropenia; Rectal Neoplasms; Remission Induction; Retrospective Studies; Survival Rate; Young Adult

IFL [irinotecan (CPT-11), 5-fluorouracil (5-FU), and folinic acid] is one of the treatments for metastatic colorectal cancer. We evaluated cytotoxic effects of a sequentially administered a combination of 5-FU with CPT-11 in human p53 mutant colon cancer. Sequential combination of 5-FU and CPT-11 in human colon cancer SW480 cells using a WST-8 colorimetric assay was studied. Cytotoxicity and cell cycle distribution for each drug were evaluated using an apoptosis assay and flow cytometry. Potential mechanisms of sequence-dependent cytotoxic effects were investigated using microarrays. Cytotoxicity of 5-FU (10, 100, 1000 microM) combined with subsequent use of CPT-11 (1 microM) was significantly greater than the reverse sequence of CPT-11 followed by 5-FU (p < 0.05). Following 24 hrs treatment with 5-FU (0.1-100 microM), no significant apoptosis was observed. In contrast, apoptosis was significantly induced after 24 hrs treatment with CPT-11 (1 and 10 microM). Flow cytometric analysis showed no significant difference in cell cycle distribution between different drug concentrations. We demonstrated up-regulation of 85 genes and down-regulation of 21 genes correlating with sequence-dependent cytotoxicities of 5-FU and CPT-11. The superiority of 5-FU-CPT-11 sequence was proven for p53 mutant colon cancer, SW480. Treatment with 5-FU followed by CPT-11 administration may be the optimal sequence for IFL treatment of metastatic colon cancers.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Gene Expression; Gene Expression Profiling; Humans; Irinotecan; Leucovorin; Mutation; Oligonucleotide Array Sequence Analysis; Tumor Cells, Cultured; Up-Regulation

Active anticancer drugs and/or combination regimens for the treatment of patients failing oxaliplatin, irinotecan and 5-fluorouracil are desperately needed. In this analysis we describe the safety and efficacy of the combination of mitomycin C, UFT and leucovorin in such an extensively pretreated patient population. Between January 2002 and June 2004, a total of 41 patients were treated with mitomycin C (8 mg/m on day 1) and UFT (350 mg/m)+ leucovorin (90 mg) both divided into three daily doses from day 1 to day 14 every 4 weeks. All patients had failed prior first-line and second-line treatment with oxaliplatin, irinotecan and 5-fluorouracil. The aim of this retrospective analysis was to evaluate the efficacy and safety data of this potential salvage therapy regimen. Thirty-nine patients were evaluable for the response. The overall response rate (intent-to-treat) was 7.3% (95% confidence interval, 2.5-19.4%) and disease stabilization was achieved in 29.3%. Median time to progression was 2.5 months (range, 1.5-13.5) and median overall survival was 6 months (range, 1.5-26). Myelosuppression was the most frequent side effect. Grade 3 hematotoxicity, however, was observed in only three patients. The most common nonhematological toxicities consisted of mild and reversible nausea, emesis and diarrhea; again, severe symptoms were only occasionally seen. These data show that the combination of mitomycin C/UFT/leucovorin is safe and active in about one-third of patients in terms of abrogation of progression in extensively pretreated metastatic colorectal cancer.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Disease Progression; Disease-Free Survival; Female; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Metastasis; Rectal Neoplasms; Retrospective Studies; Salvage Therapy; Tegafur; Uracil

We evaluated the antitumor effect of combined therapy with tegafur/uracil (UFT) plus leucovorin (LV) (UFT/LV) and protein-bound polysaccharide, PSK, in three mouse models of transplantable tumors. UFT/LV showed antitumor effect against Meth A sarcoma, and the antitumor effect was enhanced when PSK given concomitantly. UFT/LV showed antitumor effect to Lewis lung carcinoma and PSK alone also showed antitumor effect at high dose, but a combination of UFT/LV and PSK resulted in no enhanced antitumor effect. Colon 26 carcinoma was weakly responsive to UFT/LV, and no enhancement of antitumor effect was found even PSK was used in combination. In conclusion, while the effect of PSK varies depending on tumor, combined use of UFT/LV and PSK may be expected to augment the antitumor effect.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Colonic Neoplasms; Disease Models, Animal; Drug Therapy, Combination; Female; Leucovorin; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Proteoglycans; Sarcoma; Tegafur; Uracil; Xenograft Model Antitumor Assays

A 59-year-old patient with a coexisting primary choroidal melanoma and colorectal cancer was treated with external beam radiation (EBR) of his choroidal melanoma and systemic chemotherapy with leukovorin/5 fluorouracil (FU) for treatment of his metastatic colorectal cancer. Eight months following EBR, he showed evidence of radiation retinopathy with macular edema. Optical coherence tomography (OCT) showed macular edema and subretinal fluid. Subsequently, systemic bevacizumab (5 mg/kg) was added to his leukovorin/5FU chemotherapy. After the addition of bevacizumab, OCT showed complete resolution of the macular edema and subretinal fluid.. Bevacizumab may have a role in the treatment of radiation retinopathy, but further investigation is needed before any definitive conclusions can be made.

Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Bevacizumab; Choroid Neoplasms; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Liver Neoplasms; Macular Edema; Male; Melanoma; Neoplasms, Second Primary; Radiation Injuries; Radiotherapy; Tomography, Optical Coherence; Vascular Endothelial Growth Factor A; Vitamin B Complex

Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving both upper and lower motor neurons and the pathogenesis of this disorder is still unknown. To date, few reports have suggested that motor neuron diseases may have a paraneoplastic origin. However, it is still under discussion whether ALS occurring in cancer patients is paraneoplastic. A 60-year-old man with rectal cancer (Stage IV) having multiple lung, liver and para-aortic lymph node metastases underwent anterior resection of the rectum as palliative surgery. He was referred to our hospital for adjuvant chemotherapy. Lung and lymph node metastases decreased after 2 courses of chemotherapy using CPT-11 and 5-FU/LV but liver metastases were enlarged, following up increase in CEA. Thereafter, he suffered from muscle weakness in hands, arms, and legs and results of neurophysiologic studies were compatible with primary lateral sclerosis (ALS). For second line chemotherapy, he was treated with low-dose CDDP/5-FU over 6 courses. As a result, the size the of metastatic lesions markedly reduced and CEA was decreased to the normal level. Although significant tumor reduction was observed, his neurological symptoms rapidly progressed. He died of aspiration pneumonia 8 months after onset of the disease. Autopsy revealed that his neuropathological findings were compatible with ALS, and it was thought to be the primary cause of death in the because of absence of cancer progression. In this case the neurological syndrome was not affected by cancer therapy. Thus our case does not support the hypothesis that ALS in associated with cancer and the relationship between both disorders remains uncertain.

Topics: Adenocarcinoma; Amyotrophic Lateral Sclerosis; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged

To assess factors affecting long-term survival of patients undergoing radiofrequency ablation (RFA) of colorectal hepatic metastases, with attention to evolving chemotherapy regimens.. Prospective evaluation of 235 patients with colorectal metastases who were not candidates for resection and/or failed chemotherapy underwent laparoscopic RFA. Preoperative risk factors for survival and pre- and postoperative chemotherapy exposure were analyzed.. Two hundred and thirty-four patients underwent 292 RFA sessions from 1997 to 2006, an average of 8 months after initiation of chemotherapy. Twenty-three percent had extrahepatic disease preoperatively. Patients averaged 2.8 lesions, with a dominant diameter of 3.9 cm. Kaplan-Meier actuarial survival was 24 months, with actual 3 and 5 years survival of 20.2% and 18.4%, respectively. Median survival was improved for patients with 3 lesions (27 vs. 17 months, P=0.0018); dominant size<3 versus >3 cm (28 vs. 20 months, P=0.07); chorioembryonic antigen<200 versus >200 ng/mL (26 vs. 16 months, P=0.003). Presence of extrahepatic disease (P=0.34) or type of pre/postoperative chemotherapy (5-FU-leucovorin vs. FOLFOX/FOLFIRI vs. bevacizumab) (P=0.11) did not alter median survival.. To our knowledge, this is both the largest and longest follow-up of RFA for colorectal metastases. The number and dominant size of metastases, and preoperative chorioembryonic antigen value are strong predictors of survival. Despite classic teaching, extrahepatic disease did not adversely affect survival. In this group of patients who failed chemotherapy, newer treatment regimens (pre- or postoperatively) had no survival benefit. The actual 5-year survival of 18.4% in these patients versus near zero survival for chemotherapy alone argues for a survival benefit of RFA.

Topics: Adenocarcinoma; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoembryonic Antigen; Catheter Ablation; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Laparoscopy; Leucovorin; Liver Neoplasms; Longitudinal Studies; Male; Middle Aged; Organoplatinum Compounds; Prospective Studies; Rectal Neoplasms; Risk Factors; Survival Rate; Treatment Outcome; Vitamin B Complex

Peritoneal metastases are common in metastatic disease of many tumour types and thus are determinant for prognosis and development of tumour-related symptoms that jeopardise quality of life. Systemic chemotherapy has proven efficacious in improving both prognosis and quality of life in numerous tumour types and should therefore be considered as part of the treatment strategy--although there is no large body of data from predefined cohorts with"only peritoneal" manifestation. In further clinical trials therefore, improvement of systemic chemotherapy by integration of novel agents should be implemented in multimodal treatment approaches combining systemic treatment, cytoreductive surgery, and intraperitoneal treatment strategies.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Chemotherapy, Cancer, Regional Perfusion; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Neoplasm Staging; Peritoneal Neoplasms; Prognosis; Quality of Life

Combination chemotherapy of oxaliplatin, fluorouracil/leucovorin (FOLFOX) has reportedly become a standard regimen for colorectal cancer. In this study, we investigated the efficacies and adverse effects of modified FOLFOX6 (m-FOLFOX6) regimen in elderly patients. Thirty-nine patients with colorectal cancer, who received m-FOLFOX6 in our institution, were studied. Ten of the 39 patients, were older than 70 (elderly patients). Efficacies and adverse effects of m-FOLFOX6 were compared between patients over 70 years of age and those younger than 69 (younger patients). In terms of the response rate, there were no differences between the older and younger elderly patients. Moreover, the grade and frequency of adverse events were similar between them. We concluded that m-FOLFOX6 may bring about the same response rate in older and younger elderly patients. Moreover, m-FOLFOX6 may be given safely regardless of patient age.

Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Rectal Neoplasms; Remission Induction

Some conditions are predisposed to excessive lymphocyte responses, which can progress to a benign condition, ie, atypical cutaneous lymphoid hyperplasia (ACLH), or a malignant lymphoma. Clinical diagnosis of drug-associated pseudolymphoma can be based on a temporal association between drug ingestion and lesion onset followed by resolution without recurrence after discontinuation of drug administration. Herein, we report the case of a 66-year-old man with advanced colon carcinoma with ACLH developed while receiving chemotherapy regimen with oxaliplatin/5-fluorouracil/leucovorin. The authors postulate that chemotherapy can promote an aberrant immune response to an antigen that can be the drug itself or other self-antigens.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Eruptions; Fluorouracil; Humans; Immunophenotyping; Leucovorin; Lymphatic Diseases; Male; Organoplatinum Compounds

To compare the cost consequences of oral capecitabine and two different intravenous regimens of 5-fluorouracil/folinic acid (de Gramont and Mayo Clinic regimens) as adjuvant therapy in stage III colon cancer in France.. Clinical efficacy and safety data were taken from published clinical trials. Medical resource use was estimated from published data and expert opinion. Direct costs (drug acquisition, inpatient and home drug administration, laboratory tests, transportation, and management of adverse events) were considered over a time horizon of 46 months (3.8 years). The perspective taken was that of the French Sickness Funds.. In patients treated with capecitabine, relapse-free survival was 1.3 months longer than with the Mayo Clinic regimen, which has been shown to be as effective as the de Gramont regimen. In the base case analysis, capecitabine was less costly (3,654 EUR/patient) than the Mayo Clinic (10,481 EUR/ patient) and de Gramont (7,204 EUR/patient) regimens. In the sensitivity analysis, capecitabine remained dominant except when the intravenous regimens were assumed to be administered at home in all patients.. In France, capecitabine is more effective and less costly than both the Mayo Clinic and de Gramont regimens as adjuvant therapy for colon cancer.

Topics: Antineoplastic Agents; Capecitabine; Chemotherapy, Adjuvant; Colonic Neoplasms; Deoxycytidine; Fluorouracil; France; Humans; Leucovorin; Treatment Outcome

A metastatic malignancy of the umbilicus is commonly termed Sister Mary Joseph nodule (SMJN). It is a rare occurrence but may represent the first sign of a visceral malignancy and therefore should prompt a thorough search for the primary tumor. Typically, the most common origin of an umbilical metastasis is an adenocarcinoma from a gastrointestinal or gynecologic primary malignancy. The presence of SMJN carries a poor prognosis with the average survival time at the appearance of an umbilical metastasis being 10 months. We report a case of a 66-year-old man who was referred for evaluation of an enlarging umbilical lesion. Histopathology revealed adenocarcinoma. After a full metastatic workup, the tumor of origin was identified as adenocarcinoma of the sigmoid colon. Benign tumors of the umbilicus are uncommon. This case report serves to emphasize the importance of obtaining a histologic diagnosis when any new lesion presents in the umbilical region.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Diagnosis, Differential; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Skin Neoplasms; Umbilicus

This case highlights the possibility of late-onset severe cardiotoxicity resulting in sudden cardiac death from 5-fluorouracil (5-FU) therapy. Late-onset cardiotoxicity of 5-FU, after initial tolerance, has not been reported before.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fatal Outcome; Fluorouracil; Heart Arrest; Humans; Leucovorin; Male

PN401, an oral prodrug of uridine yields more bioavailable uridine than oral administration of uridine itself. PN401 may therefore be useful for permitting dose escalation of 5-fluorouracil (5-FU) with consequent improvements in antitumor efficacy.. Female BALB/c mice (Colon 26 adenocarcinoma) were treated with 5-FU with PN401 to define the MTD, and pharmacokinetic analyses were done. A comparison of 5-FU/PN401 was made to 5-FU/eniluracil (EU) and 5-FU/LV. The best timing of the first dose of PN401 relative to 5-FU was evaluated by administering groups of mice PN401 beginning 2, 24, or 48 h after 5-FU dose.. The MTD of 5-FU was 100 mg/kg/week whereas the MTD of 5-FU + PN401 was 200 mg/kg/week. A complete response (CR) of 80% and partial response (PR) of 20% was observed with 5-FU (200 mg/kg) + PN401, CR of 40% and PR of 60% with 5-FU (175 mg/kg) + PN401, PR of 10% with 5-FU (150 mg/kg) + PN401 while no response with 5-FU (100 mg/kg) + PN401. Analysis of 5-FU pharmacokinetics displayed nonlinearity as a function of administered dose in mice. In the comparison study, the best response was achieved with PN401 when compared to EU and LV. Mice that did not receive PN401 died by day 12, while other groups were alive at day 31. The proportion of mice surviving was highest in the group which received PN401 at 2 h followed by 24 and 48 h.. There is a threshold 5-FU dose after which the efficacy is dramatically improved-in mice bearing Colon 26 adenocarcinoma, that threshold is a dose of >150 mg/kg/week, and the increased efficacy correlates with about a fourfold increase in the AUC of 5-FU. PN401 used to rescue mice from the lethal toxicity of 5-FU entails that PN401 can be used as an antidote even when used up to 48 h after a 5-FU overdose.

Topics: Acetates; Adenocarcinoma; Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Survival Rate; Tumor Burden; Uridine; Xenograft Model Antitumor Assays

Folate is a B vitamin, deficiency of which appears to increase the risk of developing several malignancies including colorectal cancer. In contrast to the cancer-promoting effect of folate deficiency in normal tissues, several lines of evidence indicate that folate depletion suppresses the progression of existing neoplasms and enhance the sensitivity of cancer cells to chemotherapy. Folate mediates the transfer of one-carbon necessary for the de novo biosynthesis of purines and thymidylate, and hence is an essential factor for DNA synthesis and repair, and the maintenance of DNA integrity and stability. Folate deficiency induces DNA strand breaks, increases uracil misincorporation into DNA, impairs DNA repair and appears to induce apoptosis. Although the effects of folate depletion on DNA integrity and apoptosis and on subsequent cancer development, progression and treatment in colonic epithelial cells have been well characterized, it is largely unknown at present how folate depletion modulates specific upstream genes in apoptosis and cancer pathways that regulate these processes. We therefore investigated the effects of folate depletion on expression of genes involved in apoptosis and cancer pathways in four human colon adenocarcinoma cell lines in an in vitro model of folate deficiency. Apoptosis and cancer pathway-specific mini-microarray were used to screen for differentially expressed genes in response to folate deficiency, and the expression of seven most notably and consistently affected genes was confirmed by real time RT-PCR. Our data suggest that folate deficiency affects the expression of key genes that are related to cell cycle control, DNA repair, apoptosis and angiogenesis in a cell-specific manner. Cell-specificity in gene expression changes in response to folate deficiency is likely due to significant differences in molecular and phenotypic characteristics, growth rates and intracellular folate concentrations among the four cell lines.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Deoxyuridine; DNA; Folic Acid Deficiency; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Models, Biological; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Patients with bilobar colorectal cancer metastases to the liver present a unique problem in terms of resection. They sometimes require a staged approach to resection that takes advantage of the liver's ability to regenerate, as well as the newer chemotherapeutic agents (e.g., oxaloplatin, irinotecan (CPT-11), and bevacizumab) that have become available. In cases of multiple bilobar metastases, if segment IV is clear of tumor, a left lateral segmentectomy (LLS) can be performed, followed several months later by a formal right hepatectomy. The remnant liver composed of the hypertrophied segment IV is drained by the middle hepatic vein (MHV). In this context, patients with lesions between the origin of the MHV and the inferior vena cava (IVC) present a particularly difficult problem. Conventional excision would require an extended hepatectomy and division of the MHV along with either the right or left hepatic veins (RHV, LHV). This would make it impossible to continue with a formal resection of the remaining lesions in the contralateral liver without sacrificing the sole remaining hepatic vein. We present a novel two-step hepatectomy for lesions between the MHV and the IVC that allows the MHV to be preserved and all lesions to be resected.

Topics: Adenocarcinoma; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Camptothecin; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Follow-Up Studies; Hepatectomy; Hepatic Veins; Humans; Irinotecan; Leucovorin; Liver; Liver Neoplasms; Liver Regeneration; Male; Rectal Neoplasms; Vena Cava, Inferior

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Oxaliplatin in combination with 5-fluorouracil/leucovorin (LV5FU) improves the response rate and survival of patients with metastatic colorectal cancer. The objective of the Mosaic study was to evaluate the efficacy of this association in the adjuvant treatment of stage II and III colon cancer. This international study, including 2,246 patients, compared the efficacy of standard treatment with LV5FU2 alone to that of oxaliplatin-LV5FU (Folfox4 regimen) following R0 resection of the primary tumour. Both treatments were administered every two weeks for six months. At 3-year follow-up, the risk of relapse was decreased by 23% in the Folfox4 group (p = 0.002). The protocol was well tolerated, with an identical overall mortality during treatment (0.5%) in both groups. The main specific complication, peripheral sensory neuropathy was reversible in the great majority of cases. A new analysis at 4-year follow-up (median 48.6 months) confirmed the superior efficacy of the Folfox4 regimen compared to the standard treatment, the reduction in relapse risk being 24% (p = 0.0008). On the strength of these results, oxaliplatin was granted a marketing authorization for the indication adjuvant treatment of stage III colon cancer. Based on the data currently available, physicians should consider adjuvant treatment for stage II patients, making each individual decision for treatment on a case-by-case basis.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin

Thrombocytopenia developing in the course of chemotherapy for malignant disease is usually attributed to drug-induced marrow suppression and/or marrow replacement by tumor. We describe two patients who developed severe thrombocytopenia and hemorrhagic symptoms while being treated with oxaliplatin, 5-fluorouracil, and leukovorin for metastatic colon cancer in whom platelet destruction appears to have been caused by oxaliplatin-dependent antibodies specific for the platelet glycoprotein IIb/IIIa complex (alpha(IIb)/beta(3) integrin). Drug-induced immune thrombocytopenia (DITP) should be considered in patients who experience a sudden, isolated drop in platelet levels while being treated with chemotherapeutic agents, especially when adequate numbers of megakaryocytes are present in the bone marrow.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autoantibodies; Bone Marrow Cells; Carcinoma; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Megakaryocytes; Middle Aged; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Purpura, Thrombocytopenic, Idiopathic; Vitamin B Complex

Pemetrexed, a new generation antifolate recently approved for the treatment of mesothelioma and non-small cell lung cancer, is an excellent substrate for the reduced folate carrier (RFC). To explore the carrier's effect on pemetrexed activity, RFC was inactivated in HCT-15 colon cancer cells by mutagenesis and PT632 selective pressure. A clone (PT1) was obtained with a glycine to arginine substitution at amino acid 401, resulting in the loss of RFC function. PT1 cells were resistant to PT632 (178-fold), methotrexate (4-fold), and ZD1694 (Tomudex, raltitrexed; 20-fold), but were 3-fold collaterally sensitive to pemetrexed when grown in 25 nmol/L of 5-formyltetrahydrofolate. PT1 cells transfected with wild-type RFC had antifolate sensitivities comparable to that of wild-type HCT-15 cells, indicating that the RFC mutation was the sole basis for resistance. Folate pools were contracted in PT1 cells by 32% or 60%, as measured by radiolabeling intracellular folates or by an enzyme binding assay, respectively. This was reflected in marked (6.5-fold) collateral sensitivity to trimetrexate. The initial uptake of pemetrexed in PT1 cells was markedly reduced ( approximately 85%) but intracellular pemetrexed levels increased to approximately 60% and approximately 70% to that of wild-type cells after 2 hours and 6 days, respectively. There was increased pemetrexed inhibition of glycinamide ribonucleotide transformylase and, to a lesser extent, thymidylate synthase in PT1 cells growing in 5-formyltetrahydrofolate based on nucleoside protection analyses. Hence, loss of RFC function leads to collateral sensitivity to pemetrexed in HCT-15 cells, likely due to cellular folate pool contraction resulting in partial preservation of pemetrexed polyglutamylation and increased target enzyme inhibition. micro

Topics: Amino Acid Substitution; Antineoplastic Agents; Arginine; Carrier Proteins; Cell Line, Tumor; Colonic Neoplasms; Drug Resistance, Neoplasm; Folate Receptors, GPI-Anchored; Folic Acid Antagonists; Glutamates; Glycine; Guanine; Humans; Leucovorin; Methotrexate; Mutation; Pemetrexed; Phosphoribosylglycinamide Formyltransferase; Purines; Pyrimidines; Quinazolines; Receptors, Cell Surface; Thiophenes; Thymidylate Synthase

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Cause of Death; Chemotherapy, Adjuvant; Colonic Neoplasms; Controlled Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin

Liver is the most common site of metastasis in colorectal cancer, and 35% patients with colorectal cancer developed liver metastasis at diagnosis. The prognosis of the patients with liver metastases from colorectal cancer is poor. Surgical resection, radiofrequency ablation, and chemotherapy had been used in clinical treatment for liver metastasis from colorectal cancer with various outcomes. This study was to explore the treatment efficacy of surgical management for liver metastasis from colorectal cancer.. Clinical data of 198 patients with liver metastasis from colorectal cancer, treated from Jan. 1995 to Jan. 2000, were studied retrospectively. Of the 198 patients, 46 (23.2%) received radical resection, 43 (21.7%) received palliative resection, 29 (14.6%) received exploratory operation or supportive treatment, 41 (20.7%) received adjuvant hepatic arterial infusion, and 39 (19.7%) received adjuvant systemic chemotherapy. Survival statuses of the patients in different groups were compared.. The median survival time of radical resection group was significantly longer than those of palliative resection group, exploratory operation or supportive treatment group, adjuvant hepatic arterial infusion group, and adjuvant systemic chemotherapy group (37.1 months vs. 14.3, 6.3, 21.3, and 18.7 months, P<0.01). The 5-year survival rates of the 5 groups were 31.2%, 0, 0, 7.5%, and 0, respectively.. Radical resection could improve survival of the patients with liver metastasis from colorectal cancer. Palliative resection has no advantage over adjuvant therapy. Adjuvant hepatic arterial infusion should be applied in the unresectable cases.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Hepatectomy; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds; Prognosis; Rectal Neoplasms; Retrospective Studies; Survival Rate; Treatment Outcome

(1) The standard treatment for colon cancer is surgical excision, but without additional treatment nearly 50% of surgically treated patients die from relapse and metastatic disease progression. Adjuvant chemotherapy is designed to reduce the risk of post-surgical relapse. (2) The standard adjuvant chemotherapy is a combination of fluorouracil + folinic acid administered intravenously for 6 months (de Gramont protocol). (3) In patients with stage III disease (corresponding to Dukes stage C: lymph node involvement but no metastases), the 5-year survival rate after a 6-month course of fluorouracil + folinic acid is significantly higher than with placebo (63% versus 51%). The efficacy of this treatment has not been established in patients with stage II disease (no lymph node involvement or metastases), for whom the overall 5-year survival rate is about 80%. (4) In one trial a combination of oxaliplatin + fluorouracil + folinic acid (FOLFOX 4 protocol) failed to increase the overall 3-year survival rate more than the fluorouracil + folinic acid combination. It increased the event-free survival rate (72.2% versus 65.3%) but had more severe adverse effects, including: neuropathies (in about 12% of patients), neutropenia (41%), and gastrointestinal disturbances (5% to 10% of patients had nausea, vomiting and diarrhoea). (5) Capecitabine, a fluorouracil precursor, does not appear to be more effective than fluorouracil, but it does provide an alternative oral treatment with a slightly different profile of adverse effects (more frequent erythrodysesthesia, etc.). (6) In practice, adjuvant treatment with fluorouracil + folinic acid should be offered to patients with surgically treated stage-III colonic cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Organoplatinum Compounds; Survival Rate; Treatment Outcome

Pharmacokinetic modulating chemotherapy (PMC) is designed to boost high serum 5-fluorouracil (5-FU) concentrations via modulation by uracil. The aim of this study was to evaluate the efficacy of PMC as a second-line chemotherapy for postresectional recurrences of colorectal carcinoma.. Thirteen patients with unresectable recurrences of colorectal carcinoma were treated with PMC as the second-line chemotherapy, after 5-FU or its derivatives as the first-line chemotherapy. PMC was initiated with a 400 mg combination of uracil and tegafur daily and a 24-hour continuous intravenous infusion of 600 mg/m(2) 5-FU once weekly. The 5-FU dose was increased as the disease progressed.. Six (46%) of the 13 patients exhibited a partial response (PR) to PMC, based on the RECIST criteria. PR was achieved in 2 of 5, 2 of 5, and 2 of 3 patients undergoing oral administration of 5-FU derivatives, intravenous infusion of 5-FU/l-leucovorin and hepatic-artery infusion of 5-FU, respectively. The median survival time of the 13 patients was 17 months.Grade-2 toxicity was found only in 2 patients.. Because PMC is chronomodulating, it is an effective and safe treatment for recurrent colorectal carcinoma. PMC with a dose increase of 5-FU is recommended as a promising second-line regimen for unresectable colorectal carcinoma resistant to 5-FU.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chronotherapy; Colonic Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Rectal Neoplasms; Survival Rate; Tegafur; Uracil

We report the complete response for one year of a patient with simultaneous multiple lung metastases from colon cancer who was treated using a combination of irinotecan (CPT-11) and uracil/tegafur (UFT)/Leucovorin (LV) using a schedule reported overseas. A 61-year-old woman was admitted to our hospital and diagnosed with ascending colon cancer and simultaneous multiple lung metastases. The patient underwent a right hemicolectomy and was treated with CPT-11 (150 mg/m(2)) on day 1 and oral UFT and oral LV on days 1-14. This treatment cycle was repeated every 3 weeks. A CT examination after 4 cycles of chemotherapy revealed a partial response of multiple lung metastases, and the next examination after 6 cycles revealed a complete response. The adverse effects observed during this chemotherapy regimen were leucopenia (grade 1), neutropenia (grade 2), vomiting (grade 2) and hair loss (grade 1). The patient is now receiving her 22nd cycle of chemotherapy, and her multiple metastases have shown a complete response for one year. The CPT-11 and UFT/LV combination therapy was well tolerated and was covered by the national health insurance system in Japan. This treatment may enable prolonged survival and improve quality of life in patients with metastatic colorectal cancer.

Topics: Adenocarcinoma; Alopecia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Drug Combinations; Female; Humans; Irinotecan; Leucovorin; Leukopenia; Lung Neoplasms; Middle Aged; Neoplasms, Multiple Primary; Neutropenia; Remission Induction; Tegafur; Uracil; Vomiting, Anticipatory

The clinical efficacy and safety of tegafur/uracil (UFT) plus oral Leucovorin (LV) regimen for advanced or metastatic colorectal cancer were studied retrospectively. From September 2003 to March 2005, 82 patients were treated with UFT (300 mg/m(2)/day)/LV (75 mg/day) at our institute. The objective overall response rate was 14. 8% (95% confidence interval, 5.3 to 24.3%) in 54 evaluable patients. The response rate was 33.3% for previously untreated patients and 5.5% for previously treated patients, respectively. Grade 3 or more severe adverse reactions such as diarrhea or liver function abnormalities were only 7.3%. In 28 previously untreated patients,the median survival was 25.8 months with 1-and 2-year survival rates of 88.0% and 60.5%, respectively. This retrospective study demonstrated the reproducible activity and safety of UFT/LV for advanced or metastatic colorectal cancer in clinical practice.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Nausea; Neoplasm Recurrence, Local; Rectal Neoplasms; Remission Induction; Retrospective Studies; Survival Rate; Tegafur; Uracil; Vomiting, Anticipatory

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Gene Expression Profiling; Humans; Leucovorin; Neoplasm Metastasis; Organoplatinum Compounds

In Japan, cancer chemotherapy for advanced and recurrent colorectal cancer has not been adequately developed in comparison with the USA and Europe. However, the number of patients with advanced colorectal cancer has increased dramatically in this decade. Therefore, effective and feasible regimens against colorectal cancer are urgently needed. We designed a new regimen to evaluate the efficacy and feasibility of weekly low dose CPT-11 combined with 5-FU/l-LV therapy based on an RPMI regimen against advanced and recurrent colorectal cancer. Twenty patients were enrolled in this study. Weekly administration (CPT-11; 60 mg/m(2) div for 1st-line chemotherapy, 40 mg/m(2) div for 2nd-or 3rd-line chemotherapy, l-LV; 200 mg/m(2) div, 5-FU; 500 mg/m(2) iv, 3 consecutive weeks, 1-week break) was performed on an ambulatory basis. The treatment cycles were repeated every 4 weeks until disease progression and/or severe toxic events occurred. The overall response rate was 31.6% with 5.3% complete response and 26.3% partial response in addition to 42.1% with no changes beyond 3 months. These results suggested that the clinical benefit was shown in 73.7% of patients. Furthermore, median TTF (time to failure) of this regimen was 6.5 months and MST was 20.4 months, respectively. On the other hand, adverse events were restricted to grade 3 with 30.0% neutorocytopenia and 5.0% thrombocytopenia. Therefore, weekly low-dose CPT-11 combined with 5-FU/l-LV therapy seems to be extremely useful, with excellent anti-tumor effect and tolerable adverse reactions, for the treatment of advanced and recurrent colorectal cancer on an ambulatory basis.

Topics: Aged; Aged, 80 and over; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Quality of Life; Rectal Neoplasms

The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin. Oxaliplatin improves the efficacy of this combination in patients with stage III colon cancer and moreover its toxicity is well tolerable. We describe a rare clinical case of acute dyspnoea probably related to oxaliplatin at one month from the end of the adjuvant treatment. A 74-year-old man developed a locally advanced sigmoid carcinoma (pT3N1M0). A port a cath attached to an open-ended catheter was implanted in order to administer primary chemotherapy safely according to the FOLFOX4 schedule. One month following the end of the 6th cycle, the patient referred a persistent cough and moderate dyspnoea. Chest radiography displayed a change in the lung interstitium, chest CT scan confirmed this aspect of adult respiratory distress syndrome, spirometry reported a decreased carbon monoxide diffusion capacity. Antibiotic and corticosteroids were administered for 10 d, then a repeated chest X ray evidenced a progressive pulmonary infiltration. A transbronchial biopsy and cytology did not show an infective process, a CT scan reported radiological abnormalities including linear and nodular densities which were becoming confluents. Antimicotic and antiviral drugs did not evidence any benefit. The antiviral therapy was stopped and high dose metilprednisolone was started. The patient died of pulmonary distress after 10 d.

Topics: Acute Disease; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dyspnea; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin

To describe a patient with reversible posterior leukoencephalopathy syndrome following the administration of bevacizumab (Avastin), a monoclonal antibody against vascular endothelial growth factor.. Case report/literature review.. University hospital.. A 52-year-old man receiving chemotherapy for stage IV rectal carcinoma.. Clinical and radiographic evidence consistent with reversible posterior leukoencephalopathy syndrome was found following the administration of irinotecan hydrochloride, leucovorin calcium, and fluorouracil (FOLFIRI) regimen chemotherapy and bevacizumab.. Reversible posterior leukoencephalopathy syndrome following treatment with angiogenesis modulators can occur. In addition to raising clinical suspicion in appropriate patients, this report may yield clues to the pathophysiologic underpinnings of reversible posterior leukoencephalopathy syndrome.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aphasia; Bevacizumab; Blindness, Cortical; Blood Vessels; Camptothecin; Carcinoma; Cognition Disorders; Colonic Neoplasms; Dementia, Vascular; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Neovascularization, Pathologic; Occipital Lobe; Parietal Lobe; Vascular Endothelial Growth Factor A

Two metastatic colonic cancer patients were successfully treated by the combination therapy of UFT plus oral Leucovorin (UFT/LV). UFT was administered orally every eight hours at a dose of 300 mg/day in case of less than 1.20 m(2), 400 mg/day in case of between 1.20 and 1.70 m(2), 500 mg/day in case of over 1.70 m(2), and Leucovorin (75 mg/day) was simultaneously given for 28 consecutive days and stopped for seven days. This cycle was repeated until the patients requested the therapy be discontinued or a severe adverse reaction was observed. Case 1: A 79-year-old male had undergone sigmoidectomy for colonic cancer in 2001 and was diagnosed with pulmonary metastases in August, 2005. His performance status (PS) was grade 3. Case 2: A 61-year-old male with liver metastasis whose primary colonic lesion was surgically resected. After 2 cycles of UFT/LV therapy, a good partial response was achieved in both cases. Adverse effects were very mild, indicating that this therapy was very safe and recommendable for the treatment of metastatic colonic cancer patients with poor PS.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Colon, Sigmoid; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Remission Induction; Tegafur; Uracil

Oxaliplatin (L-OHP) is a new third-generation platinum which is efficacious in treating advanced unresectable recurrent colorectal cancer as a first-line regimen. The marketing authorization was given in Japan in March, 2005. Its increased use has resulted in rare serious adverse effects, including anaphylactic shock. We experienced a case that developed anaphylactic shock by L-OHP. We report a 69-year-old man who was treated for recurrent colorectal cancer who underwent systemic chemotherapy with FOLFOX 4. After eight cycles he developed severe L-OHP associated neuropathy and lung metastases was a progressive tendency. The FOLFOX 4 regimen was discontinued and another modality, FOLFIRI regimen, was used. After eight cycles of FOLFIRI regimen, lung and liver metastases showed progressive disease for response assessment by RECIST criteria. Although a patient was stopped L-OHP for neurotoxicity, neuropathy was disappeared after 4 months interval. Therefore, we reintroduced L-OHP, FOLFOX 4 regimen. Anaphylactic shock occurred in the second cycle of reintroduction of the FOLFOX 4 regimen (total 10 cycles), 30 minutes after infusion of L-OHP. L-OHP infusion was immediately withdrawn and he was treated with intravenous hydroxyzine hydrochloride and methylprednisolone. The anaphylaxis symptoms resolved in 30 minutes. Chemotherapy based on L-OHP for unresectable recurrence colorectal cancer causes anaphylactic shock as a rare severe complication. The prediction factor is not proved. We should take steps for early detection of anaphylactic reaction and perform the appropriate treatment.

Topics: Adenocarcinoma; Aged; Anaphylaxis; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin

A 50-year-old man with multiple liver and mediastinal LN metastases from sigmoid colon cancer was admitted to our hospital in May 2005. In October 2002, a radical resection of the original tumor and liver metastases were performed at a previous hospital. Histologically, the tumor was diagnosed as Stage IV. He was treated with an oral anticancer agent as an adjuvant therapy. In January 2005, the CEA level was increased to 3.2 ng/ml and CT scan revealed a solitary liver metastasis. Partial resection of the liver was performed. On admission to our hospital, a systemic chemotherapy by FOLFOX4 was begun. The liver metastases showed 61% reduction in size and were judged to be PR. However, the intrathoracic lymph node size was not changed. Therefore, VATS extirpation of the mediastinal lymph node was performed. After 10 courses of FOLFOX4, abdominal CT revealed liver metastases remained to be almost the same size. In January 2006, radio frequency ablation (RFA) and partial hepatectomy were enforced and then, the tumor marker returned to normal. There were no serious adverse events or postoperative complications. He has been alive without any sign of recurrence for 42 months from the initial treatment. In conclusion, intensive combination therapies for remote metastases of colon cancer might be promising to obtain a long-term survival without ruining QOL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Organoplatinum Compounds

To compare benefits and risks to adjuvant chemotherapy following complete resection of node-positive colon cancer stage III for patients aged >or=75 yr and younger.. A retrospective study compared recurrence-free and overall survival, toxicity, and dose intensity of adjuvant bolus 5-FU according to the Mayo regimen chemotherapy in consecutive patients aged 19-74 (n=203) and >or=75 yr (n=24).. The estimated 5-yr proportional survival rates were 0.65 for patients age less than 75 yr compared to 0.65 (p=0.96) for elderly. The frequencies of anemia (0%), thrombocytopenia (0%), leukopenia (4%), infection (8%), vomiting (0%), mucositis (17%), diarrhea (13%) CTC grade 3 or 4 toxicity in elderly patients were not significantly different from that in younger patients (p > 0.05). Significantly more elderly (8%) had a decline in performance status to grade 3 or 4, as compared to younger patients (4%) (p=0.002). 5-FU dose reduction was necessary for significantly more elderly (51%) as compared to younger patients (28%) (p=0.02), and fewer elderly (54%) completed the scheduled six treatment courses as compared to younger patients (82%) (p=0.05).. Adjuvant 5-FU chemotherapy should be considered for elderly patients aged >or=75 yr in good performance at high risk of recurrence of colon carcinoma after resection.

Topics: Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Prognosis; Survival Analysis; Survival Rate

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Lymphatic Metastasis; Portal Vein; Randomized Controlled Trials as Topic

This study determined the efficacy and safety of a modified FOLFOX regimen that improved patient convenience without compromising oxaliplatin dose intensity. A total of 62 patients with previously untreated metastatic colorectal cancer were enrolled to receive, entirely as outpatients, 2-weekly cycles of oxaliplatin 100 mg m(-2) i.v. over 2 h, together with leucovorin 400 mg m(-2) over 2 h, 5-fluorouracil (5-FU) 400 mg m(-2), bolus, followed by a 46-h infusion of 5-FU at 2.4 g m(-2). Treatment was given until progression or unmanageable toxicity. In all, 61 patients received > or =one oxaliplatin dose and a median of 11 treatment cycles (range 1-20 cycles); 22 (36%) reported grade 3/4 neutropenia and 13 patients (21%) experienced grade 3 neurotoxicity; 16 patients (26%) discontinued treatment due to disease progression or death, 15 (25%) due to neurotoxicity and six (10%) due to haematological toxicity. Of the 56 eligible patients, complete or partial responses were observed in 29 or 52% (95% confidence interval 38-65%). Median progression-free survival was 8.2 months (7.1-9.9) and median overall survival was 18.7 months (14.0-23.4). In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Australia; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hospitalization; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Survival Analysis

We encountered three cases of multiple liver metastases of colorectal cancer treated with hepatic resection after hepatic arterial infusion. Case 1: A 55-year-old female underwent sigmoidectomy for sigmoid colon cancer and six liver metastases. After responding postoperatively to hepatic arterial infusion chemotherapy (HIA), she underwent resection of liver metastases. Case 2: A 66-year-old man underwent colectomy and hepatic resection for cecal colon cancer and liver metastasis. Multiple liver metastases appeared six months after the operation. HIA resulted in a complete response. Liver metastases recurred twice and liver resection was performed each time. Case 3: A 52-year-old female underwent partial resection of colon and liver for ascending colon cancer and multiple liver metastases. After she responded postoperatively to HIA and systemic chemotherapy, the patient underwent resection of liver metastases. Case 1 has lung metastases at this writing. The other two patients are alive and well, and have been free from recurrence as of 4 years after operation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colon, Sigmoid; Colonic Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Hepatectomy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Sigmoid Neoplasms

Toxicities and response are different when patients with advanced colorectal cancer were treated with standard FOLFOX6 regimen. Serum level of dihydropyrimidine dehydrogenase (DPD) relates to efficacy and toxicities of chemotherapy containing 5-fluorouracil (5-FU). This study was to explore relationship of DPD to serum concentration of 5-FU in colorectal cancer patients treated with FOLFOX6 regimen, and their correlation to treatment response and adverse events.. Serum level of DPD in 72 patients with colorectal cancer was detected by high-performance liquid chromatography (HPLC) before chemotherapy. Serum concentration of 5-FU at steady state was detected by HPLC after patients received FOLFOX6 regimen. Treatment response and adverse events in the patients were assessed.. Serum levels of DPD were normally distributed in 72 patients (ranged 1.55-5.94), while serum concentrations of 5-FU at steady state were not (ranged 141.1-1 741.9 microg/L). Serum level of DPD was negatively correlated with serum concentration of 5-FU (r=-0.460, P < 0.01). Occurrence of adverse events was lower when 5-FU concentration was less than 600 microg/L than when 5-FU concentration was more than 600 microg/L (P < 0.05). The mean serum concentration of 5-FU was significantly higher in patients with complete response and partial response than in patients with steady disease, and progressive disease (513.9 microg/L vs. 409.8 microg/L, and 259.3 microg/L, P < 0.05). Serum level of DPD was lower in patients suffered oral mucositis and diarrhea of grade II-IV than in patients suffered oral mucositis and diarrhea of grade 0-I (P=0.016, P=0.047). Serum level of DPD had no relation with treatment response of the patients (r=0.312, P=0.078).. DPD level and serum 5-FU concentration vary a lot among patients with colorectal cancer. DPD level negatively correlates with serum 5-FU concentration. Serum concentration of 5-FU correlates with treatment effect and toxicities.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mucositis; Nausea; Organoplatinum Compounds; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Female; Fluorouracil; Humans; Leucovorin; Male; Maximum Tolerated Dose; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Prognosis; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; United States; United States Food and Drug Administration

Early postoperative intraperitoneal chemotherapy (EPIC) and intraoperative peritoneal hypertermic chemotherapy (IPHC) are used in addition with cytoreductive surgery to treat with curative intent peritoneal carcinomatosis arising from colorectal adenocarcinomas. Three patients with such a disease were treated with perioperative intraperitoneal chemotherapy in addition to cytoreductive surgery and presented isolated local recurrence located in the inguinal canal (round ligament in two and spermatic cord in one). All these patients were treated by local surgical excision. No patient showed evidence of intra-abdominal recurrence at the last follow-up, but one developed pulmonary metastasis. When communicating with the peritoneal cavity, the inguinal canal may act as a sanctuary site for peritoneal carcinomatosis, since it is not totally soaked by the intraperitoneal chemotherapy solution. A local recurrence is thus possible. New clinical presentations such as this one have first to be described in order to improve patient follow-up.

Topics: Adenocarcinoma, Mucinous; Adult; Antineoplastic Combined Chemotherapy Protocols; Appendiceal Neoplasms; Carcinoma; Cecal Neoplasms; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Parenteral; Inguinal Canal; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Tomography, X-Ray Computed

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01(+) PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.

Topics: Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Coculture Techniques; Colonic Neoplasms; Cross-Priming; Cytotoxicity, Immunologic; Dendritic Cells; Deoxycytidine; Drug Evaluation, Preclinical; Fluorouracil; Gemcitabine; HLA-A Antigens; HLA-A2 Antigen; HT29 Cells; Humans; Leucovorin; Leukocytes, Mononuclear; Organoplatinum Compounds; Oxaliplatin; T-Lymphocytes, Cytotoxic

Human colon cancer cells were injected subcutaneous in nude mice. After 8 days the animals were divided in two groups, the first group received triple therapy with octreotide, galanin and serotonin (40 microg/kg body weight/day) through an ALZET osmotic pump implanted intraperitoneally (i.p.) for 14 days, followed by 5 days of subcutaneous injections (200 microg/kg body weight/ day). The second group was injected i.p. for 5 days with 5-fluorouracil/leukovorin (5-FU/LV) at concentrations of 4 mg and 2 mg/kg body weight, respectively. After 9 days without any treatment, the mice received i.p. injection with 5-FU/LV (20 mg and 10 mg/kg body weight/day, respectively) for another 5 days. The volume and weight of the tumours were measured at the end of the experiment. Apoptosis, proliferation, blood vessels, epidermal growth factor (EGF) and vascular endothelial cell growth factor (VEGF) were detected with immunocytochemistry. Apoptosis was also detected using the TUNEL-method. Quantification was performed using computed image analysis. There was no statistical significance between tumours treated with 5-FU/LV or triple therapy regarding the volume and weights of the tumours, apoptotic, proliferation, VEGF indces and the density of tumour blood vessels. The EGF labelling index was, however significantly lower in the tumours treated with triple therapy than those treated with 5-FU/LV. In conclusion, treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable with 5-FU/LV that is the standard chemotherapeutic agent for colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Body Weight; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Epidermal Growth Factor; Fluorouracil; Galanin; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Leucovorin; Mice; Mice, Nude; Neovascularization, Pathologic; Octreotide; Platelet Endothelial Cell Adhesion Molecule-1; Poly(ADP-ribose) Polymerases; Serotonin; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

The aim of this study was to evaluate the efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (I-LV) in 50 patients with advanced or recurrent colorectal cancer in our institute. The dose of 5-FU was 600 mg/m2 and the dose of l-LV was 250 mg/m2. Objective response were 36.8% of patients who had administration of full-dose and 14.8% of patients who had the administration of reduced dose or prolonged interval. No significant difference was observed in clinical benefit rates between patients administrated in full-dose and patients in reduced dose or prolonged interval. Median survival time (MST) of patients in reduced dose or prolonged interval is longer than patients in full-dose. These data suggest that 5-FU/l-LV can be given in the outpatient and yields improved prognosis and minimal adverse reactions even in patients in reduced dose or prolonged interval.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Diarrhea; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Rectal Neoplasms; Retrospective Studies; Survival Rate

Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Body Weight; Camptothecin; Cell Proliferation; Colonic Neoplasms; Epidermal Growth Factor; Female; Fluorouracil; Galanin; Immunohistochemistry; In Situ Nick-End Labeling; Irinotecan; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Octreotide; Organoplatinum Compounds; Oxaliplatin; Platelet Endothelial Cell Adhesion Molecule-1; Poly(ADP-ribose) Polymerases; Serotonin; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Treatment Outcome

5-FU/LV therapy has been standard chemotherapy for advanced and recurrent colorectal cancer. Several studies reported that a new alternative chemotherapy, UFT/LV, had anti-cancer effects the same as with conventional 5-FU/LV therapy. We report a patient who had advanced and recurrent colorectal cancer treated with UFT/ LV. This 70-year-old male was admitted to our hospital because of a right lower abdominal mass, which was diagnosed as a peritoneal recurrence of transverse colon cancer by abdominal CT. UFT/LV therapy was started on an outpatient basis. After one course of chemotherapy, the intra-abdominal mass disappeared, and this therapy was continued for three courses. He did not suffer from any adverse effect during chemotherapy. Although this therapy was resumed because of the recurrence at the same site after nine months, it was refractory to chemotherapy. Thereafter, surgical resection was performed, and it was diagnosed as lymph node metastasis of previous surgery.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Humans; Leucovorin; Male; Peritoneal Neoplasms; Tegafur; Uracil

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cholangitis, Sclerosing; Colonic Neoplasms; Combined Modality Therapy; Fatal Outcome; Fluorouracil; Humans; Leucovorin; Lung Diseases, Interstitial; Lung Neoplasms; Male; Prednisolone

The aim of this study was to evaluate the efficacy of tegafur/uracil (UFT) and oral Leucovorin(UZEL) in patients with advanced or recurrent colorectal cancer. Eight patients were treated with UFT/UZEL therapy as a first-line chemotherapy. UFT(300 mg/m(2)/day) and UZEL (75 mg/body/day) were administered orally for 28 consecutive days followed by a 7-day rest period, and this schedule was repeated every 5 weeks. The mean of treatment courses given to the patients was 7.6. Tumor response was evaluated in 7 patients who had assessable lesions, and the response rate was 86% (6 PR and 1 NC). Adverse reactions of grade 3 were observed in 2 patients (25%), but toxicity did not cause a discontinuance of treatment in any case. The UFT/UZEL therapy was considered to be a promising regimen for advanced or recurrent colorectal cancer from a standpoint of effect, safety and QOL of patients.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Quality of Life; Rectal Neoplasms; Tegafur; Uracil

A 57-year-old woman underwent right hemicolectomy (D3) due to transverse colon cancer with multiple liver and peritoneal metastasis. Administration of oral UFT+Leucovorin was started postoperatively. After 6 months, the multiple liver metastases completely disappeared without any adverse reaction. After 14 months, no other recurrence was found by CT scan. This case suggests the usefulness of oral UFT+Leucovorin for progressive recurrent colorectal cancer as home chemotherapy.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Leucovorin; Liver Neoplasms; Middle Aged; Peritoneal Neoplasms; Quality of Life; Remission Induction; Tegafur; Uracil

The patient was a 78-year-old woman who underwent right hemicolectomy with lymph node dissection (D 2) for cecal cancer in June 2003. Histological diagnosis was moderately differentiated adenocarcinoma, ss, n(-), P 0, H 0, M (-), stage II. Adjuvant chemotherapy was not conducted, and the patient was periodically observed after operation. In April 2004, the serum CEA level was elevated to 14.9 ng/ml. Abdominal CT examinations revealed a tumor, 50 x 35 x 50 mm in size, on the right iliopsoas muscle close to the anastomotic site. Systemic chemotherapy with UFT + Leucovorin was initiated under the diagnosis of local recurrence. Only grade 1 body weight loss,pigmentation, pruritus, and anorexia were recognized during chemotherapy. However, these complications did not require administration. After completion of 6 courses of this chemotherapeutic regimen,the serum CEA level was normalized at 3.1 ng/ml, and CT scan revealed the tumor had disappeared in November 2004. Currently, the patient is free from any signs of recurrence and has maintained a complete remission (CR).

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Lymph Node Excision; Neoplasm Recurrence, Local; Remission Induction; Tegafur; Uracil

Progressive respiratory failure developed in a 68 year-old female who was treated with single-agent oxaliplatin for colorectal cancer. Only one cycle of 5-fluorouracil had been previously administered. Computed tomography of the chest showed lesions that suggested pulmonary fibrosis. There was an unfavourable response to treatment with corticosteroids, antimicrobial and antifungical agents. Lung biopsy findings were compatible with interstitial pneumonitis. The patient died 20 days after admission due to irreversible respiratory failure. This is the first case reported in the literature of interstitial pneumonitis related to single-agent oxaliplatin administration.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Alkylating; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Fatal Outcome; Female; Fluorouracil; Gastrointestinal Diseases; Humans; Leucovorin; Lung Diseases, Interstitial; Organoplatinum Compounds; Oxaliplatin; Prednisone; Respiration, Artificial; Respiratory Insufficiency

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Chemoradiotherapy; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Practice Guidelines as Topic; Radiotherapy, Adjuvant; Rectal Neoplasms

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cetuximab; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Rectal Neoplasms

Although single nucleotide polymorphisms may be potentially important pharmacogenetic determinants of cancer therapy, functional evidence regarding their relevance is currently lacking. The C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with changes in cellular composition of folates. We hypothesized that this polymorphism may modulate the cytotoxic effect of 5-fluorouracil (5FU) and methotrexate (MTX), two commonly used chemotherapeutic agents for colon and breast cancers, because the modes of action of 5FU and MTX are critically dependent on cellular composition of folates.. Human HCT116 colon and MDA-MB-435 breast cancer cells were stably transfected with wild-type or mutant 677T human MTHFR cDNA. MTHFR enzyme activity and thermolability, intracellular folate composition, growth rate, and catalytic thymidylate synthase activity were determined. In vitro chemosensitivity to 5FU and MTX was determined using the sulforhodamine B assay. In vivo chemosensitivity of HCT116 cells to 5FU was determined in nude mice.. Compared with cells expressing the wild-type MTHFR, HCT116 and MDA-MB-435 cells expressing the mutant 677T MTHFR had decreased MTHFR activity, MTHFR thermolability, changed intracellular folate distribution, accelerated cellular growth rate, and increased thymidylate synthase activity. The MTHFR 677T mutation increased chemosensitivity of colon and breast cancers to 5FU, but decreased chemosensitivity of breast cancer cells to MTX. In nude mice, xenografts expressing the mutant 677T MTHFR grew faster, but were more sensitive to 5FU, than xenografts expressing the wild-type protein.. Our data provide evidence that the MTHFR C677T polymorphism affects the concentration and intracellular distribution of folates and changes the growth and chemosensitivity of colon and breast cancer cells. The MTHFR C677T polymorphism may be a useful pharmacogenetic determinant for providing rational and effective tailored chemotherapy.

Topics: Alanine; Animals; Antimetabolites, Antineoplastic; Blotting, Western; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Cytosine; DNA Probes; Female; Fluorouracil; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genotype; Humans; Leucovorin; Methotrexate; Methylenetetrahydrofolate Reductase (NADPH2); Mice; Mice, Inbred BALB C; Polymorphism, Genetic; Random Allocation; Thymidylate Synthase; Thymine; Transfection; Transplantation, Heterologous; Valine

A 48-year-old woman presented with a tumor in the supra-clavicular fossa. Under a diagnosis of advanced ileocecal colon cancer with metastases to Virchow's and the paraaortic lymph nodes, ileocecal resection was performed. After surgery, the patient was given 5-FU infused continuously at 500 mg/body per day, and levofolinate was dripped intravenously at 100 mg/body over 2 hours for 5 successive days per week. Two cycles were repeated each week. She was then intravenously given weekly modulation chemotherapy consisting of 125 mg/body levofolinate and 500 mg/body of 5-FU for about 5 months on an outpatient basis. Furthermore, the same administration schedule was continued bi-weekly for 1 year and 4 months. As a result, the enlarged paraaortic lymph nodes had completely disappeared by 5 months after administration of levofolinate.5-FU. The Virchow's lymph node metastasis has not been palpable for 11 months. Throughout the period of treatment, there were no severe side effects and as of this writing, no sign of recurrence for 3 years after surgery. A high quality of life has been maintained. In conclusion, this case seems significant from the viewpoint of the complete long-term response to a moderate dose of levofolinate.5-FU therapy and the long duration of administration, which was tolerable with few side effects. Moreover, we identified the presence of TS and DPD using immunohistochemical staining techniques, when both primary tumor and regional lymph nodes were all negative for the stain test. It was suggested that this cancer especially would responded to 5-FU chemotherapy.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Aorta, Abdominal; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Remission Induction

A 58-year-old man who had colon cancer with liver and multiple lung metastases underwent ileocecal resection on May 10, 2002. MTT assay of 5-FU and CPT-11 was performed with resected material, with both medicines accepted for sensitivity. On June 4, he received combination chemotherapy with CPT-11 + 5-FU/l-LV. The liver metastasis disappeared and was judged CR from a CT of the abdomen. Almost all the multiple lung metastases had disappeared or were decreased in size. They were therefore judged NC from a CT of the chest. Moreover, CEA and CA19-9 decreased to within normal limits. While he was receiving bimonthly chemotherapy with only CPT-11 as a maintenance therapy, liver and lung metastases did not change. Combination chemotherapy with CPT-11 + 5-FU/l-LV is effective. The anticancer drug sensitivity examination is only one index, however. Considering adverse effects and medical costs, individualized therapy based on the sensitivity test for anticancer drugs should be performed.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Tumor Cells, Cultured

A 54 year-old male was admitted for highly advanced ascending colon cancer with multiple bone and liver metastases and pleuritis carcinomatosa. He was treated with pharmacokinetic modulating chemotherapy (PMC) and low-dose CPT-11. UFT (400 mg) was orally administered daily and a 2-hour infusion of l-leucovorin (250 mg/m2/day) with a continuous infusion of 5-FU (600 mg/m2/24 h) was given once a week on an outpatient basis. CPT-11 (80 mg/body/2 h) was administered every 2 weeks. Partial response was obtained in the liver for 6 months and in the primary lesion for 9 months. Significant decrease of pain from the multiple bone metastases was observed for 4 months without severe side effects, which led to an improvement in performance status and quality of life for the patient. He survived more than 11 months after initial treatment. The duration of his stay at home was 288 days, accounting for 83% of the treatment period. This case suggests the efficacy of home anticancer therapy with PMC and low-dose CPT-11 for highly advanced colon cancer in terms of QOL.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Pleurisy; Quality of Life; Tegafur; Uracil

Human colon cancer cells were implanted s.c. in nude mice. After 6 days, the mice were divided into four groups, 10 in each. During the first 5 days, the first and second groups were injected i.p. with leucovorin (LV)/5-fluorouracil (FU), and the third and fourth groups with sterile saline solution. During the subsequent 14 days, groups 1 and 4 received continuous i.p. infusion with sterile saline solution, while groups 2 and 3 received octreotide, galanin and serotonin via an implanted osmotic pump. Tumour volumes diminished significantly in mice treated with both LV/FU and LV/FU-triple therapy, as compared with controls. Both volume and weight of the tumours in mice given LV/FU-triple therapy were less than in those received LV/FU. The volume and weight of the tumours in animals treated with triple therapy was reduced as compared with controls, though not statistically significantly. The proliferation index, and the number of tumour blood vessels were both reduced, while the apoptotic index was increased in the mice treated with both LV/FU-triple therapy, and with triple therapy only as compared with LV/FU-treated mice. The present study has shown that the anti-tumour efficacy and therapeutic efficacy of triple therapy with octreotide, galanin and serotonin is equivalent to LV/FU and that sequential treatment with both could be beneficial.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Division; Colonic Neoplasms; Disease Models, Animal; Female; Fluorouracil; Galanin; Humans; Leucovorin; Mice; Mice, Inbred C57BL; Mice, Nude; Neovascularization, Pathologic; Octreotide; Serotonin; Transplantation, Heterologous

We have experienced a case of colon carcinoma with unresectable multiple liver metastases responding to various combined chemotherapies centering on hepatic arterial infusion therapy. A 42-year-old female with descending colon carcinoma and synchronous unresectable multiple liver metastases underwent left hemicolectomy in September 2001. She was treated with chemotherapy centering on hepatic arterial infusion (HAI) following implantation of a reservoir in the outpatient setting. Pharmacokinetic modulating therapy (PMC), and HAI with Leucovorin/CDDP/5-FU and Levoforinate/CDDP/5-FU were conducted sequentially. Alternative HAI of 5-FU with intravenous infusion of Levoforinate and systemic irinotecan/CDDP were continued biweekly after release of the hepatic artery occlusion. Liver metastases shrunk after 6 months of treatment and were remarkably decreased in size in May 2003. Although 3 metastatic lesions existed in both lungs, good quality of life has been maintained in the 2 years following surgery.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Cisplatin; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Quality of Life

Hepatitis C virus (HCV) infection often goes undiagnosed in asymptomatic carriers, but may become clinically relevant during periods of immunosuppression or severe illness. We report the clinical course of HCV reactivation in a patient receiving chemotherapy for metastatic colon cancer. We also review other reports showing the significance of HCV infection in patients being treated with chemotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colonic Neoplasms; Fluorouracil; Hepatitis C; Humans; Immunocompromised Host; Irinotecan; Leucovorin; Male; Recurrence

Oxaliplatin is a third-generation platinum analog that is used mainly to treat advanced colorectal cancer. The reported incidence of hypersensitivity reactions to oxaliplatin, especially after multiple cycles of therapy, is less than 1%. We report a patient with metastatic colon cancer who developed a hypersensitivity reaction to oxaliplatin during the sixth cycle of combination chemotherapy with oxaliplatin, high-dose 5-fluorouracil and leucovorin. The same reaction occurred again after re-exposure to oxaliplatin 2 weeks later even with prophylactic administration of steroids and H1 antihistamines. After failing third-line treatment with oral tegafur-uracil, we desensitized the patient by using a fixed-rate 24-h continuous infusion of dilute oxaliplatin (0.15 mg/ml), in addition to steroids and H1 antihistamines. He had no hypersensitivity reaction during or after that infusion or when the same concentration was infused in the same way 2 weeks later. Because his condition subsequently deteriorated and the cancer progressed, no further oxaliplatin was given. Our experience does demonstrate, however, that a fixed-rate 24-h continuous infusion of oxaliplatin in a low concentration may prevent a hypersensitivity reaction in a previously sensitized patient.

Topics: Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Desensitization, Immunologic; Dexamethasone; Diphenhydramine; Drug Administration Schedule; Drug Hypersensitivity; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Liver Neoplasms; Male; Neoplasm Metastasis; Organoplatinum Compounds; Oxaliplatin; Rectal Neoplasms; Taiwan; Time Factors

5-fluorouracil (5-FU), the most common antimetabolite used for the treatment of colorectal cancer, exerts its cytotoxic effects through the induction of apoptosis. Folinic acid potentiates the effect of 5-FU. Drug activity is currently limited as a result of inducible chemoresistance. Limited research suggests that the transcription factor nuclear factor kappa-B (NF-kappaB), which has antiapoptotic properties, may play a major role in inducible chemoresistance.. SW48 colon cancer cells were used for all experiments. Cell growth was determined by cell proliferation assay. Apoptosis was assessed by measuring caspase 3 activity. Activation of NF-kappaB was ascertained by electrophoretic mobility shift assay, luciferase reporter assay, and Western blot analysis.. Treatment with 5-FU (0.001-10 mm), not only inhibited growth and induced apoptosis but significantly activated NF-kappaB in SW48 cells. Folinic acid alone (0.01-100 mg/L) did not inhibit growth but improved the cytotoxic effect of 5-FU in a dose-dependent manner. Likewise, folinic acid alone did not activate NF-kappaB or induce apoptosis but enhanced 5-FU-mediated NF-kappaB activation and cell apoptosis. Transfection with adenovirus IkappaBalpha super-repressor strongly inhibited constitutive activation of NF-kappaB and significantly enhanced 5-FU and 5-FU/Folinic acid-mediated growth inhibition (P < 0.05).. Treatment with 5-FU activates NF-kappaB. Folinic acid enhances 5-FU-mediated activation of NF-kappaB. Inhibition of NF-kappaB enhances the cytotoxic effect of 5-FU with or without Folinic acid in colon cancer cells.

Topics: Adenoviridae; Antimetabolites, Antineoplastic; Apoptosis; Cell Division; Cell Line, Tumor; Colonic Neoplasms; Drug Synergism; Fluorouracil; Genetic Vectors; Humans; I-kappa B Proteins; Leucovorin; NF-kappa B; NF-KappaB Inhibitor alpha; Transfection

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cetuximab; Chemotherapy, Adjuvant; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin

The patient was a 45-year-old woman who had ascending colon cancer with multiple paramesenteric and paraaortic lymph node metastases. Combined l-LV 400 mg/body (250 mg/m2) +5-FU 950 mg/body (600 mg/m2) therapy was carried out as neoadjuvant chemotherapy. After 2 cycles of this therapy, the lymph node metastases were not detectable on computed tomography. Thus, right hemicolectomy was performed (D3, CurB). It is suggested that l-LV+5-FU therapy may be useful for advanced colon cancer as neoadjuvant chemotherapy.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Preoperative Care

We report a case in which l-leucovorin/5-fluorouracil (l-LV/5-FU) combination therapy was remarkably effective for non-resectable advanced descending colon cancer with carcinomatous peritonitis. A 65-year-old man complained of severe abdominal distension, abdominal pain and pulmonary failure, and was diagnosed as having ileus due to descending colon cancer. The patient underwent urgent open laparotomy to release the ileus condition on March 5, 2002. During the laparotomy, we established a diagnosis of nonresectable descending colon cancer accompanied by severe peritoneal dissemination and therefore performed only double-barreled transverse colostomy. The postoperative course was very good. Pathological examination of omental dissemination demonstrated moderately differentiated adenocarcinoma and cytology of ascites was class II. The levels of serum CEA and CA19-9 were within the normal ranges. l-LV/5-FU therapy was initiated postoperatively. Seven cycles of this chemotherapy regimen was performed with no apparent side effect during the treatment. There was no postoperative accumulation of carcinomatous ascites. The patient gained 15 kg compared with body weight admission. On abdominal computed tomography (CT), the primary lesion of the colon decreased 98% and there was no ascites found. To date, there has not been any sign of recurrence during the 19 months of follow-up after this therapy, and we are currently discussing closure of the transverse colostomy. This therapy may be useful for patients with advanced colon cancer accompanied by peritoneal dissemination.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Male; Peritoneal Neoplasms; Quality of Life

The patient was a 67-year-old man in whom hepatic metastasis from transverse colon cancer was detected 15 months after transverse colectomy (D2). We treated the patient by systemically administering 2 courses of 5-FU 750 mg/day with l-LV 350 mg/day (once weekly for 6 weeks per course). Assessment of therapeutic effects by CT showed PD in the patient. As a second-line therapy, we treated the patient by systemically administering 3 courses of 5-FU 750 mg/day, l-LV 350 mg/day and CPT-11 40 mg/day x 3 days (once a week for 4 weeks per course). After 3 courses of this chemotherapy, CT examination revealed a reduction in the tumor size of the liver, and CEA levels decreased at the end of this chemotherapy. This chemotherapy also showed no high-grade toxicities. l-LV/5-FU/low-dose CPT-11 seems to be effective for metastatic colon cancer, and safe from the toxicity standpoint.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Remission Induction

The patient was a 78-year-old male with a history of colon cancer. After surgical resection of colon cancer, he suffered a multiple liver metastasis. We treated him by arterial infusion chemotherapy with the catheter edge embedded at the common hepatic artery. For a long period, the lesions were defined as partial response on WHO-criteria, but a wide area of the common hepatic artery was shrunk. After changing the treatment to systemic intravenous chemotherapy, the metastatic lesions began to enlarge. Then, we somehow were able to put a microcatheter into the replaced right hepatic artery (rRHA), and could restart arterial infusion chemotherapy. We continued this procedure for over a year without any complication.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Catheters, Indwelling; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Irinotecan; Leucovorin; Liver Neoplasms; Male

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Risk Factors; Thrombophlebitis

We report Guillain-Barre syndrome (GBS), developed in a patient with metastatic colon cancer, receiving oxaliplatin-based chemotherapy. The 53-year-old patient was treated with first-line chemotherapy consisting of oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day in a weekly schedule. After 13 weeks of treatment and a cumulative oxaliplatin dose of 585 mg/m2, the patient developed unsteadiness of gait, dysphagia, and weakness of both the upper and lower limbs, as well as impairment of all sensory modalities. Clinical examination, computed tomography and magnetic resonance imaging scans of the brain, blood tests, nerve conduction studies, and cerebrospinal fluid analysis confirmed the diagnosis of GBS. Intravenous immunoglobulin G was administered for 5 days and the patient recovered fully. Oxaliplatin can cause acute and delayed neurotoxicity, but this is the first report of GBS in a patient receiving oxaliplatin-based chemotherapy. Elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin, may represent the relevant causal links involved in the cascade of events which have led to the immune-mediated demyelination in the peripheral nervous system in this patient.

Topics: Adenocarcinoma; Antineoplastic Agents; Colonic Neoplasms; Fluorouracil; Guillain-Barre Syndrome; Humans; Immunoglobulin G; Leucovorin; Magnetic Resonance Imaging; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Tomography, X-Ray Computed

Colon cancer patients with severe hepatic dysfunction secondary to liver metastases have limited treatment options. 5-Fluorouracil (5-FU) infusional therapy has been attempted, but data suggesting significant clinical benefit are lacking. Although both 5-FU and oxaliplatin have been well tolerated as single agents in patients with severe hepatic dysfunction, the combination of these drugs in this setting has not been investigated. We report on three patients with severe liver dysfunction secondary to metastatic colon cancer treated with a combination of 5-FU, oxaliplatin, and leucovorin (FOLFOX). All three patients tolerated chemotherapy well without any significant toxicity. Liver function tests improved within 2 weeks from the start of treatment. Clinical outcomes consisted of two partial responses and one disease stabilization. Two patients progressed after 4 and 7 months from FOLFOX initiation while treatment is ongoing in the third patient. FOLFOX chemotherapy is feasible and can be associated with positive outcomes in patients with metastatic colon cancer and severe hepatic dysfunction. This regimen should be investigated further in similar clinical settings.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Treatment Outcome

The efficacy and toxicity of 5-FU was various in different patients. It was reported that they were correlated to the activity of dihydropyrimidine dehydrogenase (DPD). This study is to measure DPD activity in blood and to analyze the relationship among DPD activity, the toxicity of 5-FU based adjuvant chemotherapy and the 5-FU plasma concentration in colorectal cancer patients.. 30 colorectal cancer patients were enrolled into the study to receive adjuvant chemotherapy 2 weeks after cured resection. The regimen was 5-FU 425 mg/m(2) plus CF 60 mg/m(2) continuous infused for 2 hours, daily for 5 days. The concentration of endogenous uracil (U) and dihydrouracil (UH(2)) were assayed by high performance liquid chromatography (HPLC). The UH2-U ratio in plasma was used to represent DPD activity in blood. The plasma samples were collected before chemotherapy in all patients to detect the DPD activity in blood, and after 5-FU infusion at day 1 and day 5 to measure 5-FU plasma concentration. The relationship among the DPD activity in blood, the toxicity of chemotherapy and the plasma concentration of 5-FU in all patients were analyzed.. 30 colorectal cancer patients have received adjuvant chemotherapy. The DPD activity in the blood of 30 colorectal cancer patients before chemotherapy was 4.09+/-1.21 (2.14-6.7), showed a trend of normal distribution. The 5-FU plasma concentration after 5-FU infusion was (2 079.12+/-621.41) microg/L (1 200.10-3 554.80 microg/L) at the first day, and (2 197.64+/-606.78) microg/L at the fifth day (1 259.00-3 441.03 microg/L). There was a negative relationship between the DPD activity in blood and the 5-FU plasma concentration at day 1 (r=-0.773, P=0.00), and day 5 after 5-FU infusion(r = -0.833, P = 0.00). No significant difference between the 5-FU plasma concentration of day 1 and day 5 was found (P=0.458). The 5-Fu associated toxicities had a negative relationship with DPD activity in blood, and had a positive relationship with 5-FU plasma concentration (P< 0.05).. The results indicated that the DPD activity in blood can be used to predict the toxicity and the 5-FU plasma concentration in patients with 5-FU based chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Dihydrouracil Dehydrogenase (NADP); Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Rectal Neoplasms

A 79-year-old man was admitted for advanced transverse colon cancer with large bowel obstruction. Twelve years earlier he underwent a total gastrectomy with Roux-en Y reconstruction for gastric cancer. No metastasis was detected preoperatively. Exploratory laparotomy revealed massive direct invasion of the mesenterium of the jejunum for Roux-en Y reconstruction. The primary lesion was unresected and transverse colostomy was made. Systemic chemotherapy with 5-fluorouracil and l-leucovorin was scheduled for a total of 4 courses postoperatively. After completion of this chemotherapeutic regimen, a CT scan and colonofiberscopy revealed the primary lesions had disappeared, and a histological examination of biopsy confirmed that the patient had achieved a complete remission (CR). There was no severe side effect during chemotherapy. The patient is presently enjoying a good general condition and has been free from any sign of recurrence.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colostomy; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Male; Neoplasm Invasiveness

Gastrointestinal carcinoid tumors are often associated with other tumors, particularly colon adenocarcinomas; but the association between carcinoid tumors and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has not yet been explored. We report an unusual case of a 28-year-old woman with HNPCC who underwent surgery for a transverse colon adenocarcinoma in whom an appendix carcinoid tumor was incidentally found. To assess whether the carcinoid tumor displayed the characteristic molecular features of HNPCC tumors, we investigated the expression of mismatch-repair (MMR) proteins and microsatellite instability (MSI) status in both tumors. Both tumors demonstrated normal expression of the MMR proteins hMLH1, hMSH2, hMSH6, and hPMS2. Interestingly, the adenocarcinoma exhibited an MSI phenotype but the carcinoid tumor did not, indicating that these 2 tumors arose through different molecular pathways.

Topics: Adult; Antimetabolites, Antineoplastic; Appendiceal Neoplasms; Carcinoid Tumor; Chemotherapy, Adjuvant; Colonic Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA-Binding Proteins; DNA, Neoplasm; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Microsatellite Repeats; MutS Homolog 3 Protein; Treatment Outcome

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Diseases; Colonic Neoplasms; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Randomized Controlled Trials as Topic

The patient was a 70-year-old man who had sigmoid colon cancer with multiple lung and paraaortic lymph node metastases. Sigmoidectomy was performed on August 3, 2001. After the operation, combined l-Leucovorin (LV) + 5-fluorouracil (5-FU) was carried out. As a result, lung and lymph node metastases were reduced markedly and CEA level decreased. It is suggested that this combination therapy may be useful for advanced colon cancer patients.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Male; Tomography, X-Ray Computed

Irinotecan (CPT11) has established activity against advanced colorectal cancer without cross-resistance with 5-fluorouracil + leucovorin-based therapy. We conducted this pilot study to evaluate the efficacy and tolerance of combination treatment with irinotecan and 5-fluorouracil (5-FU) for patients in whom combination treatment with oxaliplatin with 5-FU + leucovorin has failed.. Patients were enrolled in this study after oxaliplatin treatment had failed. The treatment protocol consisted of CPT11 (180 mg/m(2) for 90 min) on day 1 and a 2 h infusion of 200 mg/m(2) leucovorin followed by 400 mg/m(2) 5-FU as an intravenous bolus injection plus a 22 h continuous infusion of 600 mg/m(2) 5-FU. This regimen was repeated for two consecutive days every 2 weeks.. A total of 18 patients were eligible for this study and in total 144 cycles of therapy (median eight cycles) were given to these patients. Four patients (22.2%; 95% CI: 8-36.4%) achieved an objective response of partial remission (PR) and an additional seven obtained stable disease (SD) status or minor response. The median duration of response was 8 months and 14 patients were alive at the end of the study. Hematological toxicity (neutropenia) was the most common serious side effect (29.2%), followed by gastrointestinal effects (diarrhea, 28.5%). Grade II-III diarrhea was experienced for at least one cycle by each patient.. The results of treatment for patients after oxaliplatin failure are encouraging and this treatment protocol is also well tolerated by previously heavily treated patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Leukopenia; Middle Aged; Nausea; Pilot Projects; Rectal Neoplasms; Salvage Therapy; Survival Analysis; Treatment Outcome; Vomiting, Anticipatory

We report a case of irinotecan-resistant colon cancer responding to chronotherapy with oxaliplatin (L-OHP), 5-FU, l-LV (l-Leucovorin). A 72-year-old man was examined at a certain hospital because of constipation and appetite loss. Chest computed tomography (CT) revealed lung metastases, and abdominal CT revealed liver metastases. He was then referred to our hospital. A colonoscopy revealed type 2 tumor in the colon, at the hepatic flexure. We diagnosed adenocarcinoma of the colon with metastases to the liver and lung. Resection of the primary lesion was performed, and chemotherapy consisting of systemic administration of CPT-11, 5-FU and l-LV was performed. After 2 courses of combined treatment with CPT-11/5-FU/l-LV, CT revealed considerable reduction of the metastatic tumors. However, after 3 courses of combined treatment, progressive disease was observed and new brain and bone metastases were detected. We imported and used a non-approved/pending drug, oxaliplatin from the Remedy and Health Corporation, with informed consent from the patient and his family and our clinical ethics committee. Chronotherapeutic schedules have been performed, from which the safety and activity of oxaliplatin against advanced colorectal cancer was reported. Our patient received a 5-day course of chronomodulated 5-FU and l-LV (750 and 300 mg/body/day, respectively; peak delivery rate at AM 4:00 hours) with L-OHP on the first day of each course (100 mg/body, as a 6-hour infusion). Each course was again repeated every 21 days. A partial response was observed in the liver and lung metastases. These results indicate that chronomodulated 5-FU and LV with L-OHP therapy could be an effective regimen for cases of irinotecan-resistant colon cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Camptothecin; Chronotherapy; Colonic Neoplasms; Drug Evaluation; Drug Resistance, Neoplasm; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Organoplatinum Compounds; Oxaliplatin

Topics: Adult; Aged; Anticoagulants; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Drug Therapy, Combination; Female; Fluorouracil; Humans; Incidence; International Normalized Ratio; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Prothrombin Time; Rectal Neoplasms; Warfarin

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Fluorouracil; Humans; Ileal Diseases; Leucovorin; Male; Organoplatinum Compounds; Oxaliplatin; Vasculitis

Colorectal cancer is a common malignancy. Surgical resection is the primary treatment modality and the outcome is closely related to the extent of the disease at presentation. Adjuvant chemotherapy with 5-fluorouracil and leucovorin is the standard therapy for resected node-positive disease. This therapy can cause myelosuppression. We present a case of colon cancer with idiopathic leukopenia who tolerated chemotherapy without worsening of leukopenia.

Topics: Chemotherapy, Adjuvant; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged

To study the change of caspase-3 activity on the neoadjuvant chemotherapy-induced apoptosis by hydroxycamptothecin (HCPT) with 5-fluorouracil (5-Fu)/leucovorin (CF) in large-intestinal carcinoma, and to explore its mechanism.. HCPT 100 mg/dt-5, 5-Fu 500 mg/dt-5 and CF 200 mg/dt-5 were administered intravenously to 20 pre-operation patients. Samples were obtained during the operation. The changes of apoptotic cells and caspase-3 activity in large-intestinal carcinoma were evaluated with the optical microscopy and the colorimeteric assay respectively and were compared with non-chemotherapy group and normal intestinal tissue group.. 1. The obvious cell apoptotic change could be observed under the optical microscopy in the neo-adjuvant chemotherapy group; 2. The level of caspase-3 activity was significantly higher in the neo-adjuvant chemotherapy group than in the non-chemotherapy and normal intestinal tissue group(P < 0.05); 3. The change of caspase-3 activity was closely correlated with the tumor differentiation and Dukes stage after the induction of pre-operative chemotherapy.. HCPT combined with 5-Fu/CF may induce the apoptosis of large-intestinal carcinoma cells and caspase-3 takes part in the apoptotic process. The change of caspase-3 activity was closely correlated with the degree of the tumor differentiation and Dukes stage.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Camptothecin; Caspase 3; Caspases; Chemotherapy, Adjuvant; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Dose-Response Relationship, Drug; Fluorouracil; Humans; Leucovorin

A prospective study was carried from January 1996 to December 2000 including patients that received adjuvant chemotherapy type FUFOL for colon carcinoma after curative surgery. Chemotherapy was recommended for all stage Dukes B2 end C. Adjuvant chemotherapy was administered to 24 patients (13 men and 11 women, mean age 56.7 +/- 11.5 years) with surgically resected stage B 2 in 7 cases (29%), C in 17 cases (71%). Treatment was completed in 15 patients (62%). With a median follow-up of 31.6 months, 11 patients had no recurrence, one patient had locoregional recurrence and 2 patients developed liver metastasis. Adjuvant FUFOL chemotherapy is actually the recommended adjuvant post-surgical treatment for colon cancer. This valided protocol is easily realised with a low toxicity and it can be done in gastro-enterology unit.

Topics: Antimetabolites, Antineoplastic; Carcinoma; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Hospital Units; Humans; Leucovorin; Male; Middle Aged; Prospective Studies; Treatment Outcome

The patient was a 49-year-old man. In 1995, he underwent left hemicolectomy for descending colon carcinoma, and in 1996, partial hepatic resection was performed for liver metastasis. Post-operative chemotherapy was performed with 5'-DFUR. Five years later, he had lumbar and femoral pain. X-ray and MRI examination revealed a compression fracture and a spinal tumor at the XII thoracic vertebra. Though chemoradiotherapy was performed, the symptoms of pain, numbness and muscle weakness progressed. A resection of the metastatic spinal tumor was performed. Following several systemic chemotherapies, such as 5-FU/l-LV, CPT-11 + 5-FU/l-LV and low-dose CPT-11/UFT, radiotherapy was performed for the progressed bone tumor. At 2 years after surgery, he is still able to walk and no other site of recurrence has been detected.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Spinal Neoplasms

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoembryonic Antigen; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Practice Guidelines as Topic; Prognosis; Rectal Neoplasms

Systemic chemotherapy is used increasingly prior to resection of hepatic colorectal metastases. Previous reports have indicated an increased risk of perioperative complications associated with the use of systemic chemotherapy prior to resection. The purpose of this study was to investigate perioperative complications in patients receiving neoadjuvant systemic chemotherapy consisting of 5-fluorouracil (5-FU) and leucovorin (LV) with or without CPT-11 within 6 months of major liver resection. A retrospective review of 108 patients undergoing major liver resection for colorectal metastases with curative intent from 1997 to 2002 was performed. Patient and tumor characteristics, perioperative parameters, and morbidity and mortality were measured. Forty-seven patients (44%) received no chemotherapy, 27 patients (25%) received systemic 5-FU/LV, and 34 (31%) received systemic 5-FU/LV/CPT-11. A significantly higher number of patients in the group treated with preoperative 5-FU/LV plus CPT-11 had multiple tumors. Patients in this group also tended to have smaller tumors, fewer complications, and a higher R0 margin resection rate, but these findings were not statistically significant. Median blood loss and length of hospital stay were also not significantly different. There were no perioperative deaths. We conclude that the use of fluoropyrimidine-based chemotherapy and CPT-11 prior to major liver resection is not associated with increased morbidity or mortality. It may therefore provide a better therapeutic option, particularly in patients with multiple colorectal metastases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Folic Acid; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Postoperative Complications; Retrospective Studies

In this study, we evaluated the efficacy and tolerability of biweekly irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and folinic acid (FA) regimen (IFL) in patients with advanced stage colorectal cancer.. A total of 28 patients were examined. The median age was 51 years (range, 30-74 years). One treatment cycle consisted of CPT-11 180 mg/m(2) on days 1 and 15; 5-FU 425 mg/m(2) on days 1, 2, 15 and 16; and FA 20 mg/m(2) on days 1, 2, 15 and 16, every 4 weeks. A total of 119 cycles (median, 4.0 cycles) were administered. Of the 28 patients, 18 received the chemotherapy as first line treatment, seven received it as second line and three received it as third line.. An overall objective response rate of 21.5% was achieved in the patient group. However, the overall response rate for the 18 patients receiving first line treatment was 27.7%. The median response duration was 10.5 months (range, 3-19 months). An additional 28.6% of the patients had stable disease for a median duration of 6.5 months (range, 3-8 months). Median time to disease progression was 4.5 months (range, 1-22+ months) and median overall survival time was 11+ months (95% confidence interval, 9-15 months). Toxicities were mild and manageable.. We conclude that biweekly IFL is a practical and tolerable treatment option with a disease control rate of 50.1% in patients with advanced stage colorectal cancer.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Rectal Neoplasms; Survival Analysis

Leucovorin (LV)/5-fluorouracil combination is one of the first-line forms of chemotherapy for colorectal cancer, and in this regimen it was recommended that 5-FU be infused continuously from the venous route. However, since this regimen limits the patients' ADL, oral administration is preferable. The purpose of this study is to elucidate the mechanisms of orally-administered LV/5-FU.. The Gastrostomy was performed, and 1 x 10(6) of colon 26 was transplanted subcutaneously in CDF1 mice. In the continuous administration group, either 10, 20, 40 mg/kg of 5-FU and 100 mg/kg of LV were continuously infused for 7 days following gastrostomy using a microinfusion pump (n = 6). In the single infusion group, either 10, 20, 40 mg/kg of 5-FU was infused once a day for 7 days after gastrostomy concomitant with LV (n = 6). The other 6 animals served as the control, and LV alone was infused in this group. Tumor volume, thymidylate synthase inhibition rate (TSIR), incorporation of 5-FU into RNA (F-RNA) and body weight were measured at the end of the treatment. During the experimental period, mice were given free access to chow and water.. The tumor volume suppression rate was significantly higher along with the amount of 5-FU. However, there was no significant difference between continuous and single infusion groups. TSIR was higher in the continuous group at the dose of 20 and 40 mg/kg. In contrast, F-RNA was higher in the single group at the dose of 20 and 40 mg/kg. Significant body weight loss was not recognized in any group.. From these data, single administration of 5-FU is more effective for RNA dysfunction. On the other hand, continuous infusion is more damaging to DNA duplication. In summary, since the mechanism of the antitumor effect differs with the administration method, it is important to understand this mechanism.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Leucovorin; Mice; Thymidylate Synthase

Blood-borne metastases to the kidneys from solid tumors have received little attention in the medical literature because they usually occur in a setting of advanced systemic disease, and renal involvement is a relatively minor cause of symptoms. Although the frequency of metastases to the kidney in cancer patients is 7-13% in large autopsy series, incidental discovery of a renal metastasis as the first manifestation of a primary tumor is a very rare event. The most common primary malignancy to involve the kidney is bronchogenic carcinoma,followed by breast and gastrointestinal cancers. In this article, we report a patient with left colon cancer and isolated metastasis to the right kidney at the time of initial diagnosis. Left hemicolectomy and right nephrectomy were performed. Adjuvant systemic chemotherapy consisting of 5-fluorouracil (5-FU) and folinic acid (FA) was given. 5-FU and FA were stopped after four cycles because metastases to the lung and liver occurred about 3 mo after the surgery during adjuvant chemotherapy. Capecitabine was started. The patient died 9 mo after the discovery of the isolated renal metastasis. Nephrectomy is more for diagnostic clarification in the setting of synchronous primary because it has no effect on survival and its effect on quality of life is minimal; as seen in our case, the other organ metastases rapidly occur and the survival is limited. Nephrectomy may also compromise the choice of chemotherapy agents that require renal clearance, thus a careful evaluation of renal functions is necessary if a nephrectomy is performed. In the matter of a decreased renal clearance,the doses of these drugs should be decreased or the choice should be reevaluated.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Colectomy; Colonic Neoplasms; Deoxycytidine; Fluorouracil; Humans; Kidney Neoplasms; Leucovorin; Male; Neoplastic Cells, Circulating; Nephrectomy

The purpose of this study was to determine the efficacy and toxicity of uracil/ftorafur (UFT) plus oral leucovorin (LV) as first-line chemotherapy for patients with metastatic colorectal cancer and salvage chemotherapy with weekly high-dose 5-fluorouracil (5-FU)/LV 24 h infusion.. Adult patients with no prior chemotherapy for metastatic diseases were enrolled to receive oral UFT 300 mg/m(2)/d plus LV 90 mg/d for 28 days. Treatment was given continuously for 28 days followed by a 7 day rest period from all treatment. For UFT failed patients, weekly 24 h infusion of 5-FU 2600 mg/m(2) plus LV 100 mg/m(2) was used as salvage therapy.. Fifty-one patients with metastatic colorectal cancer were enrolled in the study. The objective response rate was 29.5% [95% confidence interval (CI), 16.8-45.2%] among the 44 evaluable patients and 25.5% in the intent-to-treat population. The median survival for all 51 patients was 16.6 months. The median time to progression was 5.9 months. Diarrhea was the major adverse effect of UFT/LV that made patients reduce dosage. Grade 3 or 4 diarrhea developed in 13.7% of patients. Twenty-six patients were treated with weekly 24 h infusional 5-FU/LV as salvage therapy and only two patients responded.. Our results suggest that this 28 day schedule of UFT/LV regimen may offer a well-tolerated, full oral treatment option with efficacy that appears comparable to that of intravenous 5-FU/LV regimens. Parenteral 5-FU/LV as salvage therapy for UFT refractory patients is not recommended.

Topics: Adult; Aged; Antineoplastic Agents; Colonic Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Rectal Neoplasms; Salvage Therapy; Tegafur; Uracil

We describe a novel method for detecting micrometastasis in the blood stream of cancer patients based on RT-PCR amplification of tumor-associated carcinoembryonic antigen (CEA) mRNA. To increase sensitivity and specificity of RT-PCR, CEA transcript was selectively up-regulated in cancer cells by exposure of peripheral blood to non-toxic concentrations of staurosporine (ST). Thereafter, polyA(+) RNA was extracted from tumor cells captured by means of magnetic beads coated with a monoclonal antibody against a common human epithelial antigen. Finally, RNA was subjected to RT-PCR analysis of CEA transcript. Using this approach, we demonstrated an ST-mediated increase in CEA transcript in blood specimens collected from a patient with metastatic colon cancer before receiving treatment with 5-fluorouracil/leucovorin. After a few cycles of chemotherapy, CEA-positive tumor cells were no longer detected. Clinical follow-up of this patient indicated that treatment with chemotherapy induced a dramatic reduction in liver metastasis. Therefore, it can be hypothesized that lack of CEA transcript detection might be consistent with disappearance or at least marked reduction of circulating tumor cells.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Colonic Neoplasms; DNA Primers; Female; Fluorouracil; Humans; Immunomagnetic Separation; Leucovorin; Liver Neoplasms; Middle Aged; Neoplastic Cells, Circulating; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Neoplasm; Sensitivity and Specificity

A 51-year-old man underwent right hemicolectomy due to ascending colon cancer with multiple liver metastases. Administration of modified pharmacokinetic modulating chemotherapy (PMC) using Leucovorin (intravenous infusion of 5-FU, 600 mg/m2/24 hours; oral administration of UFT, Taiho Pharmaceutical Co., Tokyo, Japan, 400 mg/day; and Isovorin, Wyeth Lederle Co., Tokyo Japan, 250 mg/body) was started postoperatively. Two months of modified PMC produced a drastic tumor reduction without any adverse reactions such as diarrhea or myelosuppression observed. At present the patient continues to tolerate the chemotherapy and is being followed as an outpatient clinic. This case suggests the usefulness of modified PMC using Leucovorin for progressive recurrent colon cancer.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Remission Induction; Tegafur; Uracil

One patient with pulmonary metastasis from colon cancer and one with para-aortic lymph node metastasis were treated with a combination of irinotecan and UFT. Irinotecan (100 mg/m2) was given by 24-hour intravenous infusion on day 1, and UFT (600 mg/day) was given orally on days 3 to 7 and days 10 to 14 of a 2-week course, which was then repeated. In the patient with pulmonary metastasis, the lesions in the lung resolved after 7 courses of chemotherapy. Surgery was performed after 10 courses. The patient with para-aortic lymph node metastasis had a partial response after 4 courses of chemotherapy, and underwent surgery after 6 courses. The only adverse effects were grade 2 myelosuppression and hair loss, none of which were severe enough to require treatment. With this chemotherapy regimen, patients are admitted for two days biweekly for 24-hour intravenous infusion of CPT-11. Thus, most of the treatment can be performed on an outpatient basis. The combination of irinotecan and UFT is expected to be useful for metastatic or recurrent colon cancer.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colectomy; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Fluorouracil; Humans; Irinotecan; Leucovorin; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Tegafur; Uracil

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Humans; Leucovorin; Levamisole; Neoplasm Staging; Selection Bias

Recently, angiogenesis has gained an increasing interest as a prognostic factor in a variety of solid tumours. In this study we aimed to assess the prognostic role of serum vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF) and nitric oxide (NO) levels in patients with colorectal carcinoma (CRC).A total of 52 consecutive colorectal cancer patients with stage I to IV disease was included. In addition to routine laboratory and staging procedures, serum VEGF, b-FGF levels, and nitrate levels as a surrogate marker for in-vivo NO production were assayed. Serum VEGF concentrations, adjusted to the platelet count were found to be a significant factor for overall survival in univariate analysis (P=0.033). A new angiogenic index (AI), derived from serum VEGF and nitrate concentrations, was established. AI is the only independent prognostic factor of survival in all patients (P=0.008, Cox regression analysis). Likewise, AI is also significant prognostic factor for disease-free survival (DFS) in patients with operable CRC (P=0.032, Cox regression analysis). In conclusion, serum VEGF and NO levels have prognostic role in patients with CRC and the new angiogenesis index using the serum levels of the factors seem to be useful.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carcinoembryonic Antigen; Chemotherapy, Adjuvant; Cisplatin; Colonic Neoplasms; Colorectal Neoplasms; Disease-Free Survival; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; Fluorouracil; Follow-Up Studies; Humans; Intercellular Signaling Peptides and Proteins; Irinotecan; Leucovorin; Life Tables; Lymphokines; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neovascularization, Pathologic; Nitrates; Nitric Oxide; Organoplatinum Compounds; Oxaliplatin; Prognosis; Proportional Hazards Models; Rectal Neoplasms; Survival Analysis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

The use of dendritic cells (DC) loaded with tumor antigen is one of the most advanced approaches in cancer immunotherapy. CpG motifs within microbial DNA detected by toll-like receptor 9 are responsible for the favorable properties of CpG oligodeoxynucleotides (ODN) as immune modulators. In this study, mature antigen-pulsed DC or peritumoral injections of CpG ODN, both effective for the treatment of small established tumors, were almost ineffective against large established tumors (1-cm diameter) in a syngeneic murine colon carcinoma model. For large tumors, the antitumor activity of mature antigen-pulsed DC was strongly increased by coinjection of CpG ODN, resulting in a transient control of tumor growth. Rejection of large tumors and long-term cure of mice was achieved by combining injection of antigen-pulsed DC plus CpG ODN at a site distant to the tumor with peritumoral injections of CpG ODN. Depletion of CD8 T cells abrogated the therapeutic activity. Large numbers of DEC-205-positive DC infiltrated the tumor in treated mice. Therapy with 5-fluorouracil and leucovorin was unable to control tumors of the same size. In conclusion, we demonstrate that the immune system, provided that appropriate stimulation with DC and CpG ODN is given, has the potential to cure animals of large solid tumors in situations where even chemotherapy is not efficient.

Topics: Adjuvants, Immunologic; Animals; Antigens, Neoplasm; Cancer Vaccines; CD8-Positive T-Lymphocytes; Colonic Neoplasms; Dendritic Cells; Female; Fluorouracil; Leucovorin; Mice; Mice, Inbred BALB C; Oligodeoxyribonucleotides; Tumor Cells, Cultured

5-fluorouracil (5-FU), widely used for chemotherapy of colorectal carcinoma, requires intracellular anabolic conversion to cytotoxic nucleotides and exhibits a narrow therapeutic range with dose-dependent and concentration-dependent effects. 5-FU undergoes extensive metabolic degradation to several catabolites, which are excreted mainly by the kidneys. Alteration of the pharmacokinetics of 5-FU and its catabolites as a result of renal dysfunction might augment systemic toxicity. Because no data are available for patients with severe renal failure, the pharmacokinetic parameters of 5-FU and its catabolites were determined for a patient with colorectal carcinoma and end-stage renal disease on maintenance hemodialysis therapy. Plasma was analyzed by 19F nuclear magnetic resonance spectroscopy for the first 5-day treatment cycle (daily bolus injections of 5-FU for 5 days in combination with low-dose folinic acid). On days 1 and 5, the pharmacokinetic parameters for 5-FU (total area under the plasma concentration-time curve, terminal half-life, total plasma clearance, volume of distribution based on the terminal phase) and its initial catabolite dihydrofluorouracil (total area under the plasma concentration-time curve, terminal half-life) were in the ranges reported in the literature for patients with normal renal function, implying no need for primary dose adjustment. In contrast, the final 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) accumulated to a concentration of 276 micromol/L on day 5 (approximately twofold higher than expected from the literature) despite good removal by hemodialysis with extraction ratios of 0.6 to 0.85 over the filter membrane. Negative effects of FBAL or enhancement of 5-FU-related toxicity could not be judged in this individual case, but further study is warranted to determine the possible benefits of more intensive dialysis treatment.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Colonic Neoplasms; Fluorouracil; Humans; Kidney Failure, Chronic; Leucovorin; Magnetic Resonance Spectroscopy; Male; Middle Aged; Renal Dialysis

The combination of 5-fluorouracil-folinic acid and oxaliplatin has led to a significant improvement of chemotherapy efficacy in advanced pretreated colorectal cancer. The objective of the present study was, considering the oxaplatin-5-fluorouracil-folinic acid combination, to examine the impact of one given drug on the cellular determinants of cytotoxic activity of the other drug. These cellular factors were analysed on the human colon cancer cell line WiDr in clinically relevant conditions of drug exposure ('De Gramont' schedule) with oxaliplatin-folinic acid during 2 h followed by 5-fluorouracil 48 h. The DNA binding of oxaliplatin was significantly reduced by the presence of 5-fluorouracil but this effect was time-dependent and after 50 h the platinum incorporated into DNA was identical in controls and in the drug combination. In the presence of oxaliplatin, there was less formation of FUH(2) which is the first catabolite produced in the cascade of 5-fluorouracil metabolic degradation. The effects of drugs on cell cycle were quite different from one drug to the other with oxaliplatin inducing a shift towards G(2) accumulation and 5-fluorouracil-folinic acid to a greater proportion of cells in G(1)-S. When oxaliplatin and 5-fluorouracil-folinic acid were combined the cell cycle effects were very similar to that of the 5-fluorouracil-folinic acid sequence alone. Oxaliplatin was able to reduce thymidylate synthase activity with a marked impact 28 h after the beginning of cell exposure to the drug. The 5-fluorouracil-folinic acid drug sequence led to a profound reduction in thymidylate synthase activity and this decrease was not markedly enhanced by the presence of oxaliplatin. Regarding apoptosis, changes in mitochondrial membrane permeability were observed in the presence of the tested drugs and the impact of 5-fluorouracil-folinic acid was greater than that of oxaliplatin. The addition of oxaliplatin did not amplify the action of 5-fluorouracil-folinic acid upon mitochondrial membrane permeability change. The presence of oxaliplatin itself did not modify the intracellular concentration of total reduced folates. The fact that oxaliplatin may reduce 5-fluorouracil catabolism could be central in explaining the supra-additive interaction between these drugs.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Cycle; Cell Membrane; Colonic Neoplasms; DNA Damage; Drug Administration Schedule; Drug Interactions; Fluorouracil; Humans; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Permeability; Thymidylate Synthase; Toxicity Tests; Tumor Cells, Cultured

Folates, components of the B-complex vitamins, have numerous pharmacological effects. In oncology combining folates with 5-fluorouracil (5-FU) enhances the cytotoxic effects of chemotherapy in colon cancer patients. Folic acid has been rarely involved in adverse allergic reactions. To the best of our knowledge no anaphylactic reaction secondary to folinic acid (FA) administration has ever been reported before.. An 80-year-old patient had adjuvant chemotherapy for colon cancer including FA and 5-FU and irinotecan as a second line agent after multiple metastases.. Following FA administration anaphylactic shock occurred. Diagnosis was made according to the French method of adverse reactions monitoring.. Anaphylactic shock may be an adverse reaction of FA in patients receiving chemotherapy for colon cancer.

Topics: Aged; Aged, 80 and over; Anaphylaxis; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Fluorouracil; Humans; Injections, Intravenous; Irinotecan; Leucovorin; Liver Neoplasms; Lung Neoplasms; Male; Treatment Outcome

A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)-fluorouracil (FU)-folinic acid (FA) combination and by CPT11-FU-FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU-FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC(50)) of the double association without that drug divided by the IC(50)of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU-FA.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Clinical Trials as Topic; Colonic Neoplasms; Drug Interactions; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Tumor Cells, Cultured

After curative resection (R-0) of primary colon cancer or curative metastases resection, the efficacy, toxicity and compliance of a weekly 24-h infusion of high-dose 5-FU with folinic acid was examined in a prospective feasibility trial. From June 1995 to June 1997, 19 patients were included, 11 patients with UICC stage III and 8 patients with UICC stage IV colon cancer. The patients received weekly 500 mg/m2 of calcium folinic acid (Rescuvolin) as a 1-2 h-infusion on an outpatient basis following a 24-h infusion of 2,000 mg/m2 5-FU via a pump system (intermate LV5 Baxter). The adjuvant therapy was administered for 6 months. 90% of the patients received the planned 18 chemotherapy applications. The total 5-FU dose given to each patient amounted to 34.4 g/m2 in 6 months, thus corresponding to 95% of the planned 5-FU total dose. The main toxicity was diarrhea CTC toxicity grade 3 in the case of 16% of the patients. After a median follow-up of 51 months (range: 37-59 months), 82% of the patients (9 out of 11) with stage III remained free of recurrence. The 2 cases of recurrence belonged to the pN2 subgroup. In stage IV only 12% of the patients (1 out of 8) remained free of recurrence. On an adjuvant basis, a weekly 24-h infusion of high-dose 5-FU with folinic acid is accompanied by a good complicance and a high-dose intensity of 5-FU. Now it is tested within randomized phase III trials of the "Arbeitsgemeinschaft Gastroenterologische Onkologie (AGO)" of the "Deutsche Gesellschaft für Verdauungs- und Stoffwechselerkrankungen" for UICC stage III colon cancer. Concerning stage IV, adjuvant therapy was not effective, a fact that seems to justify new drugs and new therapeutic strategies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Combined Modality Therapy; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Survival Rate

The benefit of adjuvant therapy, such as 5-fluorouracil (5-FU) combined with leucovorin, is a matter of debate for patients with Dukes' B colon cancer. Several approaches have been taken to address this issue. Initially, studies were conducted to assess treatment benefits in both Dukes' B and Dukes' C patients. These studies identified an overall benefit of adjuvant treatment and enrolled enough Dukes' C patients to determine a treatment benefit for adjuvant 5-FU/leucovorin in this subpopulation. However, the individual studies were insufficiently powered to detect a treatment benefit in Dukes' B patients. An analysis of four separate studies (National Surgical Adjuvant Breast and Bowel project) compared the benefit of adjuvant treatment in Dukes' B patients with that in Dukes' C patients and showed similar relative reductions in mortality and disease-free survival in Dukes' B and in Dukes' C patients. The Liver Infusion Meta-Analysis Group also reported similar relative benefits from a portal vein infusion of 5-FU-based chemotherapy in Dukes' B and Dukes' C patients. The International Multicenter Pooled Analysis of Colon Cancer Trials B2 study, which combined data from patients with Dukes' B colon cancer in five separate trials, failed to show a statistically significant benefit of adjuvant 5-FU/leucovorin compared with surgery alone. We review the advantages and limitations of different approaches to detect treatment benefits in patients with Dukes' B colon cancer, and we argue that there is a need for a meta-analysis of all adjuvant trials to reliably address this question.

Topics: Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Meta-Analysis as Topic; Multicenter Studies as Topic; Neoplasm Staging; Proportional Hazards Models; Randomized Controlled Trials as Topic; Statistics as Topic

The adjuvant treatment of colon cancer is now accepted as an effective therapy following surgical resection of the primary tumor in patients at high risk for relapse. Results of studies conducted in the last 10 years have confirmed the benefits of using various 5-fluorouracil (5-FU)-based chemotherapy regimens to decrease recurrence rates and improve patient survival. The North Central Cancer Treatment Group-Mayo Clinic studies have made a significant contribution to establishing the role of adjuvant therapy in colon cancer. Our first study to suggest the effectiveness of adjuvant chemotherapy in patients with stage III disease was reported in 1989. The study used a combination of 5-FU and the anthelminthic agent levamisole, tested because of its ability to positively modulate the human cellular immune system. The results of this study were confirmed by a larger Intergroup study (0035) showing significant decreases in relapse and death rates in stage III colon cancer patients treated with 5-FU plus levamisole compared with surgery alone. Clinical trials conducted throughout the 1990s tested various 5-FU based regimens against the standard 5-FU and levamisole combination. From these trials, the combination of 5-FU plus leucovorin emerged as the standard surgical adjuvant treatment of colon cancer. The efficacy of treatment with this regimen for 6 months was similar to that of a 1-year 5-FU plus levamisole regimen. These findings led to the design of trials in which 5-FU was combined with both leucovorin and levamisole. No differences in efficacy were found in any of the various combinations tested. Current clinical trials are investigating the use of newer agents such as CPT-II in the adjuvant setting. The results of these trials may further improve the efficacy of adjuvant therapy in patients with high-risk colon cancer.

Topics: Adjuvants, Immunologic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Camptothecin; Chemotherapy, Adjuvant; Clinical Trials as Topic; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Humans; Irinotecan; Leucovorin; Levamisole

Capecitabine is an orally administered fluoropyrimidine carbamate that is preferentially converted to 5-fluorouracil in tumors relative to normal tissue. Three different dosing regimens were investigated in phase I studies: continuous monotherapy, intermittent monotherapy, and intermittent therapy supplemented with leucovorin. These studies defined the maximum tolerated dose for each regimen. Dose-limiting toxicities were diarrhea, hand-foot syndrome, and leukopenia. Each phase I study recommended a dose; these were directly compared in a phase II study. This phase II study showed that the intermittent regimen of capecitabine monotherapy was the most favorable on the basis of tumor response rates, time to progression, dose intensity, and toxicities. The intermittent regimen of capecitabine has been compared with the Mayo Clinic regimen of 5-fluorouracil/leucovorin in two large, phase III studies of patients with advanced colorectal cancer. The combined data from the two studies showed that capecitabine was superior to 5-fluorouracil/leucovorin in terms of tumor response rate (22% v 13%; P < .0001) and similar in terms of time to disease progression and overall survival. Capecitabine is now being compared with the Mayo Clinic regimen as an adjuvant treatment for patients with Dukes' C colon cancer.

Topics: Administration, Oral; Antineoplastic Agents; Capecitabine; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Colonic Neoplasms; Deoxycytidine; Drug Therapy, Combination; Fluorouracil; Humans; Leucovorin; Multicenter Studies as Topic; Neoplasm Staging; Randomized Controlled Trials as Topic