levoleucovorin and Carcinoma

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Combined Modality Therapy; Cushing Syndrome; Female; Fluorouracil; Humans; Leucovorin; Pituitary Neoplasms

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

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

A 45-year-old woman, complaining of back pain and bloody stool was given a diagnosis of poorly differentiated adenocarcinoma of the rectum with disseminated carcinomatosis to bone marrow and disseminated intravascular coagulation syndrome (DIC). We started chemotherapy using mFOLFOX-6 with simultaneous DIC treatment. After we confirmed that DIC had improved following 2 courses of mFOLFOX-6, bevacizumab was added to mFOLFOX-6. Laboratory studies revealed a serum CEA level of 314.4ng/ml, which improved to 4.6ng/ml after a total of 6 courses of chemotherapy. Colonoscopy findings showed almost normal rectal mucosa after a total of 10 courses of chemotherapy. Outpatient treatment was started after 5 courses of chemotherapy, and was continuing according to schedule at 7 months from the onset of this disease.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bone Marrow Neoplasms; Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Organoplatinum Compounds; Rectal Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Clinical Trials as Topic; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Treatment Outcome

To review the literature with regard to the incidence and prognostic significance of peritoneal seeding during surgery for primary colorectal cancer (CRC), the incidence of intraperitoneal recurrence of CRC, and the current treatment strategies of established PC of colorectal origin, with special focus on cytoreductive surgery and intraperitoneal chemotherapy (IPEC).. Although hematogenous dissemination forms the greatest threat to patients with CRC, peritoneal carcinomatosis (PC), presumably arising from intraperitoneal seeding of cancer cells, is a relatively frequent event in patients with recurrent CRC.. The PubMed and Medline literature databases were searched for pertinent publications regarding the incidence and prognostic significance of exfoliated tumor cells in the peritoneal cavity during curative surgery for primary CRC, the incidence of intraperitoneal recurrence of CRC, and the therapeutic results of systemic chemotherapy or cytoreductive surgery followed by IPEC.. The incidence of peritoneal seeding during potentially curative surgery for primary CRC, as reported in 12 patient series, varied widely, from 3% to 28%, which may be explained by differences in methods to detect tumor cells. PC is encountered in approximately 7% of patients at primary surgery, in approximately 4% to 19% of patients during follow-up after curative surgery, in up to 44% of patients with recurrent CRC who require relaparotomy, and in 40% to 80% of patients who succumb to CRC. The reported median survival after systemic 5-fluorouracil-based chemotherapy for PC varies from 5.2 to 12.6 months. Median survival after aggressive cytoreductive surgery followed by (hyperthermic) IPEC in selected patients, as reported in 16 patient series, tends to be better and varies from 12 to 32 months at the cost of morbidity and mortality rates of 14% to 55% and 0% to 19%, respectively. One randomized controlled trial has been published confirming the superiority of aggressive surgical cytoreduction and intraperitoneal chemotherapy over strictly palliative treatment.. Peritoneal seeding of cancer cells possibly leading to PC is a rather common phenomenon in patients with CRC. Cytoreductive surgery and adjuvant (hyperthermic) IPEC have been shown to be efficacious in selected patients and should therefore be considered in patients with resectable PC of colorectal origin.

Topics: Antineoplastic Agents; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Fluorouracil; Humans; Incidence; Leucovorin; Neoplasm Seeding; Peritoneal Neoplasms; Postoperative Complications; Prognosis; Quality of Life; Survival Analysis

Colorectal carcinoma is one of the most common cancers in Hungary, responsible for about 5000 deaths each year. In the first line treatment the most commonly used drugs are 5-fluorouracil, oxaliplatin and irinotecan. The most frequently used drug is 5-fluorouracil, which has no effect in 90% of the cases. In combination with leukovorin or with 5-ethyl-2'-deoxyuridin fluorouracil has an increased effect. The main mechanisms of the resistance against 5-fluorouracil are due to the overexpression of dihydropyrimidine dehydrogenase, MRP8, thymidylate synthase, and NFkB p65. Oxaliplatin forms reactive platinum complexes, which are believed to inhibit DNA synthesis by forming interstrand and intrastrand cross-linking of DNA molecules. The oxaliplatin-5-fluorouracil-leucovorin combination was the first to reach more than 20 months median survival. The main mechanisms of resistance are decreased accumulation, increased detoxification and increased DNA repair. Irinotecan inhibits the topoisomerase I enzyme, resulting in the inhibition of the repair of DNA breaks occurring during DNA synthesis. With sequential 5-fluorouracil, oxaliplatin, irinotecan combination 26 months median survival was reached. Mechanisms resulting in resistance are decreased accumulation, increased enzymatic detoxification, alterations of ABC transporters, DNA repair system, apoptotic pathways and topoisomerase I. Survival can be elongated using biological therapy (cetuximab, bevacizumab). In the near future biological therapy is expected to spread.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Cancer Vaccines; Carcinoma; Cetuximab; Colorectal Neoplasms; DNA Repair; DNA, Neoplasm; Drug Resistance, Neoplasm; Fluorouracil; Humans; Hungary; Irinotecan; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Survival Analysis; Treatment Outcome

Chemotherapeutic options in the treatment of advanced colorectal cancer have markedly improved during the last years. This is partly due to the high-dose 5-FU regimen, but also to the development of new cytotoxic agents and drug combinations.. High-dose 5-FU, irinotecan, and oxaliplatin seem to be superior to low-dose 5-FU in terms of response rate and disease control. Combination of irinotecan with 5-FU/FA showed significant longer overall survival rates compared to 5-FU/FA alone in both published phase III trials. Today most patients are treated by a sequential therapeutic concept using the newer drugs mainly for second or third line therapy. However, there are reasons for the use of more intensive chemotherapy combinations in first line treatment. Combination of oxaliplatin with 5-FU/FA, that failed improvement of overall survival compared to 5-FU/FA alone, could downstage previously unresectable liver metastases for potentially curative surgery in some patients. Oral fluoropyrimidines mark another progress in the treatment of advanced colorectal cancer. They seem to be comparable to low-dose 5-FU/FA and could ease chemotherapy.. Prospective randomized phase III trials must confirm the best chemotherapy and the best strategy for the different subgroup of patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Carcinoma; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Disease-Free Survival; Fluorouracil; Humans; Irinotecan; Leucovorin; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Tegafur; Thiophenes; Uracil

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

Induction, or preoperative therapy for rectal carcinoma, is a controversial topic which appears to have clinical utility in a number of distinct settings that range from early stage to locally advanced disease. Common to all treatment scenarios is the intent of reducing the likelihood of recurrence in the pelvis following surgery. An additional and evolving role is a reduction in the extent of surgery following a complete or partial clinical response to the induction regimen. While radiation as a single modality can lead to downstaging and, perhaps, a reduction in local recurrence, combined modality with 5-fluorouracil (5-FU) and radiation appears to have a greater therapeutic benefit that may be further enhanced by the administration of leucovorin.

Topics: Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Neoplasm Staging; Preoperative Care; Rectal Neoplasms

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

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

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

Combination of cisplatine and Gemcitabine (CisGem) is the reference 1st line Chemotherapy in patients with advanced biliary cancer. FOLFIRINOX demonstrated an overall survival superiority when compared to gemcitabine in 1st line for patients with metastatic pancreatic adenocarcinoma. Because of similarities between pancreatic and biliary cancers, we proposed a randomized trial comparing mFOLFIRINOX and CisGEm.. PRODIGE38-AMEBICA is a phase II/III trial evaluating efficacy of modifed FOLFIRINOX (D1 bolus removed) or CisGEm on patients with locally advanced non resectable or metastatic biliary tract cancer.. Main inclusion criteria are histologically or cytologically proven biliary tract tumor (intra or extra hepatic or hilar or gallbladder carcinoma), measurable disease (metastases and/or primary tumor), Bilirubin <1,5 N and transaminases <5 N. The randomization (ratio 1:1) will be stratified on center, stage of the disease, tumor localization and previous adjuvant treatment. The Phase II trial has an objective of 73% patients alive and without progression at 6 months for Folfirinox (versus 59% for Gemcis). 128 additional patients should be added in the phase III trial with an objective of overall survival improvement of 4 months in favor of mFOLFIRINOX.. The study is opened in France (EudraCT no.: 2015-002282-35). All the patients (188) of the phase II part are currently randomized.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Carcinoma; Cisplatin; Deoxycytidine; Drug Monitoring; Female; Fluorouracil; France; Gemcitabine; Humans; Irinotecan; Leucovorin; Male; Neoplasm Invasiveness; Neoplasm Staging; Oxaliplatin

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

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

The optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line.. mCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS).. About 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69-1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55-1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms.. This trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

It has not been elucidated whether the clinical efficacy of oral fluoropyrimidines for adjuvant chemotherapy of colorectal cancer varies with tumor biological characteristics.. A multicenter randomized trial was performed comparing oral tegafur/gimeracil/oteracil (S-1) and uracil-tegafur/ leucovorin (UFT/LV) as adjuvant therapy for stage III colorectal cancer. Postoperative survival was compared based on the 5-FU-related mRNA levels in cancer tissues.. Among patients with tumor expressing dihydropyrimidine dehydrogenase (DPD) mRNA within the 66.7th percentile (lower 2/3) of all cases, overall survival (OS) was significantly better in the S-1 than in the UFT/LV group. In the S-1 group, patients with low DPD-expressing tumors had significantly better OS than those with highly expressing tumors. Patients with low thymidine synthase (TS)-expressing tumors had significantly better OS than those with highly expressing tumors.. The efficacy of oral fluoropyrimidines as adjuvant chemotherapy for colorectal cancer may be influenced by the level of 5-FU-related mRNA in cancer tissues.

Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Orotate Phosphoribosyltransferase; Oxonic Acid; RNA, Messenger; Tegafur; Tetrahydrofolate Dehydrogenase; Thymidine Phosphorylase; Thymidylate Synthase; Treatment Outcome

Evidence suggests that metastatic colorectal carcinoma (mCRC) has a high level of intratumor heterogeneity. We carried out a quantitative assessment of tumor heterogeneity for KRAS, NRAS, BRAF and PIK3CA mutations, in order to assess potential clinical implications.. Tumor samples (n = 182) from the CAPRI-GOIM trial of first-line cetuximab + FOLFIRI in KRAS exon-2 wild-type mCRC patients were assessed by next-generation sequencing that allows quantitative assessment of mutant genes. Mutant allelic frequency was normalized for the neoplastic cell content and, assuming that somatic mutations usually affect one allele, the Heterogeneity Score (HS) was calculated by multiplying by 2 the frequency of mutant alleles in neoplastic cells. Therefore, HS virtually corresponds to the fraction of neoplastic cells carrying a specific mutation.. The KRAS HS ranged between 12 and 260 with mean value of 87.1 and median value of 84.4, suggesting that in most CRC, the majority of neoplastic cells carry mutant KRAS. Similar findings were observed for NRAS (HS range 35.5-146.7; mean 102.8; median 117.1). In contrast, in BRAF (HS range 17.1-120; mean 54.8; median 54.3) and PIK3CA (HS range 14.3-120; mean 59.5; median 47.3) mutant cases, only a fraction of neoplastic cells seem to carry the mutant allele. The response rate was 70% in KRAS mutant patients with an HS <33 (low KRAS; n = 10) and 45.7% in KRAS HS >33 patients (high KRAS; n = 35); median progression-free survival were 7.97 and 8.37 months, respectively. Low-KRAS tumors had a higher frequency of additional mutations in PIK3CA when compared with high-KRAS (6/10 versus 8/35).. KRAS and NRAS mutations are usually present in the majority of neoplastic cells, whereas BRAF and PIK3CA mutations often affect a limited fraction of transformed cells. Resistance to cetuximab in low-KRAS patients might be driven by the complex mutational profile rather than KRAS mutation load.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Drug Resistance, Neoplasm; Fluorouracil; Gene Frequency; GTP Phosphohydrolases; High-Throughput Nucleotide Sequencing; Humans; Leucovorin; Membrane Proteins; Mutation; Organoplatinum Compounds; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Treatment Outcome

Colorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors.. In this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS).. The comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44-1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension.. Cediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Double-Blind Method; Female; Fluorouracil; Humans; Japan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Quinazolines; Treatment Outcome; Vascular Endothelial Growth Factor A

In this multicenter phase Ib study, drozitumab was given in combination with the mFOLFOX6 regimen and bevacizumab in patients with previously untreated, locally advanced recurrent or metastatic colorectal cancer on day 1 of every 14-day cycle. Nine patients were treated at 2 different cohort dose levels of drozitumab. No dose-limiting toxicities occurred at either dose level and the maximum tolerated dose was not reached. Two patients had a partial response of 4.93 and 4.96 months duration. Cohort 2 dose level is the recommended starting dose level for future trials.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Immunohistochemistry; Leucovorin; Male; Maximum Tolerated Dose; Middle Aged; Organoplatinum Compounds

The objective of the study is to investigate whether multiple chemotherapeutic agent-related genetic polymorphisms are associated with the clinical outcomes of Taiwanese metastatic colorectal cancers (mCRC) patients treated with the first-line FOLFOX-4 chemotherapy.. Consecutive mCRC patients were prospectively enrolled into this study. Peripheral blood samples were used for genotyping of polymorphisms in MTHFR, DPD, GSTP1, MDR1, TYMS, ERCC1, XRCC1, and ERCC2 genes by polymerase chain reaction-restriction fragment length polymorphism technique and DNA sequencing. The primary end point of the study was to investigate the association of each genetic polymorphism with progression-free survival and overall survival (OS).. Favorable genotypes from polymorphisms in ERCC1 codon 118C/C [hazard ratio (HR)=0.061, 95% confidence interval (CI): 0.014-0.274, P<0.001] and XRCC1 codon 399G/G (HR=0.306, 95% CI: 0.103-0.905, P=0.032) that are associated with progression-free survival were identified. Furthermore, ERCC1 codon 118C/C (HR=0.065, 95% CI: 0.011-0.377, P=0.002) and XRCC1 codon 399G/G (HR=0.152, 95% CI: 0.041-0.568, P=0.005) were significantly associated with favorable OS. Combining ERCC1 and XRCC1 genetic polymorphisms, patients with both favorable genotypes of ERCC1 codon 118C/C and XRCC1 codon 399G/G were associated with the better OS than those with one or without any favorable genotypes (P<0.001).. The genetic polymorphisms of ERCC1 and XRCC1 may be useful in predicting clinical outcome in Taiwanese mCRC patients treated with FOLFOX-4. However, further prospective studies will be needed for the potential clinical implication.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Genetic Association Studies; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Polymorphism, Genetic; Prognosis; Taiwan; Treatment Outcome

Pancreatic endocrine carcinomas are rare and heterogeneous. Published results concerning treatment of advanced tumours are inconsistent and responses to standard chemotherapy remain unsatisfactory.. To investigate the ability of the FOLFIRI regimen to manage progressive unresectable metastatic well-differentiated endocrine carcinomas of the pancreas as first-line chemotherapy.. 20 patients with metastatic or advanced well-differentiated endocrine carcinomas of the pancreas and progressive disease were enrolled in a prospective multicentre phase II trial to receive chemotherapy with FOLFIRI schedule (irinotecan 180mg/m(2) infusion combined with simplified LV5FU2) every 14 days. The primary end point was the non-progression rate at 6 months.. The 6-month non-progression rate was 80% (95% confidence interval [56-94%]), with stabilisation in 15 patients and 1 objective response. Overall survival at 24 months was 65% [40-82%]. Median progression-free survival was 9.1 months [6.5-17.3 months]. The median number of administered cycles was 12 [range 1-28]. Grade 3/4 haematologic toxicity occurred in 5 patients (25%) and grade 3 digestive toxicity in 11.. The FOLFIRI regimen, as first-line chemotherapy, achieved stabilisation in most patients whose tumours had been progressing and was well-tolerated. It could be an alternative therapy for advanced well-differentiated endocrine carcinomas of the pancreas.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Disease-Free Survival; Female; Fluorouracil; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Pancreatic Neoplasms; Treatment Outcome

This phase II study was designed in order to evaluate efficacy and safety of the combination of vinorelbine (VNB), fluorouracil (FU) and leucovorin (LV) in patients with metastatic breast carcinoma (MBC) previously treated with anthracyclines and taxanes.. From 12/2003 to 12/2007, 51 women (median age 59) were treated. Performance status (PS) (ECOG) was 0-2 (median 0). The chemotherapy consisted of VNB 25 mg/sqm on day 1 added to FU and LV (following De Gramont schedule) on day 1 and 2. Treatment was repeated every 14 days. 518 cycles of CT were administered (median 12). Most common sites of metastatic spread were: bone, liver, lymph nodes, lung.. We recorded three cases of G4 neuthropenia and in one case it was febrile; no others G4 toxicities were seen. G3 toxicities were more common, especially neuthropenia (8 patients) asthenia (4) mucositis (2) and Hand-Foot Syndrome (2). Overall response rate was 27.5% (14 patients had a PR) and disease control rate was 76.5%; 12 patients experienced disease progression. Median time to progression (TTP) was 7.70 months and overall survival (OS) was 18.70 months.. Results demonstrate that the ViFL regimen has substantial activity in patients with MBC already treated with anthracyclines and taxanes. The combination may be considered a valid choice for the treatment of MBC. Better survival results were seen in patients with visceral metastases than bone involvement. The low response rate shows that the ViFL regimen is not suitable for the neoadjuvant setting.

Topics: Adult; Aged; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Metastasis; Survival Analysis; Taxoids; Vinblastine; Vinorelbine

S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC.. S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80-120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1.. Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4-7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%).. S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Disease Progression; Drug Administration Schedule; Drug Combinations; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Oxonic Acid; Survival Analysis; Tegafur; Treatment Outcome

Patients suffering from advanced colorectal cancer can experience unintended weight loss and/or treatment-induced gastrointestinal toxicity. Based on current evidence, the routine use of parenteral nutrition (PN) for patients with colorectal cancer is not recommended. This study evaluates the effect of PN supplementation on body composition, quality of life (QoL), chemotherapy-associated side effects and survival in patients with advanced colorectal cancer.. Eighty-two patients with advanced colorectal cancer receiving a palliative chemotherapy were prospectively randomized to either oral enteral nutrition supplement (PN-) or oral enteral nutrition supplement plus supplemental PN (PN+). Every 6 weeks body weight, body mass index (BMI), chemotherapy-associated side effects and caloric intake were assessed, haemoglobin and serum albumin were measured. Body composition was assessed by body impedance analysis, and QoL was evaluated by European Organization for Research and Treatment of Cancer (EORTC) QLQC30 questionnaire.. No differences were evident at baseline between the groups for age, sex, diagnosis, weight, BMI or QoL. A difference in BMI was observed by week 36, whereas differences of the mean body cell mass could be observed from week 6, albumin dropped significantly in the PN- group in week 36 and QoL showed significant differences from week 18. Chemotherapy-associated side effects were higher in PN-. The survival rate was significantly greater in the PN+ group.. A supplementation with PN slows weight loss, stabilizes body-composition and improves QoL in patients with advanced colorectal cancer. Furthermore, it can reduce chemotherapy-related side effects.

Topics: Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Weight; Carcinoma; Colorectal Neoplasms; Energy Intake; Energy Metabolism; Female; Fluorouracil; Hemoglobins; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Malnutrition; Middle Aged; Palliative Care; Parenteral Nutrition; Prospective Studies; Quality of Life; Serum Albumin; Survival Analysis

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

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5'UTR and 3'UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug-Related Side Effects and Adverse Reactions; Female; Fluorouracil; Genotype; Humans; Leucovorin; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Polymorphism, Single Nucleotide; Prognosis; Survival Analysis; Thymidylate Synthase

The prognosis of patients with platinum refractory disease is dismal. We present data from heavily pretreated patients to whom the folinic acid, 5-fluorouracil and oxaliplatin (Folfox) regimen was administered. The objectives were to assess response rate and to evaluate the safety profile.. Patients with recurrent, resistant or refractory pretreated ovarian carcinoma were eligible for oxaliplatin (85 mg/m(2)) and leucovorin (200 mg/m(2)), both given as a 2-h infusion on day 1, followed by a 48-h infusion of 5FU 2,600 mg/m(2) every 2 weeks.. Fourteen patients were treated. Median age: 56 years (49-70). Median number of previous chemotherapy regimens: 5 (3-10) and previous platinum-based regimens: 2 (1-3). Median chemotherapy-free interval (interval since the completion of the last-line chemotherapy before the administration of the Folfox regimen): 9.5 weeks (1-39). Median number of administered cycles of Folfox/patient: 8 (2-11 cycles). Two (14.5%) patients had a disease complete response, 2 (14.5%)-partial response, 4 (29%)-stable disease and 6 (43%)-progressive disease. Four (29%) patients had a CA-125 complete response, 2 (14.5%)-CA-125 partial response, 5 (35.5%)-stable CA-125 levels and 3 (21%)-progressive CA-125 levels. There were no grade 4 adverse events or deaths due to the treatment. No dose modifications were required due to toxicity.. Folfox seems to be a valuable option for heavily pre-treated patients with ovarian cancer, with an overall response rate, according to RECIST criteria, of 29% and disease stabilization in an additional 29% of patients, with a manageable toxicity profile. These results support further assessment of Folfox as salvage treatment for patients with carcinoma of the ovary or fallopian tube.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cohort Studies; Disease-Free Survival; Fallopian Tube Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; Treatment Outcome

Peritoneal carcinomatosis (PC), which has hitherto been regarded as a lethal entity, can now be cured with surgery (treating macroscopic tumor seeding) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) (treating residual microscopic disease). The purpose of this study was to analyze the morbidity and mortality of a particular approach associating optimal (R0-R1) cytoreduction, optimal HIPEC combining oxaliplatin and irinotecan, and an optimal homogeneous intraperitoneal temperature of 43 degrees C.. A total of 106 consecutive patients were included in this prospective phase 2 study. After complete resection of the PC, HIPEC was performed by the Coliseum technique with oxaliplatin (360 mg/m2) combined with irinotecan (360 mg/m2) in 2 L/m2 of 5% dextrose, over 30 minutes at a real intraperitoneal temperature of 43 degrees C. During the hour preceding HIPEC, patients received 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) intravenously, resulting in tritherapy.. Postoperative mortality and morbidity rates were 4% and 66%, respectively. The most frequent complications were digestive fistula (24%), lung infection (16%), and severe hematological toxicity (11%). Statistical correlation was evidenced between morbidity and the carcinomatosis score (P = .0008), the number of resected organs (P = .0001), the duration of surgery (P = .0001), and blood loss (P = .0001).. This new approach, optimized in three respects (complete cytoreduction, combination oxaliplatin with irinotecan, and high temperature) has resulted in a relatively high but acceptable incidence of adverse events considering the expected advantage for survival.

Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Camptothecin; Carcinoma; Female; Fluorouracil; Humans; Hyperthermia, Induced; Injections, Intraperitoneal; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Postoperative Complications; Prospective Studies; Survival Rate; Topoisomerase I Inhibitors; Vitamin B Complex

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

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

Clinical studies regarding chemotherapy for gastric cancer patients with malignant ascites have been classically rather limited in scope, largely because peritoneal seeding produces no measurable lesions, and patients generally exhibited poor performance status. Herein, we have evaluated the efficacy and toxicity of a fortnightly modified FOLFOX-4 (m-FOLFOX) regimen.. Gastric cancer patients with cytologically confirmed malignant ascites were treated with cycles of oxaliplatin at 85 mg/m(2) plus leucovorin 20 mg/m(2) on the first day of treatment, followed by 5-fluorouracil (5-FU) via a 400 mg/m(2) bolus and a 22 h continuous infusion of 600 mg/m(2) 5-FU on Days 1-2 at 2-week intervals.. Forty-eight patients participated in this study. Twenty-two patients (45.8%) were treated with m-FOLFOX-4 as a first line palliative treatment. Twenty-one patients (43.8%) were adjudged to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Thirty-six patients were assessable and exhibited measurable lesions. Twelve (33.3%) patients evidenced partial responses. Decreases or disappearances of ascites levels were observed in 17 (35.4%) patients. The median time to progression and overall survival time were 3.5 (95% CI: 2.9-4.1) months and 8.4 (95% CI: 4.9-11.9) months, respectively. Major hematologic toxicities included Grades 1-2 anemia (53.9%), neutropenia (41.6%) and, Grades 3-4 neutropenia (15.8%). The most frequently detected non-hematological toxicities were Grades 2 and 3 nausea/vomiting (17%). We noted no deaths related to treatment.. The m-FOLFOX-4 regimen utilized herein was determined to be both safe and feasible even for gastric cancer patients with malignant ascites in poor performance status.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma; Disease-Free Survival; Drug Administration Schedule; Feasibility Studies; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Nausea; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Palliative Care; Stomach Neoplasms; Survival Analysis; Treatment Outcome; Vomiting

Only a few drugs are active in the treatment of well-differentiated endocrine carcinomas (WDEC). We evaluated the combination of the so-called 'de Gramont schedule' and irinotecan in these tumors in a phase II study.. 20 patients were enrolled in the study. The combination regimen included irinotecan, 180 mg/m(2) on day 1, followed by 200 mg/m(2) folinic acid in a 2-hour infusion, an intravenous 10-min bolus of 400 mg/m(2) 5-fluorouracil (5FU) and finally 600 mg/m(2) 5FU in a 22-hour infusion. Folinic acid and 5FU were repeated on day 2. Clinical, biological and morphological parameters were assessed by CT every 8 weeks. The site of the primary tumor was the pancreas in 10 cases, the lung in 3 cases and other sites in 7 cases. Sixteen patients had previously received chemotherapy, and 6 of them had had two lines of treatment. Six patients had previously been treated with chemoembolization.. The median number of cycles administered was 8. Grade 3-4 neutropenia was observed in 8 patients, and 1 patient experienced febrile neutropenia. There was no toxicity-related death. No complete symptomatic response was observed in 7 evaluable patients; 4 patients had an objective biological response. One patient achieved a morphological objective response, stabilization was observed in 15, but progression occurred in 3 patients. Median survival was 15 months.. The above-mentioned combination of LV5FU2 + irinotecan does not yield major activity in heavily pretreated unresectable metastatic gastroenteropancreatic WDEC, and significant toxicity was observed.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Drug Administration Schedule; Enteroendocrine Cells; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Lung Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Prospective Studies; Survival Analysis; Treatment Failure; Treatment Outcome

Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)).. Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent.. High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Neoplasm Staging; Survival Analysis; Treatment Outcome

Complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease achieves cure in some patients. We report long-term results concerning survival of a phase II study using oxaliplatin (LOHP).. From June 1998 to December 2003, thirty patients with macroscopic colorectal PC underwent complete resection of PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m2 in 2 L/m2 of iso-osmotic 5% dextrose, over 30 min at an intraperitoneally homogenous temperature of 43 degrees C and at a flow rate of 2 L/min in the continuous closed circuit. During the hour preceding IPCH, patients received 5-fluorouracil (400 mg/m2) and leucovorin (20 mg/m2) intravenously. All patients received neoadjuvant and adjuvant systemic chemotherapy.. Mean peritoneal tumor extension (Sugarbaker's Score) was 14.3 +/- 3.8, median operative duration, 450 min, and median blood loss, 940 mL. Eleven (37%) patients had associated extra-peritoneal lesions which were resected during the same procedure. There were no postoperative deaths and grade 2-3 morbidity (requiring specific treatment) was 40%. Median follow-up was 55 months (range: 31-84). Twenty-two patients (73%) relapsed after a median interval of 14 months, but 7 of them (32%) were amenable to curative repeat surgery. At 3 and 5 years, overall survival rates (95% confidence interval) were 53% (9-72), and 48.5% (31-66) respectively. At 3 and 5 years, disease-free survival rates were 41.5% (27-59), and 34% (19-52) respectively. Median survival was 60.1 months.. When feasible, this treatment modality yields a 5-year survival rate of 48.5%, with median survival attaining 60.1 months.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Confidence Intervals; Data Interpretation, Statistical; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Humans; Hyperthermia, Induced; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Reoperation; Survival Analysis; Time Factors; Vitamin B Complex

The purpose of this study was to compare the activity and toxicity of an irinotecan (CPT-11), leucovorin (LV) and 5-fluorouracil (5FU) combination with a standard regimen of 5FU and LV, in patients with advanced colorectal carcinoma. One hundred and sixty patients were randomized; 80 patients (group A) received LV 20 mg/m(2) bolus i.v. and 5FU 425 mg/m(2) bolus i.v. on days 1-5, every 28 days; 80 patients (group B) received CPT-11 80 mg/m(2) (30-90 min i.v. infusion), followed by LV 20 mg/m(2) bolus i.v. and 5FU 425 mg/m(2) bolus i.v. on days 1, 8, 15, 22, 29, and 36, every 8 weeks. The overall response rate was 30% and 47.5% in groups A and B respectively. Progression-free survival was significantly higher in the triple-drug combination arm (median 7.5 vs. 4.5 months; p= 0. 0335). However, overall survival did not differ significantly between the two arms (15 months vs. 14 months for the groups B and A respectively; p=0.3531). The main grade 3 adverse events were diarrhea (19%, in group A vs. 35% in group B; p=0.032) and mucositis (2% vs. 14%; p=0.017). The regimen containing irinotecan showed activity in advanced colorectal cancer. The overall safety data confirm this combination as a well-tolerated treatment.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Survival Analysis; Treatment Outcome

Nasopharyngeal carcinoma (NPC) is rare in children, accounting for <1% of all cases. Treatment most commonly includes radiotherapy but long-term side effects of such treatment can produce devastating cosmetic and functional sequelae in children. Chemotherapy may help to decrease the radiotherapy dose and limit the side effects of local therapies. However, little is known regarding the chemosensitivity of NPC tumors in pediatric patients.. Patients with American Joint Committee on Cancer (AJCC) Stage I/II disease (Stratum 01) received irradiation only. Patients with AJCC Stage III/IV disease (Stratum 02) received 4 courses of preradiation chemotherapy comprising methotrexate (120 mg/m2) on Day 1, with cisplatin (100 mg/m2) 24 hours later, 5-fluorouracil 1000 mg/m2 per day as a continuous infusion for 3 days, and leucovorin 25 mg/m2 every 6 hours for 6 doses. Irradiation was given after chemotherapy and consisted of 50.4 gray (Gy) to the upper neck and 45.0 Gy to the lower neck, with a boost to the primary tumor and positive lymph nodes for a total dose of 61.2 Gy.. One patient was enrolled in Stratum 01 and 16 evaluable patients were enrolled in Stratum 02. The median age of the patients was 13 years and 65% of the patients were black. All patients tested had evidence of Epstein-Barr virus infection. Two-thirds of the patients developed Grade 3-4 mucositis during chemotherapy. The overall response rate to induction chemotherapy was 93.7%. The overall 4-year event-free and overall survival rates (+/- the standard error) were 77%+/-12% and 75%+/-12%, respectively.. The current study demonstrated that childhood NPC was sensitive to chemotherapy and that chemotherapy before irradiation was feasible. Future trials should investigate equivalent efficacy with a reduced radiotherapy dose.

Topics: Adolescent; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Epstein-Barr Virus Infections; Fluorouracil; Herpesvirus 4, Human; Humans; Leucovorin; Methotrexate; Nasopharyngeal Neoplasms; Survival Rate

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

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

For patients with rectal cancer treated with full thickness local excision the risk of mesorectal nodal metastases has to be very low. The aim was to assess this risk after preoperative radiotherapy in relation to pathological T-category.. Three hundred sixteen patients with resectable cT3-4 low rectal carcinoma were randomised to receive either pre-operative 5 x 5 Gy irradiation with subsequent surgery performed within 7 days or chemoradiation (50.4, 1.8 Gy per fraction plus bolus 5-fluorouracil and leucovorin) followed by surgery after 4-6 weeks. The pathological reports of patients who fulfilled entry criteria and had preoperative irradiation followed by transabdominal surgery were analysed.. Significant downstaging of primary tumour (P<0.001) and of nodal disease (P=0.007) was observed after chemoradiation in comparison with short-course irradiation. In chemoradiation group, for patients with complete pathological response and for ypT1 category, the rate of nodal metastases was low - 5% (95% confidence interval [CI] 0-14%) and 8% (95% CI 0-24%), respectively. The rate of ypN-positive disease in chemoradiation group was similar to that recorded in short-course irradiation group for ypT2 category 26% (95% CI 14-38%) vs. 28% (95% CI 16-40%), P=0.83 and for ypT3-4 category 55% (95% CI 41-69%) vs. 64% (95% CI 54-74%), respectively, P=0.37. For ypT2 category after chemoradiation, the rate of nodal disease remained high even in subgroup with low residual cancer cells density (20%, 95% CI 4-36%).. For patients with tumours downstaged by chemoradiation to ypT0 and ypT1 full thickness local excision may be considered as an acceptable approach, because the risk of mesorectal lymph nodes metastases is low. The selection criteria for preoperative radio(chemo)therapy and local excision are discussed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Combined Modality Therapy; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Neoadjuvant Therapy; Neoplasm Staging; Prognosis; Rectal Neoplasms; Risk Factors; Treatment Outcome

Cytoreduction with hyperthermic intra-peritoneal chemotherapy (HIPEC) is a treatment with a high morbidity. Optimal patients selection can possible reduce toxicity and complications.. Complications and toxicity of 102 patients were studied. Toxicity was graded according National Cancer Institute Common Toxicity Criteria (NCI CTC) classification. A complication was defined as any post-operative event that needed re-intervention. Potential patients, tumor, and treatment factors were studied on their relation to complications.. Grade 3, 4, or 5 toxicity was observed in 66 patients (65%). Eight patients died of treatment-related causes. Surgical complications occurred in 36 patients (35%). Fistulae were frequently encountered (18 patients). The risk of a complicated recovery was higher in carcinomatosis with recurrent colorectal cancer (P = 0.009) and in the case of more than five regions affected (P = 0.044), who had a Simplified Peritoneal Cancer (SPC) score of 13 (P = 0.012) and with an incomplete initial cytoreduction (P = 0.035). Patients with blood loss exceeding 6 L (P = 0.028) and those with three or more anastomoses also had an increased post-operative complication rate (P = 0.018).. Toxicity of cytoreduction followed by HIPEC was 65% (Grade 3-5 NCI CTC), with a surgical complication rate of 35%. Patients with six or seven regions involved and those in whom complete cytoreduction cannot be reached are probably better off without this treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Appendiceal Neoplasms; Carcinoma; Cecum; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Hyperthermia, Induced; Hysterectomy; Infusions, Parenteral; Intestine, Small; Leucovorin; Male; Middle Aged; Peritoneal Neoplasms; Postoperative Complications; Postoperative Nausea and Vomiting; Rectum; Survival Analysis

To evaluate the toxicity and efficacy of concurrent chemoirradiation with cisplatin followed by adjuvant ifosfamide, 5-fluorouracil and leucovorin in patients with stage IVb nasopharyngeal carcinoma (NPC) PATIENTS AND METHODS: Between October 1998 and August 2001, 35 Chinese patients with stage IVb NPC (N3a:12, N3b:23) were treated with by concurrent chemoirradiation using cisplatin 100 mg/m2 on days 1, 22, and 43 of radiotherapy, followed by adjuvant chemotherapy with 1.4 g/m2, ifosfamide, 450 mg/m2 5-fluorouracil, and 20 mg/m2 leucovorin daily for 5 days and repeated every 3 weeks for three cycles. Radiotherapy was given using standard fractionation at 2 Gy/day to a total of 68 Gy to the nasopharynx and 66 Gy to the neck.. All patients completed the prescribed radiotherapy. Twenty-three patients (66%) completed all scheduled cycles of chemotherapy. The compliance rate for concurrent and adjuvant chemotherapy was 71% and 80%, respectively. Grade 3 mucositis occurred in 37%, and grade 3 dermatitis occurred in 11.5% during radiotherapy. Grade 3 neutropenia occurred in 17% during concurrent chemotherapy, and grade 3-4 neutropenia occurred in 48.5% during adjuvant chemotherapy. There were no treatment-related deaths. With a median follow-up of 31 months, the 3-year relapse-free rate was 60%, and the 3-year overall survival rate was 74%. Locoregional control was excellent, with a 3-year local and nodal relapse-free rate of 91% and 83%, respectively. Eleven patients (31%) had developed distant metastases, and the 3-year distant metastasis-free rate was 66%.. The chemotherapy regimen tested is practical with an acceptable compliance rate. Despite having a more advanced stage disease, the observed outcome of our patients seems to be comparable with other series using platinum-based adjuvant chemotherapy. Further investigation to confirm the benefit of using the study regimen in advanced stage NPC is warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Dermatitis; Female; Fluorouracil; Humans; Ifosfamide; Leucovorin; Leukopenia; Male; Middle Aged; Nasopharyngeal Neoplasms; Survival Rate; Vomiting

The complete resection of macroscopic colorectal peritoneal carcinomatosis (PC), followed by intraoperative intraperitoneal chemohyperthermia (IPCH) to treat residual microscopic disease, leads to cure in some patients. We report preliminary results on survival in a phase II study using oxaliplatin (LOHP).. Twenty-four patients with macroscopic colorectal PC underwent complete resection of the PC followed by IPCH with LOHP performed in an open abdominal cavity. The dose of LOHP was 460 mg/m(2) in 2 l/m(2), during 30 min at 43 degrees C, at a flow rate of 2 l/min. During the hour preceding IPCH, they received an intravenous administration of 5-fluorouracil (400 mg/m(2)) and leucovorin (20 mg/m(2)).. Mean peritoneal tumoral extension (Sugarbaker's Index) was 16.9 +/- 9.5, median operative duration was 490 min and median blood loss was 965 ml. There were two postoperative deaths (8%) by intracerebral hemorrhage, and morbidity rate was 41.6%. Minimal follow-up was 18 months and median follow-up was 27.4 months (range 18.3-49.6). At 1, 2 and 3 years, overall survival rates were 83%, 74% and 65%, and disease-free survival rates were 70%, 50% and 50%, respectively. Only 32% of the 22 postoperative living patients presented a peritoneal recurrence. A peritoneal index >24 influenced survival, with a 17% recurrence rate at 2 years versus 63% when it was <24 (P = 0.005).. This new modality of treatment, when feasible, gives encouraging preliminary results, with a promising 3-year survival rate of 65%.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Combined Modality Therapy; Female; Fluorouracil; Humans; Hyperthermia, Induced; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Prospective Studies; Survival Analysis; Treatment Outcome

Colorectal peritoneal carcinomatosis (PC) is a frequent and very lethal event. However, cure may be possible with maximal cytoreductive surgery associated with early postoperative intraperitoneal chemotherapy (EPIC).. Between 1996 and 2000, we conducted a two-center prospective randomized trial comparing EPIC plus systemic chemotherapy with systemic chemotherapy alone, both after complete cytoreductive surgery of colorectal PC. Only 35 patients could be included among the 90 who were theoretically required, mainly because of patient dissatisfaction with the inclusion criteria. For this reason, the trial was stopped prematurely.. Analysis of these 35 patients showed that complete resection of PC resulted in a 2-year survival rate of 60%-far above the classic 10% survival rate among patients with colorectal PC treated with systemic chemotherapy and symptomatic surgery. In this small series, EPIC did not demonstrate any advantage for survival.. This supports the use of complete cytoreductive surgery in selected patients and calls for a prospective randomized trial comparing adjuvant systemic chemotherapy with intraperitoneal chemohyperthermia after complete resection.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Eligibility Determination; Female; Fluorouracil; Humans; Infusions, Parenteral; Leucovorin; Male; Middle Aged; Patient Satisfaction; Peritoneal Neoplasms; Prospective Studies; Survival Analysis

The epothilone B analog, BMS-247550, is a non-taxane microtubulin-stabilizing agent with preclinical activity in taxane-resistant cell lines and phase I activity in colorectal cancer. We conducted a phase II study of single-agent BMS-247550 in advanced colorectal cancer patients who had disease progression following treatment with irinotecan-5-fluorouracil-leucovorin (IFL).. Patients were required to have histologically or cytologically confirmed advanced or metastatic colorectal cancer; progressed on or after chemotherapy with IFL; Eastern Cooperative Oncology Group performance status < or =1; peripheral neuropathy grade < or =1; and adequate laboratory parameters. BMS-247550 40 mg/m(2) was administered intravenously over 3 h every 3 weeks. Patients were evaluated for response every 6 weeks.. Twenty-five patients were enrolled; all were evaluable for toxicity and 23 were evaluable for response. There were no complete or partial responses. Thirteen patients (56%) had stable disease after two cycles of therapy; five patients (20%) received six or more cycles. The median time to progression was 11 weeks; median overall survival was 36 weeks. There was considerable grade 3/4 hematological toxicity, including neutropenia (48%) and leukopenia (36%). Grade 3/4 non-hematological toxicities included grade 3 hypersensitivity reaction (12%) and peripheral neuropathy (20%).. Single-agent BMS-247550 (40 mg/m(2)) administered every 21 days demonstrated no activity in advanced colorectal cancer. Peripheral neuropathy was treatment-limiting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Disease Progression; Epothilones; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Staging; Treatment Failure

Peritoneal carcinomatosis in the absence of distant metastasis occurs in approximately 8 per cent of patients with colorectal cancer. Cytoreduction followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a new treatment option. Patient selection is crucial to outcome.. Cytoreduction followed by HIPEC was performed in 102 patients with peritoneal carcinomatosis. The following factors were studied for association with survival: perforation and obstruction of the primary lesion, location of the primary lesion, obstruction associated with carcinomatosis, presentation, tumour differentiation and histological type. Extent of disease and completeness of cytoreduction were also studied. Hazard ratios (HRs) were used to study these factors.. Location of the primary tumour in rectum (HR 3.14 (95 per cent confidence interval (c.i.) 1.11 to 8.91); P = 0.069), poor differentiation (HR 1.73 (95 per cent c.i. 1.04 to 2.88); P = 0.031) and signet cell histological type (HR 2.24 (95 per cent c.i. 1.21 to 4.16); P = 0.008) were associated with shorter survival. Important factors predicting survival were the number of affected regions (HR 1.38 (95 per cent c.i. 1.20 to 1.59); P < 0.001), the simplified peritoneal cancer score (HR 1.19 (95 per cent c.i. 1.12 to 1.26); P < 0.001) and completeness of cytoreduction (HR 8.54 (95 per cent c.i. 4.01 to 18.18); P < 0.001). No other factor correlated with survival.. The survival of patients with peritoneal carcinomatosis of colorectal origin is dominated by the extent of disease and the amount of residual tumour after cytoreduction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Hyperthermia, Induced; Laparotomy; Leucovorin; Male; Middle Aged; Neoplasm, Residual; Peritoneal Neoplasms; Survival Analysis

To study prospectively the activity of primary chemotherapy with cisplatin, fluorouracil and leucovorin (PFL) in patients with paranasal cancer receiving surgery and postoperative radiotherapy.. Forty-nine patients, previously untreated, with resectable paranasal carcinoma were enrolled. PFL (leucovorin 250 mg/m2/day for 5 days as a 120 h continuous infusion (c.i.), 5-fluorouracil 800 mg/m2/day from day 2 as a 96 h c.i. and cisplatin 100 mg/m2 day 2 q 3 weeks) was planned for five courses.. Thirty-two patients (65%) completed three or more chemotherapy courses. Two deaths from thrombotic events were observed after the first cycle. Eight cardiac toxicities were recorded during chemotherapy causing treatment discontinuation. Objective response to PFL was observed in 21 patients [43%; 95% confidence interval (CI) 29% to 58%], including four complete responses (CRs) (8%; 95% CI 2% to 20%) and 17 partial responses (PRs) (35%). Pathological complete remission (pCR) was achieved in eight of 49 patients (16%). At 3 years, overall survival was 69% and event-free survival 57%. Overall and event-free survival in patients achieving pCR is 100%.. PFL is active in paranasal cancer. Patients who attain a pathological complete remission have a favorable prognosis. Cardiovascular complications represent the limiting toxicity. Primary chemotherapy combined with surgery-sparing treatment approaches deserves further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Paranasal Sinus Neoplasms; Prospective Studies; Survival Analysis; Treatment Outcome

Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience.. From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer's 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-alpha2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy.. Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions.. Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Humans; Hydroxyurea; Interferon-alpha; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Treatment Outcome

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m2 (7 patients) or 70 mg/m2 (48 patients). After completion of CPT-11 infusion, LV 200 mg/m2 was administered over 2 hr followed immediately by 5-FU 450 mg/m2, IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m2 weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m2. Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m2. Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Diarrhea; Disease Progression; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Neutropenia; Survival Analysis

We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions.. Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied.. Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions.. There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups.. Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.

Topics: Antineoplastic Agents; Carcinoma; Female; Fluorouracil; Hot Temperature; Humans; Hyperthermia, Induced; Hypotonic Solutions; Intraoperative Care; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Spectrophotometry, Atomic

The oral administration of 5-fluorouracil (5-FU) is hindered by erratic bioavailability due to catabolism of 5-FU by the enzyme dihydropyrimidine dehydrogenase (DPD) in the gastrointestinal tract. Eniluracil is a potent inactivator of DPD which results in 100% oral bioavailability of 5-FU. Leucovorin (LV) is another biochemical modulator of 5-FU that potentiates inhibition of thymidylate synthase, the primary target of 5-FU. The goal of this study was to determine the antitumor activity and toxicity of an oral regimen containing eniluracil, 5-FU, and LV in patients with colorectal carcinoma.. Sixty eligible patients who had previously untreated, measurable, metastatic colorectal carcinoma were treated with oral eniluracil 50 mg on Days 1-7, 5-FU 20 mg/m(2) on Days 2-6, and LV 50 mg on Days 2-6. Cycles were repeated at 28-day intervals.. The overall response rate was 13% (95% confidence interval [CI] = 6, 25%), with 1 complete response and 7 partial responses. Three additional patients had partial responses that were not confirmed at subsequent evaluations. The median time to progression of disease was 4.4 months (95% CI = 3.45, 7.69) and the median survival time was 12.6 months (95% CI = 9.1, 14.75). Grade 3-5 toxicity (1 toxic death) occurred in 51 patients (85%). Grade 4 neutropenia occurred in 25 patients (42%), and 18 patients (30%) had Grade 3-4 diarrhea. Twenty-one patients (35%) were hospitalized for toxicity, and 12 (20%) had febrile neutropenia. Baseline creatinine clearance was associated inversely with severe toxicity (P = 0.001).. Although antitumor activity was observed, the frequent occurrence of severe toxicity with this regimen limited its clinical utility. Alternate schedules with a more favorable therapeutic index are undergoing clinical testing and should be pursued. The high level of toxicity observed with orally administered low dose 5-FU underscored the potency of eniluracil as a biochemical modulator.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Dihydrouracil Dehydrogenase (NAD+); Disease Progression; Enzyme Inhibitors; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Oxidoreductases; Oxidoreductases Acting on CH-CH Group Donors; Thymidylate Synthase; Uracil

The results of chemotherapy for patients with gastric carcinoma generally have been modest, although regimens developed more recently have produced higher response rates. One such regimen is epirubicin, cisplatin, and protracted infusion of 5-fluorouracil (ECF). The advantage of a long-term oral administration of uracil and tegafur (UFT) is that this treatment may be used to mimic the protracted infusion of 5-fluorouracil (5-FU). In addition, UFT treatment combined with leucovorin had a favorable activity and tolerable toxicity in patients with advanced gastric carcinoma. Instead of the inconvenience of an infusion pump and intravenous catheter for the protracted infusion of 5-FU, the authors administered UFT plus leucovorin in an ECF regimen for the treatment of patients with advanced gastric carcinoma.. Fifty-two patients with advanced gastric carcinoma received epirubicin, cisplatin, and oral UFT plus leucovorin. Epirubicin 50 mg/m(2) and cisplatin 60 mg/m(2) were administered on Day 1 by intravenous injection. Tegafur and uracil 360 mg/m(2)/day orally was administered in conjunction with leucovorin administered at a fixed dose of 45 mg/day orally in divided daily doses for 21 days followed by a 7-day rest period. These courses were repeated every 4 weeks. The median age of the patients was 59 years with a median World Health Organization performance status of 1. Patients received a median of five courses of treatment (range, 1-10).. Among the 47 patients evaluated, three patients achieved complete response, and 24 patients had partial responses, for an overall response rate of 57.5% (95% confidence interval, 71.5-43.3%). Stable disease was reported in 11 patients (23.4%), and another 9 patients (19.1%) showed disease progression. The median duration of survival was 15 months (range, 2-33+). The main toxicity was nausea/vomiting and neutropenia. Significant toxicity (modified National Cancer Institute common toxicity Grade 3 or 4) included neutropenia in 22 patients (42%), nausea in 14(27%), vomiting in 9 (18%), oral mucositis in 3 (6%), and diarrhea in 3 (6%) patients.. The authors conclude that epirubicin, cisplatin, and oral UFT plus leucovorin, a convenient regimen, has a significant activity and tolerable toxicities in patients with gastric carcinoma.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Drug Administration Schedule; Drug Tolerance; Epirubicin; Female; Humans; Leucovorin; Male; Middle Aged; Stomach Neoplasms; Tegafur; Treatment Outcome; Uracil

The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours.. Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy.. The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7-95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed.. The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Dose Fractionation, Radiation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Nasopharyngeal Neoplasms; Neoplasm Staging; Radiotherapy, Adjuvant; Salvage Therapy; Survival Analysis; Treatment Outcome

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

Thymidine phosphorylase (TP) is an essential enzyme for the biochemical activation of 5-fluorouracil (5-FU). Interferon upregulates TP in vivo, although the dose and schedule of interferon for optimal biomodulation of 5-FU is not known. In this study, TP activity was measured in peripheral blood lymphocytes (PBLs) from patients with advanced carcinoma receiving treatment with 5-FU and folinic acid. Cohorts of patients were treated with interferon alpha (IFNalpha), immediately prior to 5-FU/folinic acid, at doses of 3 MIU m(-2), 9 MIU m(-2) and 18 MIUm(-2). IFNalpha was administered on day 0 cycle two, day-1 and day 0 cycle three and day-2, day-1 and day 0 cycle four. A fourth cohort was treated with IFNalpha 9 MIU m(-2) three times per week from cycle 2 onwards. Twenty-one patients were entered into the study with 19 evaluable for response. Six patients (32%) had stable disease and 13 (68%) progressive disease. There were no grade-IV toxicities. TP activity was detected in PBLs from all patients with wide interpatient variability in constitutive TP activity prior to chemotherapy, and in response to IFNalpha. 5-FU/folinic acid alone did not induce TP activity but a single dose of IFNalpha led to upregulation of TP within 2 h of administration with a further increase by 24 h (signed rank test, P = 0.006). TP activity remained elevated for at least 13 days (signed rank test, P= 0.02). There were no significant differences in TP activity between schedules or with additional doses of IFNalpha. A single dose of IFNalpha as low as 3 MIU m(-2) can cause sustained elevation of PBL TP activity in vivo indicating that biochemical markers are important pharmacodynamic endpoints for developing optimal schedules of IFNalpha for biomodulation of 5-FU.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Dose-Response Relationship, Drug; Enzyme Induction; Fluorouracil; Humans; Interferon-alpha; Leucovorin; Middle Aged; Thymidine Phosphorylase

This phase I biochemical modulation study evaluated the maximum-tolerated dose (MTD), toxicity, and effectiveness of the combination of folinic acid (FA)/fluorouracil (5-FU) followed by escalated dose levels of gemcitabine (FFG) in patients with advanced solid tumors.. Patients were refractory to primary treatment and/or without effective treatment options. Twenty-eight patients received an intravenous (IV) infusion of FA 100 mg/m(2) over 1 hour and a 5-FU 450 mg/m(2) IV bolus in the middle of the FA infusion. After the FA infusion, gemcitabine was administered at a steady rate of infusion of 10 mg/m(2)/min over initially 30 minutes and with increases of an additional 15 minutes at each given level. One cycle consisted of six weekly treatments followed by a 2-week rest.. The MTD of gemcitabine was established at 900 mg/m(2) given over 90 minutes. Eight patients of 21 with metastatic colorectal cancer achieved responses (one complete response; seven partial responses), for a response rate of 38%. Responses were seen across the gemcitabine doses of 300 to 900 mg/m(2). One patient had prior treatment with FA/5-FU for advanced disease. Patients with colorectal carcinoma had a median survival of 18 months, and the patient with lung carcinoma has been alive for 24+ months.. The combination chemotherapy of FFG was well tolerated and may benefit patients with advanced colorectal carcinoma. A phase II evaluation in this patient population is in progress.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasms; Neutropenia

This is an open-label, nonrandomized phase I trial to determine the safety and maximum tolerated dose of irinotecan with a fixed dose of UFT plus oral leucovorin in patients with advanced or metastatic colorectal cancer. A secondary objective of the study is to determine the response rate in this patient population. Adult patients with histologically confirmed advanced or metastatic colorectal carcinoma and no prior chemotherapy for advanced or metastatic disease, or those patients who have received adjuvant chemotherapy (> 6 months prior to the study entry) will be eligible to participate. All patients must have measurable or evaluable lesions. Symptoms will be evaluated at baseline and every 6 weeks thereafter. Computed tomography scans will be performed at baseline and every three cycles of treatment to assess tumor response. A total of six cycles of treatment may be given, depending on patient tolerance. Patients will be followed for a maximum of 12 months for time to progression, following the last dose of the study drug. Tumor response will be defined using standard World Health Organization criteria.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Humans; Infusions, Intravenous; Irinotecan; Leucovorin; Male; Middle Aged; Tegafur; Uracil

Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carcinoma; Cisplatin; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Lenograstim; Leucovorin; Male; Middle Aged; Pain; Palliative Care; Pancreatic Neoplasms; Recombinant Proteins; Survival Analysis; Treatment Outcome

The combination of 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (I-OHP) was shown to be both more active against metastatic colorectal carcinoma and better tolerated if the drug delivery rate was chronomodulated according to circadian rhythms rather than constant. This allowed the authors to intensify the three-drug chronotherapy regimen and to assess its activity as the initial treatment of metastatic colorectal carcinoma patients in ten centers from four countries.. Patients with previously untreated and inoperable measurable metastases from colorectal carcinoma received a daily administration of chronomodulated 5-FU (700 mg/m2/day, peak delivery rate at 04:00 hours), LV (300 mg/m2/day, peak delivery rate at 04:00 hours), and 1-OHP (25 mg/m2/day, peak delivery rate at 16:00 hours) for 4 days every 14 days. Intrapatient escalation of 5-FU dose was performed if toxicity was less than World Health Organization (WHO) Grade 2.. Of 90 enrolled patients, 35 had a WHO performance status of 1 or 2; 49 had metastases in > or = 2 organs. The liver was involved in 79 patients, 30 of whom had clinical hepatomegaly. The main dose-limiting toxicities were WHO modified Grade 3 or 4 diarrhea (41% of patients, 8.2% of courses), stomatitis (30% of patients, 5.1% of courses), and Grade 2 cumulative peripheral sensory neuropathy (19% of patients after 12 courses). Two patients died with severe gastrointestinal toxicity. Using the intent-to-treat method, the overall objective response rate was 66% (95% confidence limits, 56-76%). Surgical removal of previously inoperable metastases was successful in 31 patients (34%). Histologic necrosis of metastases was >90% in 7 patients and complete in 1 patient. The median progression free survival and survival durations were 8.4 months (range, 5.9-10.9 months) and 18.5 months (range, 13.2-23.8 months), respectively, with 38% of the patients alive at 2 years of follow-up.. The objective response rate appeared to be approximately 3-fold as high as that achieved with current 5-FU-based regimens and translated into an approximately 50% increase in median survival. The hypothesis that this intensified, ambulatory, chronotherapy regimen can increase survival currently is being investigated in a multicenter randomized study conducted by the European Organization for Research and Treatment of Cancer Chronotherapy Study Group.

Topics: Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Treatment Outcome

This study was designed to assess the toxicity of pelvic radiation therapy, 5-fluorouracil (5-FU) administered by protracted venous infusion, and leucovorin.. Pelvic radiation therapy consisted of 50.4-54 gray (Gy) administered in 28-30 fractions. Systemic treatment consisted of leucovorin (10 mg daily) administered orally and protracted venous infusion of 5-FU. The initial daily 5-FU dose was 150 mg/m(2). Dose escalations were planned in increments of 25 mg/m(2).. Forty eligible patients were registered, of whom 37 were evaluable for chemoradiotherapy-related toxicity. Grade 3 or 4 toxicity secondary to radiation therapy, protracted venous infusion of 5-FU, and leucovorin occurred in 2 of 17 patients at a daily 5-FU dose of 150 mg/m(2), in 5 of 10 patients at a daily 5-FU dose of 175 mg/m(2), and in 5 of 10 patients at a daily 5-FU dose of 200 mg/m(2). Diarrhea was dose-limiting in 7 of 8 patients with Grade 4 toxicity. Venous thrombosis, a treatment-related complication not directly related to chemotherapy or radiation therapy, occurred in 5 of the 40 patients entered into this study. Four thromboses occurred at the site of a central catheter. No thrombotic complications occurred in the last 7 patients, who were given warfarin orally (1 mg daily) during treatment.. Toxicity due to radiation therapy, protracted venous infusion of 5-FU, and leucovorin when 5-FU is given daily at a dose of 150 mg/m(2) is similar to that observed in current chemoradiotherapy regimens for patients with rectal carcinoma. This regimen will be considered as a possible investigational treatment arm of a future trial of adjuvant therapy for rectal carcinoma patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose-Response Relationship, Drug; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Pelvis; Rectal Neoplasms; Venous Thrombosis

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

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

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

A wide variety of fluorouracil (FU)-plus-leucovorin (LV) dose schedules are in clinical use for the treatment of advanced colorectal cancer. Only the monthly low-dose LV-plus-FU regimen, as used by the North Central Cancer Treatment Group, has demonstrated a lasting survival benefit as opposed to FU alone (J Clin Oncol 1989; 7: 1407-1417). The Swiss Cancer Group adopted this regimen for a confirmatory phase III trial but used the same dose-intensity of fluorouracil in both treatment arms.. Patients with inoperable or metastatic colorectal cancer were randomized to receive monthly FU 400 mg/m2/day plus LV 20 mg/m2/day as intravenous push daily for five days, or FU alone.. Three hundred nine of the 310 patients randomized were eligible and included in the analysis. The objective response rate for patients with measurable disease was 9% with FU alone and 22% with FU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus 6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P = 0.02). The major prognostic factors for survival were performance status, weight loss, and disease symptoms. WHO > 2 toxicity, consisting of stomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), was more pronounced for FU-plus-LV, without fatal events.. This is the largest published randomized trial to compare FU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survival benefit obtained from biomodulating monthly FU with low-dose LV. The toxic effects of FU-plus-LV were acceptable to most patients, and they responded well to FU dose reductions. In the absence of an ideal dose-intense FU monotherapy regimen, monthly FU with low-dose LV provides a simple and economical means by which to achieve adequate FU efficacy in the treatment of advanced colorectal cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Drug Interactions; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Survival Analysis

Protracted oral administration of tegafur (TG) and leucovorin (LV) attempts to simulate the continuous infusion of 5-fluorouracil, with a higher intracellular folate pool. In a prior dose-finding study with a fixed TG dose of 0.75 g/m2/day for a period of 21 days and continuous oral LV, the recommended dose of LV was 45 mg/day in 28-day cycles.. Thirty-nine patients with histologic confirmation of adenocarcinoma of the colon or rectum, either advanced or metastatic disease, and who were not candidates for radical treatment were included in a Phase II study using this schedule.. One hundred sixty-three cycles of chemotherapy were delivered (median, 4 cycles per patient). Toxicity was observed in the form of diarrhea, which was severe in 12 patients (30.7%). Grade 3 (according to the World Health Organization criteria) oral mucositis was recorded in 7 patients (18%). Asthenia was severe in 10% of the patients. Recuperation from toxicity was rapid and managed primarily on an outpatient basis. Two complete (5.1%) and 13 partial (33.3%) responses were observed, with a global response index of 38.5% (95% confidence interval, 23.2-53.6%). The median overall survival was 11.3 months.. The results of this study show that an all-oral regimen of tegafur and leucovorin can obtain biochemical modulation, with a significant response rate, in patients with advanced colorectal carcinoma. Randomized trials are needed to assess the possible advantage of this regimen over intravenous schedules.

Topics: Administration, Oral; Adult; Aged; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Colorectal Neoplasms; Drug Interactions; Drug Therapy, Combination; Female; Humans; Leucovorin; Male; Middle Aged; Survival Analysis; Tegafur

To define the activity and toxicity of preoperative chemotherapy and postoperative concomitant chemoradiotherapy in patients with carcinoma of the esophagus, and to determine the effect on survival in patients treated with this approach.. Patients were treated with two 21-day cycles of induction chemotherapy with cisplatin 100 mg/m2 on day 1, 5-fluorouracil (5-FU) 800 mg/m2/day continuous infusion on days 1-5, and leucovorin 100 mg/m2 every four hours on days 1-5. Surgical resection was performed if feasible (and could also be performed prior to chemotherapy). Patients then received radiotherapy (50 to 60 Gy) every other week x five to six weeks, concomitantly with 5-FU 800 mg/m2 continuous infusion daily and hydroxyurea 1 g twice daily x five days.. Forty-six patients were treated. With a minimum follow-up of 58 months, the median survival for the entire group was 16 months; the median survivals for patients with squamous carcinoma and adenocarcinoma were 29 months and 12 months, respectively. Toxicities of induction chemotherapy were severe neutropenia and mucositis; there was one toxic death. Toxicities of concomitant chemoradiotherapy were neutropenia, mucositis and esophagitis. There were five cases of radiation pneumonitis, one fatal.. Induction chemotherapy and postoperative concomitant chemoradiotherapy can be added to surgical resection for carcinoma of the esophagus. Combined modality therapy, as reported here, produces long-term survival benefit, particularly in patients with squamous carcinoma. However, similar outcome results have been reported with less toxic and shorter treatment regimens as tested in randomized studies.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Esophagus; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Middle Aged; Radiotherapy Dosage; Remission Induction; Survival Rate; Treatment Outcome

The activity and toxicity of UFT (Tegafur and Uracil) in a 4:1 molar concentration, plus leucovorin (LV), were evaluated in the treatment of 45 patients with advanced, bidimensionally measurable metastatic colorectal carcinoma. Initially 350 and later 300 mg/m2/day, plus 150 mg LV, as administered in divided doses every 8 h for 28 days. After two courses of treatment, responses were evaluated. The overall response rate was 42.2%, with responses observed in liver (n = 18), lung (n = 6), and bone (n = 1). Five of the 7 patients who received 350 mg/m2 UFT experienced prolonged grade 3 diarrhea, resulting in a dose reduction to 300 mg/m2; 9 patients in the 300-mg/m2 group experienced grade 3 diarrhea, vomiting, abdominal cramping, and fatigue. Minor toxic effects included oral mucositis and rash. The oral regimen of 300 mg/m2/day UFT, plus 150 mg/day LV, administered for 28 days appears to have significant activity against metastatic colorectal carcinoma. The treatment is well tolerated; neutropenia did not occur, and oral mucositis was not significant, even though both are characteristic of intravenous schedules of 5-fluorouracil plus LV. The results of this trial constitutes the basis of phase III clinical trials comparing this oral schedule with intravenous 5-FU and LV to compare clinical efficacy, impact on well-being, and cost. In addition, the current National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant colon clinical trial (CO-6) will compare this 28-day schedule of UFT plus oral leucovorin with a weekly regimen of intravenous 5-fluorouracil plus leucovorin in the postoperative adjuvant therapy of Dukes' B and C colon cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Drug Combinations; Humans; Leucovorin; Neoplasm Metastasis; Survival Analysis; Tegafur; Uracil

Previous Phase II studies using the combination of mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) in the treatment of metastatic breast carcinoma have shown this regimen to be active and well tolerated. In this randomized Phase II study, the authors compared the NFL regimen with a standard CMF regimen in the first-line therapy of patients with metastatic breast carcinoma.. One hundred twenty-eight women receiving their first chemotherapy for metastatic breast carcinoma were entered into this randomized study. Sixty-four patients were treated with NFL: mitoxantrone 12 mg/m2 IV on Day 1; leucovorin 300 mg IV over 30-60 minutes on Days 1, 2, and 3, immediately preceding administration of 5-fluorouracil; and 5-fluorouracil 350 mg/m2 IV bolus on Days 1, 2, and 3. Sixty-four patients received CMF: cyclophosphamide 600 mg/m2 IV on Day 1; methotrexate 40 mg/m2 IV on Day 1; and 5-fluorouracil 600 mg/m2 IV on Day 1. Both regimens were repeated at 21-day intervals; responding patients received at least 8 courses.. Patients treated with NFL had a higher response rate than patients treated with the CMF regimen (45% vs. 26%, respectively; P = 0.021). Median duration of response was 9 months with NFL and 6 months with CMF (P = 0.10); 11 patients had long responses (>12 months) with NFL versus 4 patients with CMF (P = 0.06). Median survival was similar for both groups. Both regimens were well tolerated, with infrequent Grade 3 or 4 toxicities.. NFL is an active, well-tolerated regimen for the treatment of metastatic breast carcinoma; it produced a higher response rate than the CMF regimen used in this study. Although more intense CMF regimens or regimens containing doxorubicin would likely increase the response rate, they would almost certainly do so with the consequence of greater toxicity as compared with NFL. NFL is an excellent initial palliative treatment option for elderly patients or patients who have exhibited poor tolerance for other chemotherapy regimens.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cyclophosphamide; Female; Fluorouracil; Humans; Leucovorin; Methotrexate; Middle Aged; Mitoxantrone; Survival Rate

Thirty-nine patients with locally advanced or metastatic gastric carcinoma received oral UFT (tegafur and uracil) plus leucovorin. Treatment consisted of UFT 360 mg/m2/day plus leucovorin 25 mg/m2/day, given orally in divided daily doses for 21 days followed by a 7-day rest period. The median age of the patients was 64 years, and the median World Health Organization performance status was 2. Patients received a median of two courses of treatment (range, 1 to 25). Among 37 evaluable patients, two patients achieved a complete response, and eight had partial responses, for an overall response rate of 27% (95% confidence interval, 15.4% to 42.9%). Stable disease was reported in 12 patients (32%) and another 15 showed disease progression. The median duration of response was 30 weeks, and the median duration of survival was also 30 weeks (range, 8 to 111). All patients were evaluable for toxicity. Significant toxicity (World Health Organization grade 3 or 4) included diarrhea in seven patients (18%), oral mucositis in six (15%), and nausea/vomiting in six patients. We conclude that oral UFT plus leucovorin, an outpatient regimen, has favorable activity in patients with gastric carcinoma and has tolerable toxicities.

Topics: Adult; Aged; Antidotes; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Diarrhea; Drug Combinations; Female; Follow-Up Studies; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Nausea; Stomach Neoplasms; Survival Rate; Tegafur; Treatment Outcome; Uracil

This retrospective study evaluates the results of a regimen of high-dose intrathecal methotrexate and the prognostic factors for the response in patients with meningeal from breast carcinoma.. From 1979 to 1994, 68 breast carcinoma patients were diagnosed with meningeal carcinomatosis at a mean age of 52 years. All but two had previous metastatic involvement. The proportion of lobular and ductal carcinomas was balanced. Malignant cells were present in cerebrospinal fluid (CSF) samples from 61 patients, whereas the 7 remaining patients had increased CSF protein associated with computerized tomographic scan evidence of meningeal metastases. From 1989, 41 of the patients received a regimen of high-dose intrathecal methotrexate with systemic folinic acid rescue (HD-MTX+FA): intrathecal MTX, 15 mg daily x 5 days, repeated every 2 weeks, and intrathecal hydrocortisone acetate, 125 mg on Day 1, and folinic acid, 10 mg intramuscularly 12 hours after each MTX injection. Systemic treatment and radiation therapy were usually associated. Patients treated before 1988 received intrathecal MTX in conventional doses (15 mg once a week).. Clinical objective response, defined as a neurological improvement for at least one month, was achieved in 17 patients (41%) and stabilization in 14 (34%) treated with the HD-MTX+FA regimen. The response rate was significantly higher compared with that of the group treated with the conventional doses (P = 0.03). Median survival was 14 weeks for patients treated with the HD-MTX+FA regimen, compared with 7 weeks for patients who received conventional doses of MTX (P = 0.01). Grade 3 or 4 neutropenia was the main toxicity that occurred in 16 16 patients (39%) treated with the HD-MTX+FA regimen, and in 7 patients (33%) treated with conventional doses of MTX. In a univariate analysis, three parameters were singled out as having a favorable prognostic value for response to therapy; controlled systemic disease at diagnosis (P < 0.05), low initial CSF protein level (P < 0.05), and concomitant systemic chemotherapy during intrathecal therapy (P < 0.02). Multivariate analysis was not performed because the sample size was too small.. Although this study was retrospective, the intrathecal HD-MTX+FA regimen appears to be a more efficient strategy than conventional doses of MTX to induce neurologic improvement and perhaps better survival. It should be recommended in combination with systemic chemotherapy for selected patients with meningeal carcinomatosis from breast carcinoma who are likely to benefit from intensive therapy, i.e., patients with a CSF protein level less than 5 g/L and in whom systemic disease has been controlled.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Dose-Response Relationship, Drug; Female; Humans; Hydrocortisone; Injections, Spinal; Leucovorin; Meningeal Neoplasms; Methotrexate; Middle Aged; Prognosis; Retrospective Studies

A phase II trial was performed with oral UFT plus leucovorin (LV) in 16 patients with advanced gastric carcinoma. Treatment consisted of UFT, 480 mg/m(2)/day, in conjunction with LV administered at 25 mg/m(2)/day per os in divided daily doses for 21 days followed by a 7-day rest period. The median age of patients was 64 years, with a median World Health Organization (WHO) performance status of 2. One patient was previously treated with etoposide, doxorubicin, and cisplatin (EAP). A median of four courses of treatment were given per patient (range: 1-9). Among 14 evaluable patients, one patient achieved a complete response and 3 had partial responses (response rate: 28.5%, 95% confidence interval, 4.9 to 52.3%). Stable disease was reported in 5 patients (35.7%) and another 5 showed progression. The time to progression was 17, 18, 27, and 76+ weeks for the responding patients, respectively. The median duration of survival was 25 weeks (range: 10-76+) for 14 evaluable patients. All patients were evaluable for toxicity. The main toxicity was diarrhea and oral mucositis. Significant toxicity (WHO grade 3 or 4) included diarrhea in 7 patients (43.8%), oral mucositis in 2 (12.5%), and nausea/vomiting in 2, respectively. We conclude that oral UFT plus LV, an out-patient regimen, has favorable activity in gastric carcinoma patients and has tolerable toxicities.

Topics: Administration, Oral; Adult; Aged; Antibiotics, Antineoplastic; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Diarrhea; Disease Progression; Doxorubicin; Etoposide; Female; Humans; Leucovorin; Male; Middle Aged; Remission Induction; Stomach Neoplasms; Stomatitis; Survival Rate; Tegafur; Vomiting

The prognosis of patients with locally advanced esophageal cancer (LAEC) remains poor when treated with local modalities. An intensive preoperative program with chemoradiotherapy was used to evaluate the curative resection rate, pathologic response, and survival of patients with LAEC.. Ninety patients with LAEC were treated preoperatively with chemotherapy (three courses of fluorouracil, leucovorin, etoposide, and cisplatin [FLEP]) followed by concurrent chemoradiotherapy (one course of cisplatin plus etoposide in combination with 40 Gy of radiation). Transthoracic esophagectomy was performed 4 weeks after the end of radiation.. Seventy-two patients were included in this evaluation. Forty-four (61%) underwent a complete tumor resection, and 16 (22%) had no tumor in the resected specimen (pathologic complete response [PCR]). The operative mortality rate was 15%. At a median follow-up time of 22 months (range, 12 to 41), the median survival duration of all 72 patients was 17 months (range, 1 to 41+). The calculated survival rates at 3 years were 33%, 42%, and 68% for all patients, patients after complete resection, and patients with PCR, respectively.. This combined treatment modality is active in LAEC, with a PCR in 33% of the patients undergoing surgery. The results appear improved compared with those reported with surgery alone, by approximately doubling the 3-year survival rate. The high efficacy of preoperative chemoradiation warrants evaluation of the role of surgery in LAEC.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cause of Death; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Etoposide; Female; Fluorouracil; Humans; Leucovorin; Male; Preoperative Care; Survival Analysis; Treatment Failure

Most patients with esophageal carcinoma present with locally advanced disease and a poor prognosis. Surgery or radiation provides palliation for locally advanced esophageal carcinoma. The role of neoadjuvant therapy remains to be defined. We administered neoadjuvant chemotherapy consisting of 5-fluorouracil (5-FU), leucovorin, interferon-alpha, and cisplatin to 11 patients with locally advanced disease.. Eleven patients with squamous cell or adenocarcinoma of the esophagus were treated peroperatively with two to three cycles of combination chemotherapy. Nine patients underwent resection with curative intent.. Six patients received three cycles of chemotherapy, and five received two. Dose reduction was necessary for two patients. One patient achieved a pathologic complete response, histologically confirmed. Of the eleven patients, two did not undergo surgery because of progressive disease during chemotherapy. Seven of the 9 patients relapsed after surgery and 2 have been disease free for 27 months.. The combination 5-FU leucovorin, interferon-alpha-2a, and cisplatin administered in a neoadjuvant setting resulted in a median survival of 11.8 months with a median time to relapse of 7 months.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Female; Fluorouracil; Humans; Immunotherapy; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Recombinant Proteins; Survival Analysis

Both the biochemical modulation and the continuous administration of 5-fluorouracil (5-FU) have achieved promising results in patients with gastric carcinoma. Conversely, several studies on gastric carcinoma have demonstrated that the combination of etoposide (VP-16), leucovorin (LV), and 5-FU (ELF) is efficacious and moderately toxic. UFT is a combination of uracil and tegafur (ftorafur) in a 4:1 molar ratio. It can be administered orally for several weeks, thus stimulating the effects of a continuous infusion of 5-FU. Its combination with LV increased the efficacy of UFT. We conducted a Phase II study on patients with gastric carcinoma using the combination VP-16-LV-UFT. This combination is administered mainly orally (p.o) and could yield a good response rate and low toxicity.. Forty-six patients with bidimensionally measurable disease were entered into the study. Patients received VP-16 100 mg/m2 IV on Day 1 and 200 mg/ m2 p.o. on Days 2 and 3; LV 500 mg/m2 administered intravenously (i.v.) on Day 1, followed by p.o. LV 15 mg every twelve hours on Days 2 to 14. Patients also received UFT p.o. 390 mg/m2/day on Days 1 to 14. Treatment was repeated every 28 days for a minimum of 3 courses per patient. All courses were given on an outpatient basis.. Four patients (9%) had a complete response, and 12 a partial response (26%) for an overall response rate of 35% (95% confidence interval: 22-51%). The median duration of response was 10 months. The median overall survival was 9 months. The main side effects were gastrointestinal. Grade 3 to 4 toxicity was encountered as follows: diarrhea in 17% of the patients, nausea/vomiting in 11%, anemia in 13%, mucositis and leukopenia in 4% each, and thrombocytopenia in 2%. One patient died of sepsis and neutropenia.. VP-16-LV-UFT has an activity comparable to that of other schemes and a low incidence of side effects. Furthermore, since it is administered mainly orally, hospitalization is avoided, which makes this scheme suitable for patients with advanced gastric carcinoma.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anemia; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Diarrhea; Drug Administration Schedule; Etoposide; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Middle Aged; Nausea; Remission Induction; Stomach Neoplasms; Survival Rate; Tegafur; Vomiting

From January 1990 to April 1993, 60 oesophageal cancer patients were enrolled in a protocol of non-surgical treatment that consisted of induction chemotherapy followed by concurrent chemoradiotherapy. Induction chemotherapy consisted of cisplatin 40 mg/m2 intravenous bolus days 1, 2, 14, 15; 24 h continuous infusion of 5-fluorouracil (5-FU) 1000 mg/m2 days 1 and 14; leucovorin 20 mg/m2 days 1 and 14 given before and with 5-FU; bleomycin 30 UI days 1 and 14; mitomycin C 10 mg/m2 day 14. Concurrent chemoradiotherapy consisted of 60 Gy (6 weeks) from day 21 and cisplatin 70 mg/m2 days 28, 42 and 56; leucovorin 20 mg/m2 followed by 5-FU 425 mg/m2 days 28, 35, 42, 49 and 56. Complete response occurred in 44 of 55 evaluable patients (80%). The median survival is 32 months; the actuarial survival at 40 months is 35% (CI 18-53). These results appear improved over those reported with surgery or radiation alone, and suggest that organ preservation as a secondary treatment goal should be vigorously investigated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Cisplatin; Combined Modality Therapy; Disease Progression; Esophageal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycins; Radiotherapy; Remission Induction; Survival Analysis

Leucovorin (LV) enhances the activity of 5-fluorouracil (5FU). Based on these data, we performed a randomized trial with 5FU, epirubicin (EPI), mitomycin C(MMC) with/ without LV in advanced gastric cancer (AGC). The purpose of our study was to investigate if the addition of LV improved the response rate of the combination 5FU EPI, MMC (FEM) over FEM. From January 1988 until April 1994, 88 patients with recurrent or metastatic AGC were randomly received 5FU, EPI, MMC with (group A) or without (group B) LV. Between the two arms of the study no difference was noticed in sex, performance status, primary site of tumor, and lymph node metastases. Therapy included group A (5FU 600 mg/m2/day, i.v. bolus, on days 1, 8, 29, 36, and EPI 45 mg/m2/day, i.v. bolus, on days 1 and 29, MMC 10 mg/m2/day, i.v. bolus, on day 1) and group B (the same as group A plus LV 200 mg/m2/day by 2 h intravenous infusion with 5FU intravenous push at midinfusion). No significant difference in response rate was noticed between the two treatment arms; there were two (5%) patients with complete response in group A, and five (12%) in A and 11 (26%) partial responders in group B (p < 0.1). A significantly higher number of patients achieving stable disease was observed in group B; 19 (44%) in comparison to group A 10 (24%) (p < 0.048). There were more patients with progressive disease in group A 25 (59%) than in group B 12 (28%) (p < 0.003) (Table 2). No difference was noted in mean duration of response: group A, 15.8 (6-31) weeks; and group B, 17.6 (6-28) weeks. The mean time to progression was for group A [11.4 (6-35) weeks] and for group B [17.6 (8-33) weeks]. Mean survival was for group A [27.4 (12-59) weeks] and for group B [30.6 (17-53) weeks], for 50% of patients. Causes of death were, for group A, 40 patients from disease progression and two sudden deaths; for group B, causes of death were for 41 patients disease progression and two sudden deaths. There were two patients in group A and one in group B that were not evaluable because they abandoned therapy after the first cycle. Toxicity was increased in group B; anemia, nausea and vomiting, and alopecia (p < 0.055) were more severe in group B, but not statistically different when compared to group A. Neutropenia, thrombocytopenia, mucositis, and fatigue of any grade were significantly more common and severe in group B. Significant dose reductions due to toxicity were required more commonly in group B. We conclude that the response rate

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Stomach Neoplasms; Survival Rate

To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea.. A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest.. Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed.. 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.

Topics: Adenocarcinoma; Administration, Oral; Aged; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Disease Progression; Drug Administration Schedule; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Hydroxyurea; Infusions, Intravenous; Injections, Intravenous; Italy; Leucovorin; Leukopenia; Male; Middle Aged; Pancreatic Neoplasms; Remission Induction; Survival Rate

A phase I trial of 5-fluorouracil (5-FU), leucovorin (LV) and interferon (IFN) was conducted in 15 advanced colorectal cancer patients refractory to a bolus regimen of 5-FU/LV. Therapy consisted of a weekly i.v. infusion of 5-FU at 2600 mg/m2 administered concomitantly with LV at 500 mg/m2 over a 24 h period. IFN-alpha 2b was administered by 24 h infusion from the second cycle at escalating dose (4.5, 9, 18 and 27 MU/m2). The maximum tolerated dose of IFN was 18 MU/m2. At 27 MU/m2 two patients complained of diarrhea grade 3, so that the escalation of IFN dose was stopped. Two patients achieved a partial response (IFN level dose 9-18 MU/m2). Eight patients had stable disease. Pharmacokinetics of 5-FU were not influenced by IFN at any level dose. Our results show that doses of IFN of 18 MU/m2 given by a 24 h infusion can be administered safely to an established and active schedule of weekly 24 h infusion of 5-FU and LV. A phase II study has been planned to define the level of activity of this regimen.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma; Colorectal Neoplasms; Diarrhea; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Leukopenia; Male; Middle Aged; Recombinant Proteins; Stomatitis

Cisplatin-based induction chemotherapy has been extensively tested in nasopharyngeal carcinoma for the improvement of local and systemic control and survival of this disease. In this study, we report the results of the treatment with induction chemotherapy in 40 patients with locally advanced carcinoma of the nasopharynx (LANPC) with four courses of cisplatin (P) 25 mg/m2 per day and 5-fluorouracil (F) 1000 mg/m2 per day both in a 4-days continuous infusion, with or without leucovorin (L) 250 mg/m2 per day in 2-hour infusion at the beginning of daily administration of PF, followed by sequential radiotherapy. All except one were in stage IV. The overall response after induction chemotherapy was 93%, with 55% CR and 38% PR. Definitive overall response after radiotherapy was 98%, with 80% CR and 18% PR. At a maximum follow up of 11 years, the overall survival rate is 55%. Induction chemotherapy with continuous infusion of PF with or without leucovorin followed by radiotherapy is a highly active regimen for the treatment of locally advanced nasopharyngeal carcinoma with response and survival rates comparable to other combinations of sequential or simultaneous chemotherapy and radiotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Life Tables; Male; Middle Aged; Nasopharyngeal Neoplasms; Remission Induction; Survival Rate; Treatment Outcome

Background In a previous phase I to II trial, we have shown that the maximum tolerable dose (MTD) of 5-Fluorouracil (5-FU) in 48-hour continuous infusion (CI) weekly was 3.5 gr/m2. In a subsequent confirmative phase II trial with 85 evaluable patients, a 38.5% response rate was obtained and the median survival reached was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with Leucovorin. On this basis we tried to modulate high-dose 5-FU (3 gr/m2) with oral leucovorin (LV) but the regimen was too toxic and the dose had to be reduced. A new phase II trial with 2 g/m2/week plus oral leucovorin was planned. Patients received a median dose intensity of 5-FU of 1.6 g/m2/week (range 0.9-2). Three complete responses and 36 partial responses were observed. Overall response rate was 37.5% (95% CI, 28% to 46.8%). Median time to progression has been 7.4 months, and median survival 14.4 months. WHO grade 3 diarrhea was seen in 27 patients (24.5%). Grade 3 mucositis was also seen in 9 (8.1%) patients, and grade 4 was observed in one. Grade 3 nausea and vomiting was reported in 13 (11.7%) patients. Grade 3 hand-foot syndrome was detected in only 5 (4.5%) patients. Grade 4 leukopenia was observed in 1 case and grade 3 to 4 thrombocytopenia was observed in two cases, respectively. Oral leucovorin modulation of weekly 48-hour continuous infusion of 5-FU at 2 g/m2 is an active regimen, with diarrhea and mucositis as main limiting toxicities. Its antitumor activity does not seem superior to that obtained with a weekly 48 hour continuous infusion of 5-FU alone at a dose of 3.5 g/m2.

Topics: Administration, Oral; Adult; Aged; Anemia; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Colorectal Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Leukopenia; Male; Middle Aged; Spain; Treatment Outcome; Vomiting

A total of 14 patients with platinum-resistant advanced epithelial ovarian cancer were treated with a continuous infusion of high-dose 5-fluorouracil (5-FU, 1200 mg/m2 per day) for 2 consecutive days weekly for 4 weeks and, thereafter, every 2 weeks in combination with a push injection of folinic acid (20 mg/m2) given just before 5-FU and after 24 h. No objective response was documented, and only five patients showed stable disease. The median survival was 6.5 months. There was minimal toxicity. This schedule of 5-FU in combination with folinic acid is not effective as second-line chemotherapy in advanced ovarian cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Cisplatin; Drug Resistance; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Ovarian Neoplasms; Survival Rate

In this series 49 patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy received leucovorin 200 mg/m2 i.v. bolus followed by 5-fluorouracil at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses and subsequent courses were given every 5 weeks. Of this group, 47 patients were evaluable for toxicity and 44 for response. Of the patients evaluable for response, 15 were considered platinum-sensitive and 29 were platinum-refractory. The overall response rate was 6/44 (13.6%). There were two complete responders (4.5%) and four partial responders (9.1%). In the platinum-sensitive patients, there was one complete response, yielding a response rate of 6.6%, whereas in the platinum-refractory patients, there were four partial responses and one complete response for a response rate of 17.2%. Five responses were in the pelvis and there was one response at an extrapelvic site in the abdominal mesentery. The median number of courses delivered was three (range: 1-10). The major adverse effect was myelosuppression with 16/47 (34.0%) experiencing granulocytopenia < 1,000/mm3. The median white blood count nadir for the patients experiencing any leukopenia was 2,700 (range: 400-3,900/mm3). There was one episode of grade 3 thrombocytopenia. Grade 3 intestinal toxicity was seen in seven patients (14.9%). There were no treatment-related deaths. In this previously treated population, 5-fluorouracil with high-dose leucovorin exhibited activity of interest in the platinum-refractory population and warrants further investigation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Drug Resistance; Female; Fluorouracil; Humans; Injections, Intravenous; Leucovorin; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Treatment Outcome

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

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

Cisplatin, 5-flourouracil (5-FU), and leucovorin (PFL) chemotherapy has been reported to be effective in the treatment of cancers but severe mucositis or neutropenia are dose limiting toxicities. This Phase II study evaluated the anticancer effect and the toxicities of a new weekly 24-hour infusional PFL chemotherapy in patients with nasopharyngeal carcinoma (NPC).. Forty-two patients with stage IV NPC were studied. Cisplatin 25 mg/m2/d, 5-FU 2200 mg/m2/d, and leucovorin 120 mg/m2/d were adminstered weekly by 24-hour intravenous continuous infusion in an outpatient setting. Clinical response and toxicity were evaluated weekly.. The complete response rate (CR) was 30% and the partial response (PR) rate 60% in the localized previously untreated group. The CR rate was 22.7% and PR rate 45.5% in local recurrent/metastatic group. The overall response rate was 79%. Eighty-one percent of patients who had no previous chemotherapy and 67% of patients who had previous chemotherapy responded to weekly PFL. There were no dose limiting toxicities. No patient had grade 3 or 4 mucositis or neutropenia. Thirty-two patients (76%) had no oral mucositis. Seven patients (17%) had grade 1 mucositis and 3 patients (7%) had grade 2 mucositis.. Elimination of dose limiting toxicities is possible using a weekly 24-hour infusion schedule of PFL chemotherapy while retaining significant anticancer activity as demonstrated in these patients with advanced NPC. To discover whether this schedule is superior to cisplatin and 5-FU or other PFL chemotherapy regimens requires further investigation.

Topics: Adult; Aged; Ambulatory Care; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fluorouracil; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Neutropenia; Remission Induction; Stomatitis; Survival Rate

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m2 on day 1, levofolinic acid 100 mg/m2 plus 5-fluorouracil 375 mg/m2 on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m2/day until the dose limiting toxicity (DLT) was reached. At the dose of 40 mg/m2/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent patients were treated at the maximal tolerated dose of EDXR (35 mg/m2/day). In the group of 18 patients treated at 35 mg/m2/day the overall response rate was 78%, with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cyclophosphamide; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Leucovorin; Leukopenia; Middle Aged; Recombinant Proteins; Treatment Outcome

5-Fluorouracil (5-FU) activity for various carcinomas of adults has been enhanced through the synergistic effect of leucovorin. Few pediatric studies of 5-FU in pediatric patients have been previously reported.. Fifty-eight patients were treated with a 4-hour infusion of leucovorin, 400 mg/m2, administered daily for 5 days every 3-4 weeks. 5-Fluorouracil was administered by bolus injection 1 hour into each leucovorin infusion. Eleven adolescent patients with colorectal carcinoma, Stage 3 or 4, were treated with therapeutic intent, and other patients with a variety of drug-resistant pediatric solid neoplasms received similar treatment.. Patients with measurable disease of colorectal carcinoma responded favorably to 5-FU/leucovorin. Stable disease activity was seen with other tumor types. Specifically, there were no objective responses in 12 patients with Ewing's Sarcoma or 11 with osteosarcoma. There were 4 deaths in this study from causes related to toxicity. Nonfatal grade 3/4 toxicities included mucositis, rash, myelosuppression, nausea, vomiting, diarrhea, and infection.. The authors do not plan further evaluation of 5-FU/leucovorin in additional pediatric patients with colon cancer or other heavily pretreated malignant solid tumors and are presently treating their patients with colon carcinoma with 5-FU/leucovorin/interferon-alpha 2a.

Topics: Adolescent; Carcinoma; Child; Child, Preschool; Colorectal Neoplasms; Drug Administration Schedule; Drug Synergism; Female; Fluorouracil; Humans; Infant; Leucovorin; Male; Neoplasms; Osteosarcoma; Sarcoma, Ewing; Treatment Outcome

Standard combination chemotherapy for metastatic breast cancer produces response rates between 30-60% with limited impact on survival. We undertook a phase II trial to determine the activity of 5 fluorouracil (5FU) and folinic acid (FA) in patients with measurable metastatic or recurrent breast cancer who had received no prior chemotherapy. Patients meeting the eligibility criteria received 5FU 370 mg/m2/day and FA 200 mg/m2/day for 5 days repeated every 28 days, toxicity allowing. Response defined by standard criteria was assessed every 8 weeks and toxicity according to WHO criteria was determined on every course. Thirty-three patients were entered on trial. Thirty-two patients were evaluable for response and 33 for toxicity. The dose limiting toxicity was stomatitis with 7/32, 19/32, and 5/32 patients experiencing grade 1, 2, and 3 toxicity. Grades 1 and 2 diarrhea occurred in 17/32 and 11/32 patients respectively. Myelosuppression was not significant. Two complete and 11 partial responses were observed. The overall response rate was 41% (95% CI, 24-58%). Responses were seen in soft tissue and visceral sites. Patients who had received adjuvant chemotherapy more than 6 months prior to receiving 5FU and FA responded also. Six of 29 patients receiving standard combination chemotherapy as second line treatment responded subsequently. We concluded: 1) 5FU and FA is an active combination in the treatment of breast cancer warranting further evaluation in combination with other drugs; 2) the dose-limiting toxicity of stomatitis is tolerable; 3) patients receiving 5FU and FA as first line therapy can respond to conventional combination chemotherapy as second line treatment.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Diarrhea; Female; Fluorouracil; Humans; Leucovorin; Remission Induction; Stomatitis

The combination of cisplatin, epirubicin, and leucovorin preceding fluorouracil (PELF) includes three novel agents compared with the standard combination of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric carcinoma. We report the results of a prospective randomized comparison of the two combinations in previously untreated patients.. One hundred thirty assessable patients were entered onto the trial; 52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental treatment was chosen. Approximately 90% of patients had measurable tumor masses.. The overall response rates (complete responses [CRs] and partial responses [PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a statistically significant advantage for the experimental treatment (P = .001). Time to progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2 months), and survival durations (median, 5.6 and 8.1 months) were not significantly different between the FAM and PELF regimens, respectively. The PELF combination was more toxic compared with FAM, but generally tolerable.. This study showed that the PELF combination is about three times more effective than the FAM combination in inducing objective responses. Due to tolerability, it is not recommended for routine clinical use. However, it should be considered, among other second-generation chemotherapy combinations, in future randomized studies aimed to improve the therapeutic outcome in gastric carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Doxorubicin; Epirubicin; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Mitomycin; Prospective Studies; Remission Induction; Stomach Neoplasms; Survival Analysis; Treatment Outcome

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

Twenty-two patients with metastatic colorectal cancer entered a Phase I-II trial to assess the maximum tolerable dose of alpha-2B-interferon administered intramuscularly three times per week in combination with fixed doses of 5-fluorouracil (450 mg/m2 IV for 5 days, and, from day 28, weekly) and folinic acid (200 mg/m2 IV before 5-fluorouracil) and the efficacy of this combination. Diarrhea and mucositis were the most frequent 5-fluorouracil-related toxicities and were > or = ECOG grade 3 in 23% and 18% of patients, respectively. Of 15 patients receiving interferon > or = 9 x 10(6) IU, 10 required interferon dose reduction mostly because of severe fatigue, anorexia, and declining performance status. Among 19 patients evaluable for response, 3 achieved a partial response and 1 a complete response for an overall response rate of 21% (95% confidence interval, 6-46%). In conclusion, our study demonstrates that IFN-alpha 2B at doses higher than 6 x 10(6) IU intramuscularly three times per week in the combination with 5-fluorouracil and folinic acid we used is too toxic for the majority of patients; this combination has moderate activity in metastatic colorectal cancer, although similar response rates have been reported, with less toxicity, with 5-fluorouracil plus folinic acid without IFN-alpha. A larger Phase III study would be required to determine the value of IFN-alpha in this combination.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Middle Aged; Recombinant Proteins; Remission Induction; Survival Analysis

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

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

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

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

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Retrospective Studies

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma; Combined Modality Therapy; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Male; Radiotherapy Dosage; Survival Rate; Urinary Bladder Neoplasms

The majority of patients with head and neck cancer die of locoregional recurrence of disease following surgery and/or radiotherapy.. Our purpose was to administer induction chemotherapy, perform surgery, and administer concomitant chemoradiotherapy in rapid sequence and to evaluate their impact on locoregional and distant tumor control.. Sixty-four patients with previously untreated, locoregionally advanced head and neck cancer received two cycles of cisplatin, bleomycin, and methotrexate (PBM) (33 patients) or cisplatin, fluorouracil (5-FU), and leucovorin (PFL) (31 patients). PFL was given to patients who were unable to receive bleomycin. Local therapy consisted of surgery and/or concomitant chemoradiotherapy with 5-FU, hydroxyurea, leucovorin, and radiotherapy (FHX-L), all administered every other week.. Complete and overall induction response rates were 21% and 79%, respectively, for PBM and 29% and 81%, respectively, for PFL. At completion of local therapy, 81% of the patients were disease-free. With a median follow-up of 35 months, the median survival and time to progression are 22 and 17 months, respectively, for PBM and have not been reached for PFL. Locoregional recurrence of disease is 30% for PBM and 26% for PFL. Distant disease progression is 24% for PBM and only 3% for PFL.. The sequencing of induction chemotherapy and concomitant chemoradiotherapy is feasible and results in a high local control rate and in an encouraging survival rate with PFL. The high distant failure (i.e., outside the head and neck area) rate of PBM suggests insufficient systemic activity for that regimen.. Concomitant FHX-L chemoradiotherapy may improve regional control rates of advanced head and neck cancer. Effective systemic therapy may be needed to control systemic micrometastases. PFL, but not PBM, appears to be suitable to accomplish that goal.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Hydroxyurea; Leucovorin; Male; Methotrexate; Middle Aged; Radiography; Time Factors; Treatment Outcome

Twenty-one patients with recurrent epithelial ovarian carcinoma not amenable to cure with further surgery or radiotherapy were entered into a Phase II trial utilizing i.v. leucovorin at 20 mg/m2 followed by i.v. 5-fluorouracil at 425 mg/m2 administered daily for 5 days every 4 weeks for the first two courses and then every 5 weeks. Twenty-one patients were entered. Of these, 20 were eligible for toxicity assessment and 19 for response. Five had received prior radiotherapy, and all had received prior cisplatin-based chemotherapy. There was one patient response (5.3%; 95% confidence intervals for response of 0% to 26%). Toxicity was moderate with 5 of 20 (25%) grade 3 or 4 leukopenia, 12 of 20 (60%) grade 3 or 4 granulocytopenia, 1 of 20 (5%) grade 3 thrombocytopenia, 5 of 20 (25%) grade 3 GI toxicity, and 2 of 20 (10%) grade 3 neurotoxicity. There was one toxic death in a patient who developed granulocytopenia and pneumonia after her third course of treatment. This dose schedule of 5-fluorouracil and leucovorin has minimal activity in patients with recurrent epithelial ovarian carcinoma who have received prior cisplatin chemotherapy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Middle Aged; Ovarian Neoplasms; Recurrence

A phase I study of 5-fluorouracil 600 mg/m2/week and folinic acid 500 mg/m2/week on day 1 and cisplatin administered weekly on day 2 was carried out on 30 patients with metastatic colorectal carcinoma of which 20 patients were pretreated with 5-fluorouracil. The first group of patients received cisplatin at the dose of 5 mg/m2/week. Cisplatin was then escalated to 10, 15, 20, 25, 30, and 35 mg/m2/week for subsequent groups of patients. Gastrointestinal side-effects were the dose-limiting toxicity. A therapy related death was seen at the dose of 35 mg/m2/week of cisplatin. The maximally tolerated dose of cisplatin in combination with 5-fluorouracil and citrovorum factor is 20 mg/m2/week. The optimally tolerated dose of 5-fluorouracil is 400 mg/m2/week in modulation with citrovorum factor 500 mg/m2/week. The recommended doses for a phase II study are cisplatin 20 mg/m2/week, 5-fluorouracil 400 mg/m2/week, and citrovorum factor 500 mg/m2/week.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Colorectal Neoplasms; Drug Evaluation; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Remission Induction

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

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

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

Recent in vitro and animal tumor studies suggest that sequential methotrexate (MTX) and 5-fluorouracil (5-FU) may be much more tumoricidal than either drug when used alone or in conventional combinations. Seventeen evaluable female patients with advanced carcinoma of the breast were treated with MTX 200 mg/M2I.V. followed one hour later with 5-FU 600 mg/M2I.V. Leucovorin 10 mg/M2 was begun orally 24 hours later and continued every six hours for six doses. Thirteen of these patients had not responded to prior drug treatment. Of the 17 patients, 11 responded to therapy, 9 had an objective response of greater than 50% tumor regression, and 2 had a minimal response of less than 50% tumor regression. The greatest number of responses was seen in skin and soft tissue. Disease-free interval, hormonal status, and prior therapy, with the exception of MTX and 5-FU containing drug regimens, did not appear to affect response rates. Toxicity was minimal and not life threatening. Based on these results it is believed that large trials with this drug sequence are warranted.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma; Clinical Trials as Topic; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluorouracil; Humans; Leucovorin; Methotrexate; Middle Aged

Nineteen patients with non-small-cell carcinoma of the lung were treated with high-dose methotrexate and leucovorin rescue. Two partial responses (10.5%) were observed, lasting 13 and 17 weeks. Toxicity was acceptable. It is concluded that the occasional benefit of high-dose methotrexate with leucovorin rescue at this dose and according to the schedule described for these patients does not warrant further study.

Topics: Adult; Carcinoma; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Lung Neoplasms; Male; Methotrexate; Middle Aged

The application of some basic principles derived from studies of the cell cycle and proliferative kinetics of normal and malignant cells has provided a rational basis for designing cancer treatment protocols. Using this approach in advanced head and neck cancer it is possible (a) to increase the response rate, (b) to reduce toxicity and (c) to reduce in-patient hospital stay time. Seventy-one patients with advanced carcinoma of the head and neck were randomized for treatment between two combination schedules, one with and the other without adriamycin. Responses (more than 50% tumour regression) were 74% overall with 70% responding to the combination without adriamycin and 82% responding to the schedule containing it. The increase in response rate seen with adriamycin is not statistically significant. Prior radiotherapy significantly reduced the likelihood of response to chemotherapy. These results have major implications for adjuvant chemotherapy and suggest a possible way of increasing the survival time in this group of diseases.

Topics: Bleomycin; Carcinoma; Carcinoma, Squamous Cell; Doxorubicin; Female; Head and Neck Neoplasms; Humans; Leucovorin; Male; Methotrexate; Middle Aged; Neoplastic Cells, Circulating; Vincristine

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 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

The occurrence of colorectal liver metastases (CRLM) impairs prognosis, yet long-term survival can be achieved by enabling liver resection. This study aims to describe factors associated with conversion therapy leading to liver surgery and treatment outcome.. A retrospective cohort study was conducted including all patients with CRLM discussed at multidisciplinary team conference at Karolinska University Hospital, Stockholm, Sweden, from 2013 to 2018. Factors associated with conversion therapy and outcome following conversion therapy were analysed with logistic regression and survival analyses.. Out of 1023 patients with CRLM, 100 patients (10%) received conversion chemotherapy, out of whom 31 patients (31%) subsequently underwent liver resection. Patients in whom conversion chemotherapy resulted in liver resection were younger (median age 61 vs. 66 years, p = .024), less likely to have a KRAS/NRAS-mutated primary tumours (25% vs. 53%, p = .039) and more likely to have received anti-EGFR agents (32% vs. 4%, p = .001) than patients progressing during conversion chemotherapy. The median OS for patients treated with conversion chemotherapy leading to liver resection was 24 months, compared to 14 months for patients progressing during conversion chemotherapy, p < .001. The OS for patients progressing during conversion chemotherapy was similar to patients given palliative chemotherapy, approximately 13 months.. Conversion therapy offers a survival benefit in selected patients. Despite treatment advances, the majority of patients undergoing conversion chemotherapy never become eligible for curative treatment.

Topics: Ablation Techniques; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Logistic Models; Male; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Retrospective Studies

Although no data have been reported beyond second-line therapy, aflibercept is approved in this setting in many countries. We conducted a multicenter study to analyze the efficacy and safety of a aflibercept-chemotherapy regimen beyond second-line therapy in patients with metastatic colorectal cancer.. Metastatic colorectal cancer patients treated with aflibercept beyond second-line therapy were included. Objective response rate, overall survival (OS), and progression-free survival (PFS) were assessed.. A total of 130 patients were included. Median OS and PFS were 7.6 months (95% confidence interval, 6.2-9.3) and 3.3 months (95% confidence interval, 2.7-3.8), respectively. The best response rates were partial response 6.9%, stable disease 38.5%, progressive disease 42.5%, and not evaluable 12%. According to whether patients received previous FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin)-bevacizumab or not, OS was 7.7 and 8.1 months (P = .31), and PFS was 2.9 and 3.9 months (P = .02), respectively. Interestingly, PFS and OS were both significantly improved by 4% and 5% per month, respectively, without antiangiogenic treatment before the initiation of the aflibercept regimen. The negative effect of prior FOLFIRI-bevacizumab or shorter time since last bevacizumab was maintained in multivariate analysis for both OS and PFS.. The aflibercept-chemotherapy regimen is a therapeutic option in patients with chemorefractory disease beyond second-line therapy, in particular in patients with an antiangiogenic-free interval.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Progression-Free Survival; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins; Retrospective Studies

Peritoneal carcinomatosis (PC) from colorectal cancer is associated with poor prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for patients with colorectal peritoneal carcinomatosis. However, standardization of HIPEC protocols, including which chemotherapeutic agent to use, is lacking in the literature. Therefore, we sought to report survival outcomes from colorectal cancer patients undergoing CRS/oxaliplatin-based HIPEC at our institution over the last 10 years.. Colorectal PC patients treated with CRS/oxaliplatin-based HIPEC 2004-2015 were included. Demographic, clinical, and oncologic data were abstracted from the medical record. Overall (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Univariate/multivariate Cox regression analysis was done.. Laparotomy was performed in 113 patients for colorectal PC; 91 completed a curative intent CRS/HIPEC. At 3 and 5 years, OS for the CRS/HIPEC cohort was 75% and 55%, and DFS was 50% and 25%, respectively. On multivariate analysis, incremental increases in peritoneal carcinomatosis index (PCI) were associated with worse OS (p = 0.0001) and DFS (p = 0.0001). Grade III/IV complications were also associated with worse OS.. A standardized regimen of CRS and oxaliplatin-based HIPEC for colorectal PC is effective with favorable OS and DFS and acceptable complication rates.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Fluorouracil; Follow-Up Studies; Humans; Hyperthermia, Induced; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Peritoneal Neoplasms; Prognosis; Prospective Studies; Retrospective Studies; Survival Rate

Hepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection.. The nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured.. Based on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5 cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection.. The proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Disease-Free Survival; Female; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver Neoplasms; Lymph Nodes; Male; Metastasectomy; Middle Aged; Neoadjuvant Therapy; Nomograms; Organoplatinum Compounds; Oxaloacetates; Prognosis; Retrospective Studies; Survival Rate; Tumor Burden

Undifferentiated carcinoma of pancreas (pancreatic cancer - PC) is a rare subtype of malignant PC. It was thought to be a sarcoma of the pancreas due to its typical morphological pattern. There are three histomorphological variants: anaplastic, sarcomatoid, and carcinosarcoma. There is also a separate category: undifferentiated pancreatic carcinoma with osteoclast-like giant cells. In contrast to ductal adenocarcinoma of the pancreas, undifferentiated carcinoma of pancreas is characterized by more aggressive behavior, other predilection localization of tumor and different predilection for localization of tumor and metastasis, a larger primary tumor, and different symptomatology at the time of diagnosis.. We present the case of a patient who was diagnosed with undifferentiated PC and was treated at the National Cancer Institute in Bratislava. We provide information about the clinical, radiological, and histomorphological characteristics of the disease, along with the diagnostic and therapeutic approach and a brief review of the literature.. The patient was diagnosed with inoperable locally advanced disease and was treated with first line chemotherapy comprising gemcitabine and cisplatin, followed by second line treatment with FOLFIRINOX. No response was achieved; on the contrary, we observed progression of the disease and deterioration in the patients condition. Overall survival was 4.5 months from the time of diagnosis.. The only appropriate therapeutic approach to this highly malignant disease is most likely “en-bloc” resection, which is possible only at the early stage of the disease. At present, no curative chemotherapy or radiotherapy regimen exists. The dominant features of undifferentiated PC described in the literature are aggressive behavior, an unfavorable prognosis, and chemo-refractoriness. Key words: pancreatic cancer - prognosis - chemotherapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 4. 6. 2018 Accepted: 25. 10. 2018.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Deoxycytidine; Fatal Outcome; Fluorouracil; Gemcitabine; Humans; Irinotecan; Leucovorin; Oxaliplatin; Pancreatic Neoplasms

Metastatic colorectal cancer (mCRC) patients with mutant KRAS or NRAS are ineligible for anti-epidermal growth factor receptor (anti-EGFR) therapy, as RAS mutations activate downstream pathways independently of EGFR and induce primary resistance. However, even among RAS wild-type (WT) patients, only a fraction responds to anti-EGFR therapy, suggesting that other mechanisms of resistance exist. We hypothesise that different (epi)genetic alterations can lead to primary anti-EGFR resistance and that the crucial end point is the activation of protein signalling pathways.. We analysed the expression and activation of proteins involved in cell signalling, using reverse phase protein arrays, on a multicentre French cohort of RAS WT mCRC treated with anti-EGFR treatment.. We identify activated EGFR and HER3 as protein biomarkers predictive for better overall survival. Active EGFR signalling and downstream PI3K, but not MAPK, pathway activation are associated with response to anti-EGFR treatment. Left-sided mCRC displays active ErbB2/3 and Wnt pathways and a better response to anti-EGFR therapy compared to right-sided mCRC.. We identify active EGFR and PI3K signalling as a key factor for response to anti-EGFR treatment in mCRC and highlight the importance of developing these biomarkers in clinical practice for the selection of RAS WT mCRC patients that would benefit from anti-EGFR treatment.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Camptothecin; Carcinoma; Cetuximab; Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Drug Resistance, Neoplasm; Epigenesis, Genetic; ErbB Receptors; Female; Fluorouracil; Genes, ras; Humans; Leucovorin; Male; MAP Kinase Signaling System; Middle Aged; Mutation; Organoplatinum Compounds; Panitumumab; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Receptor, ErbB-2; Receptor, ErbB-3; Response Evaluation Criteria in Solid Tumors; Retrospective Studies; Wnt Signaling Pathway

We evaluated the impacts of a series of novel histopathological factors on clinical-surgical outcomes and survival of patients who underwent surgery for colorectal cancer liver metastasis, with and without neoadjuvant chemotherapy.. A prospective database including 150 consecutive patients who underwent 183 hepatic resections for metastatic colorectal cancer was evaluated. Among them, 74 (49.3%) received neoadjuvant chemotherapy before surgery. The histopathological factors studied were: a) microsatellitosis, b) type and pattern of tumour growth, c) nuclear grade and the number of mitoses/mm(2), d) perilesional pseudocapsule, e) intratumoural fibrosis, f) lesion cellularity, g) hypoxic-angiogenic perilesional growth pattern, and h) the tumour normal interface.. Three or more metastatic lesions, R1 resection margins, and <50% tumour necrosis were prognostic factors for a worse OS, but only the former was confirmed to be an independent prognostic factor in the multivariate analysis. Furthermore, tumour fibrosis <40% and cellularity >10% were predictive of a worse neoadjuvant therapy response, but these findings were not confirmed in the multivariate analysis. Finally, tumour necrosis <50%, cellularity >10%, and TNI >0.5 mm were prognostic factors for a worse DFS and AS in the univariate but not in the multivariate analysis.. Several factors seem to influence the outcomes of surgery for colorectal cancer liver metastasis, especially the number of the lesions, the margins of resection, the percentage of necrosis and fibrosis, as well as the cellularity and the TNI.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Capecitabine; Carcinoma; Cetuximab; Colorectal Neoplasms; Databases, Factual; Deoxycytidine; Fibrosis; Fluorouracil; Hepatectomy; Humans; Leucovorin; Liver; Liver Neoplasms; Metastasectomy; Mitotic Index; Multivariate Analysis; Necrosis; Neoadjuvant Therapy; Neoplasm Grading; Organoplatinum Compounds; Oxaloacetates; Panitumumab; Prognosis; Retrospective Studies; Tumor Burden

The aim of this study is to discuss the curative effect of introperitoneal hyperthermic perfusion chemotherapy(IHPC) combined with systemic neoadjuvant chemotherapy on the gastric cancer patients with peritoneal carcinomatosis.. Sixty-four patients with gastric cancer and peritoneal carcinomatosis who were hospitalized in the Department of Gastrointestinal Surgery of First Hospital of Jilin University from December 2006 to December 2013. After peritoneal carcinomatosis was confirmed during laparoscopic exploration, FOLFOX6 (oxaliplatin and calcium folinate and 5-Fu) was performed for systemic chemotherapy. One course was 14 days and a complete treatment includes four courses. At the same time, patients underwent peritoneal catheter insertion and received IHPC(5-Fu 1 500 mg/m(2) and Cisplatin 35 mg/m(2) were added into 0.9% NaCl solution 2 000 ml, the infusion velocity was 35-45 ml/min, infusion time was 45-60 minutes, the temperature was controlled to 41°C). A comprehensive evaluation was taken after the fourth course of treatment before operation. Further surgical therapy was performed according to the assessment result.. Sixty-four patients received IHPC combined with systemic chemotherapy. Thirty-two patients(50.0%) had partial response, 18(28.1%) stable disease, and 14(21.9%) progressive disease after chemotherapy. No severe complications or death occurred during the neoadjuvant chemotherapy. Thirty-two patients(50.0%) received radical resection, 10(15.6%) palliative operation, and another 22 patients(37.4%) didn't comply with inclusion criteria of operation. Patients receiving operation had a median survival time of 678 days, which was significantly longer than patients without operation, with a median survival time of 251(χ(2)=23.34, P=0.02).. IHPC combined with systemic chemotherapy is an effective therapeutic method for gastric cancer patients with peritoneal carcinomatosis in terms of reducing preoperative tumor load and achieving radical resection.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Combined Modality Therapy; Digestive System Surgical Procedures; Fluorouracil; Humans; Hyperthermia, Induced; Laparoscopy; Leucovorin; Neoadjuvant Therapy; Organoplatinum Compounds; Peritoneal Neoplasms; Peritoneum; Stomach Neoplasms; Treatment Outcome

Although Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) confers health benefits in peritoneal carcinomatosis (PC) treatment, it is associated with significant postoperative morbidity and mortality rate with increased length of hospital stay. The goal of this study is to determine whether a new comprehensive physiotherapy program including epidural loco-regional analgesia can improve the quality of care and patients recovery.. Between 2009 and 2013, 124 patients with PC were operated for CRS and HIPEC procedures. These patients were analyzed and divided in 2 groups by means of time. No Physio group included patients operated from 2009 to 2011 (n = 57) having a thoracic patient controlled epidural analgesia (PCEA) but no preoperative physiotherapy program. The Physio group included patients operated from 2012 to 2013 (n = 67) having both a PCEA with a preoperative physiotherapy program.. The mortality rate was 1.6% (n = 2). The median length of stay in the intensive care unit (ICU) was lower in the Physio group, 2 days vs. 0 for No Physio group (p < 0.0001). The first time of mobilization after surgery was shorter in the Physio group (day 3 vs. 2, p = 0.0043). The overall satisfaction in the Physio group was achieved in 93% of patients, helping in decreasing fear of surgery and mobilization in 70% and 84% of cases respectively.. Our study demonstrates that a clear pre-operative information and education by a physiotherapist, associated with a PCEA-pain management significantly benefits the patient's post-operative recovery and reduces the length of stay in the ICU.

Topics: Analgesia, Epidural; Analgesia, Patient-Controlled; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Cytoreduction Surgical Procedures; Early Ambulation; Female; Fluorouracil; Humans; Hyperthermia, Induced; Infusions, Parenteral; Intensive Care Units; Length of Stay; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pain, Postoperative; Peritoneal Neoplasms; Physical Therapy Modalities; Postoperative Care; Postoperative Period; Preoperative Care; Quality of Health Care; Retrospective Studies

Ampullary carcinoma (AC) is a relatively rare entity often managed as a biliopancreatic carcinoma. AC has a better prognosis than peri ampullary tumors after resection, but more than a third of patients relapse. Factors predictive of recurrence are controversial, mainly because the relevant studies are very small or also included non AC tumors. There are no guidelines on the use of adjuvant or neoadjuvant chemotherapy. The aim of this study was to identify prognostic factors for recurrence after AC resection in a large multicentric cohort, and to establish a simple, practical, predictive score for recurrence in order to guide multidisciplinary decisions.. We included 152 consecutive patients who underwent Whipple's pancreaticoduodenectomy for ampullary carcinoma from January 2000 to December 2010 in 10 gastrointestinal oncology departments.. The estimated overall 5-year disease-free survival rate (DFS) was 47.1%. In multivariate analysis, age≥ 75 years at diagnosis (p < 0.0001), poor general condition (p = 0.01), poorly (p = 0.005) or moderately differentiated tumors (p = 0.01) and TNM stage IIb or III (p = 0.05) were associated with poor DFS. Based on this multivariate analysis, we developed a prognostic score with three levels of risk: DFS at 5 years was 73.5% in the low-risk group and 20.1% in the high-risk group.. This simple score based on age, general condition, tumor differentiation and TNM stage can classify patients into subgroups with different risks of recurrence and could help with therapeutic decisionmaking.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Ampulla of Vater; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemoradiotherapy, Adjuvant; Chemotherapy, Adjuvant; Common Bile Duct Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Health Status; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Pancreaticoduodenectomy; Retrospective Studies; Risk Assessment; Survival Rate

The aim of this report was to describe the way in which a rare and niche disease like ampulla of Vater carcinoma (AVC) was treated in real-world clinical practice.. A retrospective analysis of consecutive patients with a diagnosis of AVC treated at our medical oncology unit between August 2004 and August 2013 was performed.. We evaluated 8 consecutive patients with a median age of 60 years (range 56-84). At the last follow-up, 4 patients were alive without evidence of disease and 4 patients had died. The median follow-up time was 21.51 months (range 1-100.43), the median overall survival 23.19 months (range 7.07-102.2), and the median disease-free survival 18.26 months (range 0-102.2). Six patients underwent surgery, which consisted of pylorus-preserving pancreaticoduodenectomy, R0 in all cases. Tumor histology was adenocarcinoma in all patients. Two patients presented with locally advanced disease. Only 1 patient presented with metastases while 3 patients subsequently developed metastases. Two patients received chemotherapy for metastatic disease; in both cases disease progression was observed at the first disease evaluation.. We can consider AVC as a pathology niche and pancreaticoduodenectomy as the effective treatment for these patients.

Topics: Adult; Aged; Ampulla of Vater; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Capecitabine; Carcinoma; Common Bile Duct Neoplasms; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Gemcitabine; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organ Sparing Treatments; Organoplatinum Compounds; Pancreaticoduodenectomy; Pylorus; Retrospective Studies; Treatment Outcome

Nasopharyngeal carcinoma is an extremely rare pediatric malignancy predominantly occurring in adolescent males. Its multifactorial pathogenesis is most strongly associated with the exposure to Epstein-Barr virus in genetically susceptible hosts. In younger patients, more aggressive biological behavior has been observed, although the overall survival is better compared to adults. Due to its rarity and nonspecific clinical presentation, the diagnosis in children is often delayed and misinterpreted.. We report a case of a 16-year-old boy with stage IVB nasopharyngeal carcinoma. He presented with a painless palpable neck mass, nasal congestion and a history of occasional epistaxis and headaches. Four years after the completion of a multimodal treatment, the patient is in complete remission.. Although exceedingly rare, pediatricians should consider nasopharyngeal carcinoma in the differential diagnosis of palpable neck masses, especially in male adolescents. A multidisciplinary approach in the diagnosis, treatment, supportive care and follow-up is of utmost importance.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Fluorouracil; Humans; Leucovorin; Lymph Nodes; Lymphatic Metastasis; Male; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neck; Neoadjuvant Therapy; Neoplasm Staging; Radiotherapy; Tomography, X-Ray Computed

Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancer, although there are no reports on stage III colorectal cancer (CRC). The purpose of this study was to examine the association between neutropenia and prognosis in stage III CRC patients receiving adjuvant chemotherapy consisting of oral uracil and tegafur (UFT) plus leucovorin (LV). We retrospectively analysed 123 patients with stage III CRC who received UFT/LV as adjuvant chemotherapy. The end-point was disease-free survival (DFS). Survival curves of the two categories (neutropenia absent vs. present) were estimated using the Kaplan-Meier method and compared by the log-rank test. We estimated the hazard ratio (HR) for DFS according to neutropenia after adjustment for covariates by multivariate analyses using Cox's regression analysis. A total of 33 (26.8%) patients experienced neutropenia. Patients without neutropenia showed a significantly lower DFS than those with neutropenia (3-year DFS 57.3% vs. 81.2%, P = 0.0213). By multivariate analysis, neutropenia and histological type were independent prognostic factors, with HR of 0.410 (neutropenia absent vs. present, P = 0.045) and 4.793 (well to moderately differentiated vs. poorly differentiated, P = 0.004) respectively. We demonstrated that neutropenia occurring during adjuvant chemotherapy consisting of UFT/LV may be a prognostic factor of recurrence in stage III CRC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cohort Studies; Colorectal Neoplasms; Female; Humans; Leucovorin; Male; Middle Aged; Neoplasm Staging; Neutropenia; Prognosis; Proportional Hazards Models; Retrospective Studies; Tegafur; Treatment Outcome; Uracil

Patients with stage IV colorectal cancer and peritoneal carcinomatosis are increasingly treated with curative intent and perioperative systemic chemotherapy combined with targeted therapy. The aim of this study was to analyze the potential impact of bevacizumab on early morbidity after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin.. From 2004 to 2010, in three referral centers, 182 patients with colorectal carcinomatosis were treated with complete cytoreduction followed by HIPEC after either preoperative systemic chemotherapy alone or in combination with bevacizumab. Because there was no control on treatment allocation, propensity score methods were used to control for this bias.. The median time from discontinuation of bevacizumab to HIPEC was 7 weeks (range 6-10 weeks). Major morbidity was greater in the bevacizumab group (34 vs. 19 %, p = 0.020). Nine patients died postoperatively, 5 (6.2 %) in the bevacizumab group (n = 80) and 4 (3.9 %) in the group treated with chemotherapy alone (n = 102) (p = 0.130). The rate of digestive fistulas was greater in the bevacizumab group, although not statistically significant (18 vs. 10 %, p = 0.300). The effect of bevacizumab on major morbidity (including death) was found to be statistically significant (odds ratio 2.28, 95 % confidence interval 1.05-4.95) (p = 0.04).. Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for colorectal carcinomatosis is associated with twofold increased morbidity. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated.

Topics: Abdominal Abscess; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Cytoreduction Surgical Procedures; Digestive System Fistula; Female; Fluorouracil; Hematoma; Humans; Hyperthermia, Induced; Length of Stay; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Peritoneal Neoplasms; Wound Healing

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

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

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

Anaplastic pancreatic carcinoma is a rare tumor with poor survival. Data on surgical and medical therapies are currently limited to case reports and case series with small numbers.. We describe a case of multifocal anaplastic pancreatic carcinoma treated with neoadjuvant FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) and total pancreatectomy with subsequent patient disease-free survival currently at 12 months.. The goal for anaplastic pancreatic carcinoma treatment should continue to be complete surgical resection. Optimum chemotherapeutic options continue to be investigated.

Topics: Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Combined Modality Therapy; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Organoplatinum Compounds; Oxaliplatin; Pancreatectomy; Pancreatic Neoplasms; Treatment Outcome

Topics: Abdominal Pain; Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Bile; Carcinoma; Cholecystostomy; Colorectal Neoplasms; Colostomy; Drainage; Fluorouracil; Gallbladder; Humans; Ischemia; Leucovorin; Male; Organoplatinum Compounds; Treatment Outcome

Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Camptothecin; Carcinoma; Cohort Studies; Drug Monitoring; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Neutropenia; Pancreatic Neoplasms; Secondary Prevention; Severity of Illness Index; Survival Analysis

The purpose of the study is evaluation and assessment of parameters of cardiac toxicity in patients subjected to 5-FU based chemotherapy. Cardiac morbidity is a reported outcome in different 5FU/LV regimens; however none of them are definite or proximate. The bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective as compared to the monthly regimen of low dose leucovorin. We report the detailed assessment of few cardiac parameter of toxicity in patients of advanced colorectal carcinoma subjected to two Schedules of high and low dose Folinic Acid, 5-Fluorouracil, bolus and continuous infusion. The correlation of elevated cardiac biomarkers, angina and hypertension is comparatively assessed in patients with normal general status, hyperglycemia and known cardiac disorders subjected to two different 5FU based chemotherapeutic regimen.

Topics: Angina Pectoris; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Blood Pressure; Carcinoma; Chi-Square Distribution; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Heart Diseases; Humans; Hypertension; Leucovorin; Male; Middle Aged; Prospective Studies; Risk Factors; Time Factors; Treatment Outcome

The development of ovarian metastases from gastric cancer indicates a turning point of the disease progression and is usually associated with poor prognosis. Efficacy of modern chemotherapy protocols in ovarian metastases from gastric cancer is unknown. In this case series, we have evaluated the chemosensitivity of ovarian metastases from gastric cancer in eight consecutive patients treated in our institution between January 2000 and April 2012. Median age at gastric cancer diagnosis was 48.3 years and ovarian metastases were mainly metachronous (88%). Patients were treated with FOLFOX or FOLFIRI protocols in first-line and with EOX protocol in second-line chemotherapy. These protocols of chemotherapy used in first- and second-line treatment were able to control the disease in 33.3% for ovarian metastases compared to 66.7% for extraovarian metastases. Mean overall survival (OS) from ovarian metastases diagnosis was 14.2 months. The four patients treated by bilateral oophorectomy had a longer mean OS (16 months) than the four patients who did not experienced surgery (12.3 months). In conclusion, this case series suggests that ovarian metastases from gastric cancer are less sensitive than extraovarian metastases to modern protocol of chemotherapy. To confirm these observations, a large retrospective study is ongoing.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Organoplatinum Compounds; Ovarian Neoplasms; Ovariectomy; Stomach Neoplasms

According to the 7th edition of the TNM staging system, stage IV metastatic colorectal cancer (CRC) at the time of initial diagnosis is sub-classified into stage IVA or IVB disease. Peritoneal carcinomatosis (PC), considered to have a dismal prognosis, is exclusively sub-classified into stage IVB, even though other metastases to a sole organ are sub-classified into stage IVA, which is considered to be associated with better survival. This retrospective study was undertaken to investigate the overall survival in metastatic CRC patients, focusing on PC patients.. We reviewed data on patients with metastatic CRC at initial diagnosis surgically treated between January 2006 and June 2011. A survival analysis was performed paying special attention to PC and sub-classifying patients with PC into three categories according to metastatic sites.. There were 69 stage IVA patients (IVA group) and 83 stage IVB. Among stage IVB patients, 20 had isolated PC (PC-I group), 28 had PC with one or more other sites of metastasis (PC-II group), and 35 had at least 2 metastatic without peritoneal involvement (NPC group). Of 152 stage IV patients, 132 (87 %) underwent resection of the primary tumor and 19 (12 %) underwent radical resection of metastatic disease with microscopic free margins (R0 resection) including 5/20 (25 %) patients in the PC1 group. A total of 139 patients received oxaliplatin-based chemotherapy in a palliative (n = 125), neoadjuvant (n = 3), or adjuvant setting after R0 resection (n = 11). Compared with 36.6 months in the PC-I group, median survival was 32.5 months (P = 0.48) in the IVA group, 14.7 months (P = 0.07) in the PC-II group, and 12.9 months (P < 0.01) in the NPC group.. The sub-classification of isolated PC into stage IVA instead of IVB might be more appropriate in the era of modern chemotherapy. Further investigation is warranted.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Organoplatinum Compounds; Palliative Care; Peritoneal Neoplasms; Prognosis; Retrospective Studies

The aim of this study was to evaluate the intraoperative detection rate of residual liver metastases after chemotherapy and to assess the correlation between disappeared liver metastases (DLMs) upon preoperative imaging and complete pathological response.. Between February 2004 and December 2008 clinicopathological data of 292 consecutive patients who underwent liver resection for colorectal liver metastases were prospectively collected and analyzed in a "per lesion" study. Thirty-three patients with 67 DLMs were included.. During laparotomy, we identified 45 out of 67 DLMs (67%). Six DLMs were detected by macroscopic liver examination (9%) and 39 (58%) by intraoperative ultrasound (IOUS). Overall, persistent microscopic residual disease at pathological examination of the resected specimen or recurrence in situ identified during the follow-up were observed in 41 (61.2%) of 67 LMs that had shown a complete response by imaging. At multivariate analysis moderate or severe hepatic steatosis (p = 0.016), subglissonian localization of nodules (p = 0.019) and residual microscopic disease (p = 0.0006) were associated with IOUS detection of residual metastases. Preoperative chemotherapy with more than six cycles (p = 0.022) and intraoperative detection of nodules by IOUS (p = 0.001) were independent predictors of residual disease.. Systematic US exploration of the liver leads to increase the intraoperative detection rate of DLMs. Furthermore, the majority of DLMs identified by IOUS presents residual disease at pathological examination and should be treated.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chi-Square Distribution; Colorectal Neoplasms; Female; Fluorouracil; Hepatectomy; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Multivariate Analysis; Neoplasm, Residual; Organoplatinum Compounds; Oxaliplatin; Positron-Emission Tomography; Proportional Hazards Models; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography

The study aimed to evaluate the efficacy of concurrent chemoradiotherapy (CCRT) with platinum-based chemotherapy as a primary treatment for nasopharyngeal carcinoma (NPC) and to further compare the results of CCRT with these of neoadjuvant chemotherapy (NAC) followed by radiotherapy (RT).. Before 1998, 21 patients with NPC received NAC followed by RT (NAC-RT). Between 1999 and 2008, a total of 25 NPC patients received CCRT. The CCRT group received a regimen including docetaxel (50 mg/m(2), day1), cisplatin (CDDP, 60 mg/m(2), day4) and continuous 5-fluorouracil (5-FU) infusion (600 mg/m(2), day 1-5), the TPF regimen, or a regimen including CDDP (60 mg/m(2), day4), continuous 5-FU infusion (600 mg/m(2), day 1-5), methotrexate (MTX, 30 mg/m(2), day 1) and leucovorin (LV, 20 mg/m(2), day 1-5), PFML regimen. The CCRT group received 2 cycles of chemotherapy during definitive RT. The NAC group of patients received a PFML regimen.. The overall response rate after CCRT was 96%. The 3-year and 5-year disease-specific survival rates were 75.6% and 60.1%, respectively. In patients receiving NAC-RT, the 3-year and 5-year disease-specific survival rates were 84.1% and 67.3%, respectively. There was no difference observed in terms of survival rates between the group receiving CCRT and that receiving NAC-RT.. CCRT with the TPF or PFML regimen was tolerable, and the NPC patients receiving this treatment showed excellent survival rates. In comparison to the group receiving NAC-RT, CCRT had no advantage in terms of the survival rate. In the future, the control of distant metastasis might play an important role in improving the survival rate of patients with advanced NPC receiving CCRT.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemoradiotherapy; Chemotherapy, Adjuvant; Cisplatin; Docetaxel; Female; Fluorouracil; Humans; Induction Chemotherapy; Leucovorin; Male; Methotrexate; Middle Aged; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoadjuvant Therapy; Retrospective Studies; Taxoids

Topics: Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; DNA-Binding Proteins; Enhancer of Zeste Homolog 2 Protein; Fluorouracil; Genotype; Humans; Leucovorin; Middle Aged; Polycomb Repressive Complex 2; Polymorphism, Single Nucleotide; Prognosis; Risk Assessment; Survival Analysis; Transcription Factors

We report the case of a 62-year-old woman with a metastatic gastric cancer complicated by diffuse bone marrow carcinomatosis, disseminated intravascular coagulation (DIC) and microangiopathic hemolytic anemia (MHA) treated by modified FOLFOX-6 as front-line chemotherapy regimen. This chemotherapy showed clinical, morphological and biological efficiency and safety in this rare and severe hematological complication at initial diagnosis. Furthermore, this is the first case of diffuse bone carcinomatosis from a gastric cancer to be monitored by positron emission tomography integrated computed tomography (PET-CT) scan using 18-fluorodeoxyglucose (18-FDG).

Topics: Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Carcinoma; Carcinoma, Signet Ring Cell; Diagnostic Imaging; Disease Progression; Disseminated Intravascular Coagulation; Drug-Related Side Effects and Adverse Reactions; Fatal Outcome; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Lymphatic Metastasis; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Purpura, Thrombotic Thrombocytopenic; Sensitivity and Specificity; Stomach Neoplasms; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Signet Ring Cell; Colonic Neoplasms; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Young Adult

Although systemic therapies have shown to result in survival benefit in patients with metastatic colorectal cancer (mCRC), outcomes in patients with peritoneal carcinomatosis (PC) are poor. No data are available on outcomes of current chemotherapy schedules plus targeted agents in mCRC patients with PC.. Previously untreated mCRC patients treated with chemotherapy in the CAIRO study and with chemotherapy and targeted therapy in the CAIRO2 study were included and retrospectively analysed according to presence or absence of PC at randomisation. Patient demographics, primary tumour characteristics, progression-free survival (PFS), overall survival (OS), and occurrence of toxicity were evaluated.. Thirty-four patients with PC were identified in the CAIRO study and 47 patients in the CAIRO2 study. Median OS was decreased for patients with PC compared with patients without PC (CAIRO: 10.4 versus 17.3 months, respectively (p ≤ 0.001); CAIRO2: 15.2 versus 20.7 months, respectively (p < 0.001)). Median number of treatment cycles did not differ between patients with or without PC in both studies. Occurrence of major toxicity was more frequent in patients with PC treated with sequential chemotherapy in the CAIRO study as compared to patients without PC. This was not reflected in reasons to discontinue treatment. In the CAIRO2 study, no differences in major toxicity were observed.. Our data demonstrate decreased efficacy of current standard chemotherapy with and without targeted agents in mCRC patients with PC. This suggests that the poor outcome cannot be explained by undertreatment or increased susceptibility to toxicity, but rather by relative resistance to treatment.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Staging; Peritoneal Neoplasms; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Failure; Treatment Outcome

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Colitis; Colonic Neoplasms; Diverticulosis, Colonic; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin

A 64-year-old woman was introduced to our hospital with liver tumors. Our examination revealed that she had advanced colon carcinoma with multiple liver metastasis. Without symptoms from the primary cancer, she underwent chemotherapy of avastin FOLFOX. After 2 courses of chemotherapy, she suffered ileus and underwent operation. The resected specimen showed marked tumor necrosis and fibrosis, but few tumor cells remained in the primary lesion. We think this was a rare case of suffered ileus because of marked response of chemotherapy in primary colon carcinoma.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Cicatrix; Colorectal Neoplasms; Female; Fluorouracil; Humans; Ileus; Leucovorin; Liver Cirrhosis; Liver Neoplasms; Middle Aged; Organoplatinum Compounds

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

Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF(165)b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF(165)b levels treated with bevacizumab.. Blinded tumor samples from the phase III trial of FOLFOX4 ± bevacizumab were assessed for VEGF(165)b and VEGF(total) by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF(165)b:VEGF(total) for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio.. Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF(165)b:VEGF(total) ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF(165)b:VEGF(total) ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF(165)b group, but this did not reach statistical significance. There was no difference in the high VEGF(165)b:VEGF(total) group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3 months).. Low VEGF(165)b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Kaplan-Meier Estimate; Leucovorin; Multicenter Studies as Topic; Organoplatinum Compounds; Protein Isoforms; Randomized Controlled Trials as Topic; Vascular Endothelial Growth Factor A

The -460T → C polymorphism of vascular endothelial growth factor (VEGF) gene significantly increases its promoter activity. A pilot study was conducted to assess the influence of this polymorphism on clinicopathological features of patients with colorectal carcinoma. In total, 228 patients were enrolled, including 100 with stage II/III colorectal carcinoma receiving curative surgery and 128 with metastatic disease. An excellent correlation in VEGF -460 genotypes based on white blood cells and tumor tissues existed, but there was no between-group difference in patients with or without colorectal carcinoma. A marked increase in intratumor and circulating VEGF levels were observed in patients with the T/C or C/C genotypes (P < 0.01), which was associated with increased extent of invasion, nodal involvement, poor histological differentiation, subsequent metastasis and shorter survival in stage II/III patients treated with curative surgery (P < 0.01). For patients with metastatic disease, this polymorphism was associated with a lower response rate to FOLFOX-4 (P = 0.03) and shorter survival (P < 0.001). By multivariate analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). These data suggest that -460T → C polymorphism of VEGF gene, by increasing VEGF expression and subsequent angiogenesis, could be a key determinant for increased tumor recurrence and a poor prognosis of patients with colorectal carcinoma. However, this study is exploratory and is not adjusted for multiple comparisons, requiring independent replication.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Gene Expression; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasm Staging; Organoplatinum Compounds; Polymorphism, Genetic; Treatment Outcome; Vascular Endothelial Growth Factor A

Several long-standing chemotherapy regimens are available to treat metastatic colorectal cancer (mCRC) including: oxaliplatin plus 5-fluorouracil (5-FU) and leucovorin (FOLFOX); and irinotecan plus 5-FU and leucovorin (FOLFIRI). More recently, new biologic therapies were approved for use in mCRC.. This study examined treatment patterns and trends in metastasectomy among newly diagnosed mCRC patients after the introduction of capecitabine (CAP) in 2001 and the biologic therapies in 2004.. Using a large, US-based administrative medical claims database of a national commercially insured population, patients with newly diagnosed mCRC were identified from 2001 to 2005. At least 6 months of patient history prior to mCRC diagnosis were required to confirm patients were newly diagnosed. Patients were followed from initial mCRC diagnosis to death, disenrollment, or 12/31/2006. Chemotherapy and biologic treatments and rates of metastasectomy over time were analyzed.. A total of 3781 mCRC patients met the study criteria. The average time from mCRC diagnosis to initiation of systemic treatment decreased from 134.4 days (SD 261.2) to 61.7 days (SD 89.3) in 2001-2005 (p < 0.001). The most common first-line regimens were FOLFIRI (40%), 5-FU/LV (31%), and capecitabine (21%) in 2001, and FOLFOX plus bevacizumab (22%), FOLFOX alone (15%), 5-FU/LV (15%), and capecitabine (15%) in 2005. Among patients with ≥1 year of follow-up, the use of biologics increased from 37.3% in 2004 to 52.0% in 2005 (p < 0.001). The percentage of patients who underwent resection after systemic treatment increased from 2.9% to 5.6% in 2001-2005 (p = 0.169).. Over time the standard of care chemotherapy for 1st-line mCRC has changed from FOLFIRI to FOLFOX, and the use of biologics has become common. The percentage of patients who underwent resection after systemic treatment almost doubled during the study period.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Camptothecin; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Metastasis; Organoplatinum Compounds; Professional Practice; Standard of Care; Treatment Outcome; Young Adult

When applying the topoisomerase inhibitor irinotecan (CPT) with the infusional fluorouracil/levofolinate (FOLFIRI) ± bevacizumab chemotherapy regimen in cases of advanced colorectal carcinoma, the international standard dose for CPT is 180 mg/m(2). Despite this, 150 mg/m(2) CPT is widely prescribed and is the maximum dosage covered by Japanese health insurance. Consequently, the safety of dosing at the international standard has not been tested comprehensively and the efficacy of FOLFIRI in Japan may be underestimated.. To evaluate the safety of FOLFIRI (+bevacizumab) in clinical practice using international standards, we reviewed medical records of 53 patients who received FOLFIRI (+bevacizumab) with CPT 180 mg/m(2) as first-line treatment between September 2004 and August 2009. The primary endpoint of the study was to measure the relative dose intensity (RDI) of CPT after four courses. The secondary endpoint was to assess treatment completion rate, adverse events, response rate, progression-free survival (PFS) and overall survival (OS) among all patients.. The RDI and the treatment completion rate were 88.9% and 69.8%, respectively, in the 53 patients. Accompanying grade 3 or 4 adverse events included neutropenia (35.8%), febrile neutropenia (7.5%), and diarrhea (3.8%). Supportive care managed all toxicity symptoms. Median durations for PFS and OS were 10.3 and 26.5 months, respectively.. FOLFIRI (+bevacizumab) with the international standard dose of CPT is feasible in clinical practice. In order to minimize deviation of the Japanese regimen from global best practice, international dose standards should be followed.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Camptothecin; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Humans; Japan; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Neutropenia; Retrospective Studies

A 71-year-old man with eosinophilia was given a diagnosis of poorly differentiated adenocarcinoma of the rectum. Further examination showed that it had invaded the bone marrow. He had disseminated intravascular coagulation (DIC) from disseminated carcinomatosis of the bone marrow after colostomy. Chemotherapy (mFOLFOX6) was successful and his eosinophil count, DIC score and tumor markers normalized. We were able to continue chemotherapy after 5 months from the outbreak of disseminated carcinomatosis of the bone marrow. It is said that disseminated carcinomatosis of the bone marrow has a poor prognosis, but we were able to obtain a good response in this case by chemotherapy.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Neoplasms; Carcinoma; Disseminated Intravascular Coagulation; Eosinophilia; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds; Rectal Neoplasms

Several studies have proven an ameliorated prognosis after a neoadjuvant therapy for locally advanced Barrett's carcinoma in case of response. The necessary amount of neoadjuvant chemotherapy within a multimodal therapy concept with following oesophageal resection has never been evaluated so far.. The clinical course of 122 patients with Barrett's carcinoma, who all underwent a neoadjuvant chemotherapy with cisplatin, five fluorouracil and leucovorin and following oesophagectomy, was reviewed. The pretherapeutic clinical and postoperative histopathological staging, histopathological response, clinical course, recurrence rates and long-term survival were retrospectively analysed and compared to the data of 30 patients, who were included in the same multimodal therapy concept, but who had to cease the chemotherapy early because of toxicity.. Postoperative pathological staging showed that the response rate correlates with the N and R status. The responding patients benefit from longer survival. Comparing the two subgroups, we could not find a significant difference in response rate, tumour staging, resection rate, long-term survival or pattern of recurrent disease. However, postoperative morbidity and mortality did not correlate with severe chemotherapy-induced toxicity.. This is the first study on the necessary number of chemotherapy cycles in terms of a neoadjuvant therapy for Barrett's carcinoma. We could show a similar downstaging effect, a good histopathological response and a comparable ameliorated long-term survival of patients with one compared to patients with three chemotherapy cycles. A biological selection seems to determine the course of the disease already at this early stage.

Topics: Aged; Antineoplastic Agents; Barrett Esophagus; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Cohort Studies; Esophageal Neoplasms; Esophagectomy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoadjuvant Therapy; Survival Rate; Treatment Outcome; Vitamin B Complex

We present the case of a 57-year-old patient who initially presented with a constellation of symptoms including intense pruritis, flushing and diarrhoea. Following several months clinical deterioration, the patient was investigated radiologically, where multiple hepatic tumours were identified. Liver biopsy confirmed the presence of a well-differentiated metastatic gastroenteropancreatic endocrine carcinoma with biochemical evidence of serotonin secretion. Over a period of six months, the clinical course of the patient's disease progressed whereby severe hypoglycaemia became the major manifestation. Subsequent biochemical investigations confirmed the diagnosis of an insulinoma. Extensive radiological investigation revealed a solitary primary pancreatic tumour, indicating the presence of a metastatic pancreatic endocrine tumour (PET) secreting both insulin and serotonin. The patient was treated with a chemotherapy regimen consisting of 12 cycles of 5-fluorouracil/oxaliplatin, responding clinically - improved World Health Organization performance score from 3 to 1, biochemically - significantly reduced plasma chromogranin A and cancer antigen 19-9 concentrations and improved liver function tests, and radiologically - reduced pancreatic and hepatic tumour size. This is the first report of a primary PET secreting insulin and serotonin. Due to the association of serotonin-secreting gastroenteropancreatic endocrine tumours (GEP-ETs) with multiple endocrine neoplasia type-1 (MEN1) and biochemical evidence of an insulinoma, MEN1 should also be considered in such cases. The case provides further evidence for the biological heterogeneity of GEP-ETs and the myriad secretory humoral products and resultant clinical syndromes arising from such tumours.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma; Fluorouracil; Humans; Hyperinsulinism; Hypoglycemia; Leucovorin; Liver Neoplasms; Malignant Carcinoid Syndrome; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Pancreatic Neoplasms; Vitamin B Complex

Operation results of 81 colorecatal cancer-patients with peritoneal carcinomatosis (PC) treated with peritonectomy plus perioperative chemotherapy are reported. The patients who had the following evidences are considered to be eligible for peritonectomy: 1) No evidence of N3 lymph node involvement, 2) No evidence of hematogenous metastasis, 3) No progressive disease after preoperative chemotherapy, 4) No severe co-morbidities or no poor general condition. Complete cytoreduction resection is aimed for removing all macroscopic tumors by peritonectomy using electrosurgical techniques. The completeness of cytoreduction (CC scores) after peritonectomy is classified into the following 4 criteria: CC-0-no peritoneal seeding was exposed during the complete exploration, CC-1-residual tumor nodules are less than 2.5 mm in diameter, CC-2-nodules are between 2 .5 mm and 25 mm in diameter, CC-3-nodules are greater than 25 mm in diameter, CC-2 and CC-3 are regarded as incomplete cytoreduction. Operation time and blood loss were 237 ± 124 min. (799-90 min) and 1,598 ± 1,411 mL (6,500-20 mL), respectively. Postoperative complications developed in 37( 46%) patients. The patients received CC-0/ -1 resection survived significantly longer than those of CC-2/ -3 group. The patients with PCI ≤ 10 survived significantly longer than those with PCI≥ 11. CC and PCI scores are the independent prognostic factors. The relative risk for death of CC-2/-3 group was 4.6-fold higher than that of CC-0/ -1 group. Accordingly, peritonectomy is indicated for patients with PCI score≤ 10.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pelvic Exenteration; Peritoneal Neoplasms; Young Adult

To evaluate the results of a prospective therapeutic protocol with long-term follow up in terms of survival rates in a cohort of patients treated with Intermediate and Advanced GBC (GBC).. Prospective cohort of patients with intermediate and advanced stages of GBC treated between 1996 and 2006. All cases were treated with a partial hepatic segmentectomy on segments IVb and V and a regional lymph node dissection and six cycles of out-patient chemotherapy (5-FU and leukovorin). With an average follow-up of 31.5 months, the morbidity, operative mortality, hepatic and lymphatic infiltration and actuarial survival were measured. Descriptive statistics were applied as well as bivariate analysis applying Fisher's exact test and non-parametrical tests and Kaplan Meier survival curves. Also logistic regression and proportional risk of Cox were applied.. 40 patients were included in this protocol, with an average age of 59.5 years (40-85 years), of which 28 were women (70%). Depth of wall infiltration: muscular 8 patients (20%), subserosal 12 patients (30%), serosal 12 patients (30%) and perivesicular adipose tissue 8 patients (20%). The series morbidity was 27.5%. There was no operative mortality. The chemotherapy was well tolerated. The overall actuarial survival in the series was 50% at 60 months.. Our protocol treatment has morbidity, mortality and survival rates similar to previously reported series.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma; Chemotherapy, Adjuvant; Chile; Cholecystectomy; Clinical Protocols; Epidemiologic Methods; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Invasiveness; Sex Factors; Treatment Outcome

Liver failure due to disseminated hepatic secondaries represents a therapeutic dilemma in patients with metastatic breast cancer (MBC). Reduced liver function and non-assessable toxicity are limiting factors in the selection of chemotherapeutic agents. Currently, there is no standard treatment after failure of anthracycline-and taxane-based first-line therapies, although there is a variety of well evaluated drugs such as capecitabine.. We report on a 45-year-old breast cancer patient with disseminated hepatic metastases. She presented in markedly poor condition, showing substantial ascites and extensive jaundice. Blood chemistry analysis showed increased serum levels of liver enzymes (aspartate aminotransferase 271 U/l, alanine transaminase 101 U/l), bilirubin (7.9 mg/dl), and CA 15-3 (1,459 U/l). We induced a palliative chemotherapy with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU). The patient improved impressively after the first cycle of systemic therapy. Liver enzymes stabilized continuously, CA 15-3 returned to normal. The patient was discharged 2 weeks after the treatment start. Chemotherapy was well tolerated under dose escalation, no grade 3/4 toxicity was observed. The progression-free interval was 5 months.. A combination therapy with Mi/Fo/FU appears to be a reasonable and tolerable alternative salvage strategy for patients with liver failure due to hepatic breast cancer metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Female; Fluorouracil; Humans; Leucovorin; Liver Failure; Liver Neoplasms; Middle Aged; Mitomycin; Treatment Outcome

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

A 66-year-old man was referred to our hospital because of a two-week history off ever and low back pain. There was a hard anal mass on rectal examination. Colonoscopy and computed tomography showed anal adenocarcinoma, multiple metastases to lymph nodes and bones. Blood test showed severe disseminated intravascular coagulation (DIC). Microscopic examination of the bone marrow aspirate revealed disseminated carcinomatosis of the bone marrow. Systemic chemotherapy (mFOLFOX6) was started, then remission of DIC and shrinkage of the tumor were observed. Although the patient had cerebral infarction during the first course of chemotherapy, he received nine courses of treatment. He died six months later because of cerebellar hemorrhage.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Anus Neoplasms; Bone Marrow Neoplasms; Carcinoma; Disseminated Intravascular Coagulation; Fluorouracil; Humans; Leucovorin; Male; Organoplatinum Compounds

We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes.. One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test.. Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001].. A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Chemotherapy, Adjuvant; Colorectal Neoplasms; Female; Fluorouracil; Germany; Health Status Indicators; Humans; Irinotecan; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Patient Selection; Peritoneal Neoplasms; Predictive Value of Tests; Proportional Hazards Models; Retrospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Survival Rate; Time Factors; Treatment Outcome

Xeroderma pigmentosum group D (XPD) participates in DNA unwinding during nucleotide excision repair, which may alter the efficacy of platinum-based chemotherapy. We analyzed the influence of codon 751 Lys-->Gln polymorphism of XPD on its protein expression levels, clinico-pathological features, and outcome of 188 Chinese patients with metastatic colorectal carcinoma (CRC) that had been treated with first-line Oxaliplatin + Leucovorin + 5-Fluorouracil (FOLFOX-4) chemotherapy. The results showed that in comparison with Caucasian populations, a remarkably lower prevalence of Lys/Gln genotype was noted (16%, n = 30). No between-group difference in XPD protein expression of patients with or without this polymorphism was noted (56.5%vs 59.7%; P = 0.783). Patients with Gln751 allele have a significantly lower response to FOLFOX-4 treatment (36.7%vs 58.2%, P = 0.03), and shorter progression-free (7 vs 11 months; P < 0.01) and overall (14 vs 22 months; P < 0.01) survivals. The incidence of grade 3/4 oxaliplatin-neuropathies was very similar in both groups (13.3%vs 16.5%; P = 0.67). By adjusted analysis, this polymorphism was further identified as an independent prognostic factor (P = 0.03). These data suggest that Asian populations have a significantly lower prevalence of codon 751 Lys/Gln polymorphism in XPD, which could be a key determinant for good response to oxaliplatin-based treatment and favorable outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asian People; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Polymorphism, Genetic; Prevalence; Xeroderma Pigmentosum Group D Protein

Previously we developed membrane-arrays as a promising tool to detect circulating tumor cells (CTC) with KRAS oncogene in patients with malignancies. This study was conducted to determinate the predictive values of CTCs with KARS mutation by membrane-arrays for metastatic colorectal cancer patients treated with cetuximab plus chemotherapy.. Seventy-six metastatic colorectal cancer patients receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy were enrolled. KRAS mutation status in the peripheral blood of these patients was analyzed using membrane-arrays, and KRAS mutation status in tumors was analyzed by DNA sequencing.. Among 76 metastatic colorectal cancer patients, KRAS mutations in tumors and in peripheral blood were identified in 33 (43.4%) and 30 (39.5%) patients, respectively. The detection sensitivity, specificity, and accuracy of membrane-arrays for CTCs with KRAS oncogene were 84.4%, 95.3%, and 90.8%, respectively, and indeed a highly significant correlation to KRAS mutations in tumors (P < 0.0001) was observed. Forty-five (59.2%) patients responded to cetuximab plus chemotherapy, and 41 and 40 were wild-type KRAS in tumors and peripheral blood, respectively (both P < 0.0001). Patients with tumors that harbor wild-type KRAS are more likely to have a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001). Likewise, patients with CTCs of wild-type KRAS in peripheral blood express a better progression-free survival and overall survival when treated with cetuximab plus chemotherapy (P < 0.0001).. These findings provide evidence that detection of KRAS mutational status in CTCs, by gene expression array, has potential for clinical application in selecting metastatic colorectal cancer patients most likely to benefit from cetuximab therapy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Cetuximab; Colorectal Neoplasms; DNA Mutational Analysis; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Organoplatinum Compounds; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins p21(ras); ras Proteins; Retrospective Studies; Treatment Outcome

Granulocyte-colony stimulating factor (G-CSF)-producing cancer has been reported to occur in various organs, especially the lung. However, G-CSF-producing colorectal cancer (CRC) has never been reported in the English literature.. A 57-year-old man was admitted for the surgical removal of a rectal cancer. Some hepatic tumors in the liver were revealed concurrently, and their appearance suggested multiple liver metastases. Low anterior resection was performed. with the help of histopathological examination and immunohistochemical studies, we diagnosed this case to be an undifferentiated carcinoma of the rectum. After the operation, the white blood cell (WBC) count increased gradually to 81,000 cells/microL. Modified-FOLFOX6 therapy was initiated to treat the liver metastases, but there was no effect, and peritoneal dissemination had also occurred. The serum level of G-CSF was elevated to 840 pg/mL (normal range, <18.1 pg/mL). Furthermore, immunohistochemistry with a specific monoclonal antibody against G-CSF was positive; therefore, we diagnosed this tumor as a G-CSF-producing cancer. The patient died from rapid growth of the liver metastases and peritoneal dissemination 2 months after surgery.. This is the first case of G-CSF-producing rectal cancer, and its prognosis was very poor.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colectomy; Fatal Outcome; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Immunohistochemistry; Leucovorin; Liver Neoplasms; Male; Middle Aged; Organoplatinum Compounds; Peritoneal Neoplasms; Prognosis; Rectal Neoplasms

To detect the nuclear factor kappa B (NF-kappaB) condition in human stage IV gastric carcinoma patients and to explore the correlation between NF-kappaB activation and survival of these patients after chemotherapy.. Expression of NF-kappaB-p65 was determined by immunohistochemical analysis. Activity of NF-kappaB DNA-binding in carcinoma tissue was detected by electrophoretic mobility shift assay. Kaplan-Meier survival analysis was performed to show the relation between NF-kappaB and progression-free survival (PFS) or overall survival (OS) of the patients.. The positive expression rate of NF-kappaB-p65 in 60 gastric cancer tissue samples was 76.7% (46/60). The expression of NF-kappaB-p65 was reduced in adjacent carcinoma and normal tissue samples. Electrophoretic mobility shift assay (EMSA) analysis showed a strong activation of NF-kappaB in cancer tissue samples. A survival difference was found in NF-kappaB-p65 positive and negative patients. NF-kappaB-p65 expression was negative in cancer tissue samples (n=14). PFS was 191.40+/-59.88 d and 152.93+/-16.99 d, respectively, in patients with positive NF-kappaB-p65 expression (n=46) (P=0.4028). The survival time of patients with negative and positive NF-kappaB-p65 expression was 425.16+/-61.61 d and 418.85+/-42.98 d, respectively (P=0.7303). Kaplan-Meier analysis showed no significant difference in PFS or OS. The 46 patient tissue which positive NF-kappaB-p65 expression was found in the tissue samples from the 46 patients whose PFS and OS were 564.89+/-75.94 d and s 352.37+/-41.32 d, respectively (P=0.0165).. NF-kappaB is activated in gastric carcinoma tissue, which is related to the OS after chemotherapy.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma; Disease-Free Survival; Electrophoretic Mobility Shift Assay; Female; Fluorouracil; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Leucovorin; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Paclitaxel; Stomach Neoplasms; Time Factors; Transcription Factor RelA; Treatment Outcome

Patients with advanced head and neck (H/N) and esophageal squamous cell carcinoma (SCC) often have a poor performance status and a dire prognosis. Our aim was to evaluate the feasibility, activity and quality of life (QOL) of an outpatient chemotherapy regimen consisting of cisplatin, 5-fluorouracil and leucovorin (CFL).. Prospective phase II study conducted at a Brazilian public institution.. Fifteen patients with residual, recurrent or metastatic SCC of the H/N or esophagus received bolus infusions of leucovorin 20 mg/m(2)/day and 5-fluorouracil 370 mg/m(2)/day on days 1-4, and 90 minutes of infusion of cisplatin 25 mg/m(2)/day on days 1-3, every 21 to 28 days, depending on hematological recovery. We also evaluated QOL by applying the European Organization for Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC QLQ-C30) before each cycle.. The overall response rate was 36%, and the mean overall survival and progression-free survival were six and three months, respectively. We observed grade 3 or higher hematological toxicity in seven patients and one patient had grade 3 nausea and vomiting. One patient died because of neutropenic fever. Seven out of the 12 patients who could be evaluated regarding QOL presented an improvement in their overall health status and functional QOL scores over the course of the treatment.. CFL is an active outpatient protocol with tolerable toxicity and a favorable QOL impact. Larger studies are warranted, in order to confirm these results.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cisplatin; Cost-Benefit Analysis; Epidemiologic Methods; Esophageal Neoplasms; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Outpatients; Quality of Life; Young Adult

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

The radical removal of mesopharyngeal tumors necessitates very extensive, aggressive surgery. In certain cases, therefore, they strive to ensure the quality of life of these patients by means of two other possibilities in the complex treatment: chemotherapy and irradiation; in this way, over radicality can be avoided.. One of the elements of the complex therapy may be intraarterial chemotherapy. The present work relates to a study of the effects and side-effects of primary intraarterial chemotherapy administrated in the period 1995-2000, and the overall survival of the patients.. Remission was attained in a total of 30 patients who participated in primary intraarterial chemotherapy. The degree of severity of any complications that occurred was studied, as was the duration of survival. Treatment was performed by retrograde cannulation of the external carotid artery and the administration of a relatively low dose of drug for a relatively long time (5-14 days). The intra-arterial chemotherapy was supplemented with other modes of treatment.. A clinically observable degree of tumor regression was detected in 83.3% of the cases after the intraarterial treatment. The 5-year survival rate was approximately 30%.. The overall survival rate for oropharyngeal carcinoma patients treated with combined procedures is reported to range between 32% and 83%. Since our patients (with 2 exceptions) were in stage III or IV, and in many cases were inoperable, our 5-year survival rate of approximately 30% may be stated to be acceptable, while the quality of life of the patients was much more favourable than following the primary radical operation.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Disease Progression; Epirubicin; Female; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Methotrexate; Middle Aged; Pharyngeal Neoplasms; Retrospective Studies; Survival Analysis; Treatment Outcome; Vincristine

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

Topics: Antimetabolites, Antineoplastic; Carcinoma; Colectomy; Colorectal Neoplasms; Disease-Free Survival; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Time Factors

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Carcinoma; Case-Control Studies; Cisplatin; Combined Modality Therapy; Disease Progression; DNA, Viral; Fluorouracil; Genotype; Herpesvirus 4, Human; Humans; Infusions, Intravenous; Leucovorin; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Polymerase Chain Reaction; Sensitivity and Specificity; Survival Analysis

Introducing irinotecan and oxaliplatin in to the treatment of advanced colorectal cancer substantially improved the therapeutic results for this malignancy. The first results of clinical trials with these two drugs were published in 2000.. Between 1999 to 2004 we treated 51 patients with the combination of irinotecan 180mg/m2 on day 1 and two hour infusion of leucovorin 200mg/m2 and 5-FU push of 400mg/m2 followed by infusion of 5- FU for 22 hours on days 1 and 2 every 2 weeks. Six patients (11.7%) achieved complete response, 11 (21.57%) partial response, stabilisation was observed by 23 patients (45.1%) and 21 patients were progressive (21.5%). The median survival time was 18 months (95% CI, 16.93-19.7), median duration of response was 9 months (Cl 95% 8.25-11.5).. The combination of FOLFIRI is an effective and tolerable treatment of advanced colorectal cancer. However new treatment modalities to improve further the results of the treatment are still warranted.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged

Topics: Administration, Oral; Anticonvulsants; Antimetabolites, Antineoplastic; Carcinoma; Drug Interactions; Epilepsy; Humans; Leucovorin; Male; Middle Aged; Phenytoin; Rectal Neoplasms; Tegafur

Although 5-fluorouracil (5-FU)-related cardiotoxicity is well known, atrial arrhythmia, as a potentially serious complication has not been studied in detail. The aim of this study was to determine the P max and Pd in the electrocardiograms (ECG) of patients receiving 5-FU treatment.. Twenty-five patients (mean age: 62 years) receiving a 5-FU bolus plus continuous infusion with calcium leucovorin over 48 h and with normal pre-treatment cardiac physical examinations, ECG and echocardiography were enrolled. P maximum (P max), P minimum (P min) and P dispersion (Pd) (maximum minus minimum P wave duration) were measured from the 12-lead ECG at the 0th and 48th hour of the first chemotherapy cycle. Echocardiography was also obtained in all patients at the same times.. Clinical cardiotoxicity was observed in two patients. P max and Pd were both significantly longer after 5-FU treatment at the 48th hour (P < 0.001). P min did not change (P > 0.05).. Treatment with 5-FU based regimens may increase Pd and prolong the P max in cancer patients. These alterations may be predictive of patients at risk of atrial arrhythmias during 5-FU treatment.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Carcinoma; Colorectal Neoplasms; Coronary Artery Disease; Coronary Vasospasm; Coronary Vessels; Dose-Response Relationship, Drug; Drug Administration Schedule; Echocardiography; Electrocardiography; Female; Fluorouracil; Humans; Infusions, Intravenous; Injections, Intravenous; Leucovorin; Male; Stomach Neoplasms; Time Factors

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

In nasopharyngeal carcinoma, both, a short metastasis-free interval after primary treatment and the occurrence of epidural metastasis have been associated with poor prognosis. We present the clinical course of a young patient with these two conditions and review the literature.. A 26-year-old male with stage T2N3M0 non-keratinizing carcinoma (WHO type 2) of the nasopharynx was treated with induction chemotherapy and radical radiotherapy, 6 months after documentation of a clinical complete remission, the patient experienced metastatic disease to the C7-D1 vertebral bodies associated with an epidural soft tissue mass. Since no further metastatic lesions were detectable, the patient was treated with radiotherapy alone (3 960 cGy/22 fractions).. Treatment resulted in compete resolution of neurological and radiological signs of the disease and the patient continues to be disease-free, 32 months after salvage treatment. In a literature search, we identified 54 reported cases with long-term survival after treatment for metastatic nasopharyngeal cancer. The vast majority of them had primary tumors with undifferentiated histology and was treated with combination chemotherapy. In 25 of them, radiotherapy was given as consolidation therapy (in 19 cases for bone and in six cases for mediastinal lymph node metastases).. Epidural metastatic disease from a nasopharyngeal carcinoma is highly sensitive to moderate doses of fractionated radiotherapy. MR imaging is essential for the detection of relevant soft tissue disease extensions within the epidural space and proper selection of the radiation target volume in vertebral metastases. In patients with nasopharyngeal carcinoma, the occurrence of a solitary epidural metastasis after a short metastasis-free interval is not incompatible with long-term survival.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma; Cervical Vertebrae; Cisplatin; Combined Modality Therapy; Dose Fractionation, Radiation; Epidural Neoplasms; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Nasopharyngeal Neoplasms; Prognosis; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Thoracic Vertebrae; Time Factors

Distant metastasis rather than locoregional recurrence is the major site of failure after adequate radiotherapy in nasopharyngeal carcinoma (NPC). The aim of this study is to evaluate the toxicity and survival of outpatient weekly 24-hour infusion adjuvant chemotherapy for NPC patients with high-risk of distant failure.. Our definition of high-risk NPC included patients with (1) 1992 AJCC staging system of N3, T4N2, or N2 with one of nodal size > 4 cm; (2) supraclavicular node metastasis; and (3) residual disease after radiotherapy or neck relapse. From August 1994 to August 1997, 41 NPC patients matching the preceding criteria agreed to receive weekly PFL (cisplatin 25 mg/m(2), 5-fluorouracil 1250 mg/m(2), and leucovorin 120 mg/m(2)) adjuvant chemotherapy for a total of 18 weeks. Clinical data of another 88 patients with similar disease status who did not receive adjuvant chemotherapy during the same period were collected and analyzed for comparison. Survival analysis was investigated by the Kaplan-Meier method and the Cox proportional hazards model.. A total of 700 weekly chemotherapy doses was delivered to 41 patients. The ratio of actual/planned dose delivery was 94.9%. Grade 3-4 toxicity of adjuvant chemotherapy included leucopenia (7.3%), anemia (2.4%), thrombocytopenia (2.4%), and nausea/vomiting (2.4%). After a median follow-up of 70 months, 26.8% (11 of 41) and 47.7% (42 of 88) of patients in PFL and no adjuvant chemotherapy groups had distant metastasis (p =.0247). The 5-year metastasis-free survival rates were 71.9% for the PFL group compared with 48.4% for no adjuvant chemotherapy patients (p =.0187). The 5-year overall survival rates were 53.7% (PFL group) and 38.3% (no adjuvant chemotherapy group), respectively (p =.0666). Multivariate Cox analysis showed PFL adjuvant chemotherapy was the independent factor that predicted metastasis-free survival after adjustment for other variables.. Outpatient weekly 24-hour continuous infusion PFL adjuvant chemotherapy is a well-tolerated regimen with promising results in high-risk NPC patients and merits investigation in phase III studies.

Topics: Adolescent; Adult; Aged; Ambulatory Care; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Cisplatin; Disease-Free Survival; Drug Administration Schedule; Female; Fluorouracil; Humans; Leucovorin; Lymphatic Metastasis; Male; Middle Aged; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Neoplasm, Residual; Patient Compliance; Proportional Hazards Models; Risk Factors; Survival Analysis; Taiwan

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

Afferent loop syndrome (ALS) is a debilitating complication of recurrent gastric cancer. Surgical intervention is usually not feasible in the face of poor general performance, presence of advanced peritoneal carcinomatosis and limited survival of the patients. Non-surgical approaches include internal drainage by stenting at the stenotic or anastomotic site and external drainage via the percutaneous routes. Percutaneous transhepatic duodenal drainage (PTDD) has been shown to provide effective palliation for ALS, but long-term catheterization is usually inevitable. We hereby present two cases of recurrent gastric cancer whose ALS was successfully treated with PTDD followed by weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin (HDFL). PTDD rapidly ameliorated the incapacitating symptoms of ALS, and the effective, low-toxicity chemotherapy subsequently led to tumor regression, restoration of bowel patency and removal of the drainage tube. At present, both patients have remained ALS-free and drainage-free for 16 and 17 months, respectively. Our results indicate that this non-surgical approach with PTDD followed by weekly HDFL could serve as a safe and effective treatment for ALS in recurrent gastric cancer complicated by peritoneal carcinomatosis.

Topics: Adenocarcinoma; Afferent Loop Syndrome; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Combined Modality Therapy; Dose-Response Relationship, Drug; Drainage; Fluorouracil; Follow-Up Studies; Gastrectomy; Humans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Recurrence, Local; Palliative Care; Peritoneal Diseases; Peritoneal Neoplasms; Stomach Neoplasms; Treatment Outcome

Liver cryosurgery is one of the treatment options for unresectable liver metastases. Indications for the use of this treatment instead of classic surgery are bilobar disease, location of the tumor at an irresectable anatomic site, and comorbid conditions of the patient. Possible complications of cryosurgery are hemorrhage, coagulopathy, pneumonia, pleural effusion, abdominal abscess, and bile fistula. We describe a patient in whom a hepatobronchial fistula developed after cryosurgery. The patient had cryosurgery because of an unresectable liver metastasis in a Dukes' C rectal carcinoma. More details are given in the case report. To our knowledge, a hepatobronchial fistula as a complication of cryosurgery has never been reported. It therefore should be added to the list of possible cryosurgery complications.

Topics: Antimetabolites, Antineoplastic; Bronchial Fistula; Carcinoma; Cryosurgery; Fistula; Fluorouracil; Humans; Leucovorin; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Postoperative Complications; Rectal Neoplasms; Ultrasonography

Locoregional chemotherapy is one of the possible ways of treatment of inoperable metastatic affection of the liver by colorectal carcinoma. The advantage of regional administration of the cytostatic is the possibility to achieve a higher local concentration of the cytostatic associated with a higher percentage of therapeutic responses. In our department we preferred combined locoregional intraarterial chemotherapy (5-fluorouracil/Mitmycin C/Doxorubicin) combined with systemic intravenous chemotherapy (5-fluorouracil/leukovirin). Locoregional cghemotherapy was administered in the majority as chemotherapy of series 2 or 3 with a very good tolerance. In 2/19 patients we observed marked diminution of liver metastases and subsequent operability and with a duration of complete response for 13 and 18 months. In 7/19 patients a partial therapeutic response was achieved. The total therapeutic response (complete and partial) was 47%. Locoregional chemotherapy attains a higher therapeutic response as compared with systemic chemotherapy and is associated with an acceptable toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Doxorubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Liver Neoplasms; Male; Middle Aged; Mitomycin; Retrospective Studies

A left radical mastectomy was performed on a 53-year-old woman, diagnosed with left inflammatory breast cancer, after local arterial chemotherapy with cyclophosphamide (CPA), doxorubicin and 5-fluorouracil (5-FU). Adjuvant therapy was added with irradiation and ECF. Four months after the operation, a red eruption was detected on the left upper chest wall. The lesion was diagnosed by skin biopsy as a recurrent breast cancer with carcinoma erysipeloides. Tumor marker levels suggested the recurrent cancer was ECF resistant, so we changed the chemotherapy regime to a single dose of TXT. Although tumor marker levels and the skin eruptions improved at the beginning of the therapy, pleuritis carcinomatosa was found. We changed the regime again to a continuous dose of 5'-DFUR and LV for day 1 to 7. With this regime the clinical symptoms improved, and 2 courses of this modified FL therapy were carried out. After the therapy, the tumor seemed resistant to this modified FL therapy. Therefore, we tried a sequential therapy with TXT and the modified FL, which induced an improvement in clinical symptoms. Two years later, the patient died from the breast cancer. Therefore, we conclude that the sequential therapy may be beneficial in managing untreatable carcinoma erysipeloides of recurrent breast cancer.

Topics: Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Cyclophosphamide; Docetaxel; Doxorubicin; Drug Administration Schedule; Female; Floxuridine; Fluorouracil; Humans; Injections, Intra-Arterial; Leucovorin; Mastectomy; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Skin Neoplasms; Taxoids

We report the results of a chemotherapy regimen combining oxaliplatin, 5-fluorouracil, and folinic acid in patients with metastatic renal cell carcinoma. The objective of this pilot study was to define the potential efficacy of this second-line combination in patients previously treated with interleukin-2 alone or in combination with interferon alpha. Fourteen patients with metastatic renal cell carcinoma in failure after immunotherapy were included in this trial. During treatment, patients received six chemotherapy courses (Folfox regimen) administered every 2 weeks. Each cycle combined oxaliplatin day (D) D1 and folinic acid plus 5-fluorouracil D1 and D2. At completion of treatment, no objective response was observed and two patients presented stable disease. This chemotherapy schedule in patients with metastatic renal cell carcinoma previously treated with immunotherapy does not seem to be effective.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Female; Fluorouracil; Humans; Immunotherapy; Interferon-alpha; Interleukin-2; Kidney Neoplasms; Leucovorin; Male; Middle Aged; Organoplatinum Compounds; Pilot Projects; Prognosis

Lymphoepithelioma-like carcinoma (LELC) of the lung, an Epstein-Barr virus-associated undifferentiated carcinoma, is a rare entity of pulmonary malignancy. It tends to affect young non-smoking Asians and is often resectable. However, little is known of the treatment of the even rarer locally advanced or metastatic cases. We report our experience of three Chinese patients with advanced LELC of the lung who were treated with combination-chemotherapy (5-fluorouracil, leucovorin, and cisplatin) and radiotherapy. The encouraging response of these patients supports the use of this regime in other patients.

Topics: Adult; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Prospective Studies; Tomography, X-Ray Computed; Treatment Outcome

Topics: Administration, Oral; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Clinical Trials as Topic; Colorectal Neoplasms; Drug Administration Schedule; Humans; Infusions, Intravenous; Leucovorin; Prodrugs; Prospective Studies; Tegafur; Treatment Outcome; Uracil

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Chemotherapy, Adjuvant; Child; Colorectal Neoplasms; Female; Fluorouracil; Humans; Interferon alpha-2; Interferon-alpha; Leucovorin; Male; Neoplasm Staging; Radiotherapy, Adjuvant; Recombinant Proteins; Survival Analysis; Treatment Outcome

Although many factors have been investigated in connection with the prognoses of colorectal carcinoma patients with metastases to the liver, a means for evaluating response and prognosis prior to the administration of standard chemotherapy has not been available. Positron emission tomography (PET) is a noninvasive means of measuring the distribution of radiolabeled cytostatic agents in tumor regions.. Prior to the administration of 5-fluorouracil chemotherapy, the authors examined 14 colorectal carcinoma patients with unresectable liver metastases using a single PET scan and 18F-labeled fluorouracil (18F-FU). Clinical response and survival time were correlated with 18F-FU uptake values (SUV) measured in liver metastases 120 minutes after tracer infusion.. Trapping of 18F-FU varied even among different metastases in the same patient. The range of SUV was 0.9-4.3 (mean, 2.20). Four patients with SUV exceeding 2.8 had stable disease for longer than 12 months and survived longer than 21 months. Three patients with SUV less than 1.2 had progressive disease and survived less than 12 months. The 6 patients with partial remission or stable disease had a mean SUV of 2.96 and a mean survival of 31.6 months. Eight patients with progressive disease had a mean SUV of 1.59 and a mean survival of 14.5 months (Student's t-test, P < 0.012). In scatterplot analysis, there was a statistically significant correlation between SUV and survival time.. Patients with high 18F-FU uptake values are more likely to achieve at least stabilization of disease with planned chemotherapy. 18F-FU PET may be a valuable new tool for determining, prior to 5-FU-based chemotherapy, which patients are likely to have good responses and prolonged survival.

Topics: Aged; Antidotes; Antimetabolites, Antineoplastic; Carcinoma; Colorectal Neoplasms; Drug Interactions; Female; Fluorodeoxyglucose F18; Fluorouracil; Humans; Leucovorin; Liver; Liver Neoplasms; Male; Middle Aged; Prognosis; Radiopharmaceuticals; Tomography, Emission-Computed

In spite of the high prevalence of cancer in the elderly, little information is available about the efficacy and toxicity of chemotherapy in elderly patients. In a previous study, the authors demonstrated that the combination of uracil and tegafur (UFT) with leucovorin (LV) was active and well tolerated in patients with advanced colorectal carcinoma (ACC). The objective of the current study was to determine the efficacy and toxicity of this regimen in elderly patients with ACC.. Thirty-eight unselected patients older than 70 years (median age, 74 years) with measurable ACC were included. All patients were evaluable for toxicity and response. The regimen consisted of intravenous LV 500 mg/m2 on Day 1, oral LV 15 mg every 12 hours on Days 2-14, and oral UFT 390 mg/m2 on Days 1-14. Treatment was repeated every 28 days for a minimum of 4 courses per patient.. Two hundred eighty-eight cycles of chemotherapy were delivered (median, 7 per patient). Two patients (5%) achieved a complete response and 9 (24%) a partial response, for an overall response rate of 29%. Toxicity was mild, without dose-limiting myelosuppression. Four patients (10%) experienced Grade 3-4 diarrhea, 1 patient had Grade 3-4 nausea/vomiting, and 1 had Grade 3-4 mucositis. Grade 3-4 toxicity was more frequent among women than men (38% vs. 4%, P < 0.05).. Treatment with oral UFT modulated with LV is effective, well tolerated, and feasible on an outpatient basis for elderly patients with ACC. However, elderly women should be followed closely for the early detection of toxicity.

Topics: Administration, Oral; Aged; Aged, 80 and over; Ambulatory Care; Antidotes; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carcinoma; Clinical Protocols; Colonic Neoplasms; Diarrhea; Feasibility Studies; Female; Humans; Injections, Intravenous; Leucovorin; Male; Nausea; Rectal Neoplasms; Remission Induction; Sex Factors; Tegafur; Uracil; Vomiting

To conduct a serial evaluation of the cardiac effects of antineoplastic therapy with 5-fluorouracil (5-FU) and low-dose folinic acid.. Sixteen patients with colon-rectal carcinoma, without cardiac disease, treated with 400 mg/ m2/die of 5-FU and 20 mg/m2/die of folinic acid for five days, once a month, for six months. Parameters evaluated: blood pressure, ECG, two-dimensional and digitized M-mode echocardiograms before and after the first and fifth drug administrations of the first cycle, after the fifth drug administration of the sixth cycle and six months after the treatment.. Blood pressure, heart rate, left ventricular (LV) diameter and LV mass index did not change; all of the patients showed a decrease in the peak shortening rate of the LV diameter index of systolic function, and of the peak lengthening rate of the LV diameter and peak thinning rate of LV posterior wall, indexes of diastolic function, with abnormal values in 11 patients at the end of treatment LV wall motion remained normal in all; two patients developed transient T wave inversion without chest pain and with normal cardiac enzymes and myocardial scintigraphy during dypiridamole stress test. Six months after the treatment all indexes of LV systolic and diastolic function had returned within the normal limits and were similar to pre-treatment values.. 5-FU and low-dose folinic acid treatment induced a decrease of LV systolic function and an impairment of diastolic function, that developed without symptoms and were transient and reversible.

Topics: Adult; Aged; Antidotes; Antineoplastic Agents; Carcinoma; Colorectal Neoplasms; Fluorouracil; Follow-Up Studies; Heart; Humans; Leucovorin; Male; Middle Aged

The optimal schedule for the administration of 5-fluorouracil (5-FU) in the management of advanced colorectal cancer remains to be determined. It has been suggested that this drug may be given by the subcutaneous route and that following a short infusion the bioavailability is similar to that observed after intravenous administration. We report the results we obtained in a patient treated with an intravenous bolus of 5-FU followed by a 22-h subcutaneous infusion. In this patient the bioavailability of 5-FU given by subcutaneous infusion was 0.94. The steady-state plasma levels of 5-FU reached during subcutaneous infusion were comparable with those achieved during intravenous infusion. Following four cycles of subcutaneous therapy, painless blistering was noted at the infusion sites, which healed following the cessation of subcutaneous therapy. Further studies are required to evaluate this route of therapy as an alternative to protracted intravenous therapy. The main dose-limiting side effect appears to the local skin toxicity.

Topics: Antidotes; Antimetabolites, Antineoplastic; Biological Availability; Carcinoma; Colorectal Neoplasms; Fluorouracil; Humans; Injections, Intravenous; Injections, Subcutaneous; Leucovorin; Liver Neoplasms; Male; Middle Aged; Peritoneal Neoplasms; Skin

1843U89 is a potent inhibitor (Ki = 0.09 nM) of thymidylate synthase (TS; EC 2.1.1.45) that is in clinical trial for the treatment of solid tumors. Although it is an excellent substrate for the folate anabolizing enzyme folylpolyglutamate synthetase (FPGS), 1843U89 differs from other folate-based inhibitors of TS (e.g., CBC3717, D1694, and LY231514), in that the parent compound is as potent an enzyme inhibitor as its polyglutamated analogues. As reported (D.S. Duch et at., Cancer Res., 53:810-818, 1993), 1843U89 is 10-80-fold more cytotoxic than the close structural analogue 1031U89, which is an equipotent inhibitor of TS but is a less efficient substrate for FPGS. This correlation between substrate efficiency for FPGS and cytotoxicity suggests that polyglutamation of 1843U89 contributes to its cytotoxicity. In the current study, we measured intracellular levels of polyglutamated anabolites of 1031U89, 1843U89, and three other benzoquinazoline inhibitors of TS as well as anabolites of D1694 in HCT-8 ileocecal carcinoma cells. Each TS inhibitor was anabolized to polyglutamated analogues with one to five added glutamyl residues after exposure for 24 h to IC90 concentrations (those that inhibit growth by 90% after 72 h of constant exposure). D1694, which requires polyglutamation for potent enzyme inhibition as well as for cytotoxicity, was anabolized mostly to penta- and hexaglutamates, whereas approximately 80% of intracellular 1843U89 was the diglutamate analogue. The substrate efficiency of the benzoquinazolines for FPGS was predictive of the extent of intracellular anabolism. The diglutamate analogue of 1843U89 was only 1/100 as efficient a substrate for further glutamation as was 1843U89 itself. The efficient anabolism to the diglutamate analogue and the lack of dependence on further polyglutamation for enzyme inhibition or cytotoxicity provide a rationale for the reported 1843U89 sensitivity of cells with impaired FPGS activity. As part of an investigation of the effects of polyglutamation, we measured the retention of intracellular 1843U89 and D1694 anabolites after 24 h of exposure to 20 nM of each compound. After 48 h in drug-free medium, 7% of intracellular 1843U89 (mostly diglutamate analogue) and 36% of D1694 (mostly penta- and hexaglutamates) remained in the cells. Because prolonged retention (associated with tissue storage of polyglutamates) can contribute to clinical toxicities, 1843U89 may present fewer long-term toxicities than D1694.

Topics: Animals; Carcinoma; Enzyme Inhibitors; Folic Acid; Folic Acid Antagonists; Humans; Indoles; Intestinal Neoplasms; Isoindoles; Leucovorin; Liver; Metabolic Clearance Rate; Peptide Synthases; Polyglutamic Acid; Quinazolines; Swine; Thymidylate Synthase; Tumor Cells, Cultured

Chemotherapy for cervical cancer patients with recurrent and/or advanced disease has been complicated by excessive toxicity and short duration of responses, leading to little or no improvement in survival. Modification of drug scheduling and delivery of platinum, bleomycin, methotrexate, and 5-FU has resulted in a new combination regimen with little toxicity and a survival advantage for responders. PBM (platinum 80 mg/m2 D1, bleomycin 10 mu/m2/day D3-6, methotrexate 150 mg/m2 D15, 22 with leucovorin) is alternated with PFU (platinum 100 mg/m2 D1, 5-FU 1000 mg/m2/day D2-5) q 4 weeks for 3-6 months. The platinum, bleomycin, and 5-FU were delivered by continuous infusion. Twenty-three patients with recurrent and 17 with advanced cervical cancer are evaluable; 91% of patients with recurrent disease had received prior radiation therapy. The response rate was 30.4% in those with recurrent disease, and 41.2% in those with advanced disease, with 86 and 42.9% of responders respectively achieving a CR. Survival data were analyzed for each group separately, as well as for the combined recurrent/advanced disease group (N = 40). The results and significance were not changed by the groupings. In the combined recurrent/advanced group, median duration of response was 10.5 months, mean 20.1, and the median overall survival was 11 months, mean 20.5 +/- 3.5. There was a survival advantage accrued to the responders (median, 28 months) vs the nonresponders (10 months) (P = 0.0005 by log rank test). Moreover, there was a significant difference in progression-free interval between responders vs nonresponders (P = 0.0001), as well as between responders and those with stable disease (P = 0.001). This regimen was very well tolerated and there was no significant pulmonary toxicity. Furthermore, in the subset of 23 patients who had recurrent disease, 67% achieved palliation of pain. Experience with this protocol supports the continuing use of chemotherapy in the management of cervical cancer patients.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma; Cisplatin; Female; Fluorouracil; Humans; Leucovorin; Methotrexate; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome; Uterine Cervical Neoplasms

The cytotoxicity and molecular effects of antifolate thymidylate synthase inhibitor, ICI-D1694, against human ileocecal carcinoma, were evaluated. The drug concentration for 50% inhibition of cell growth by ICI-D1694 is 73 nM and 3 nM following 2 hr and 72 hr exposure, respectively. The drug induces high level of DNA single strand breaks in a time dependent manner, but subsequent to maximum inhibition of thymidylate synthase. Drug effects can be reversed by thymidine and leucovorin at > 1 microM concentrations. Leucovorin action is primarily at the cell membrane level, competing with the transport and activation of ICI-D1694. Thymidine, however, exerts its competitive effect primarily at the level of thymidylate synthase.

Topics: Antimetabolites, Antineoplastic; Carcinoma; Dose-Response Relationship, Drug; Drug Interactions; Evaluation Studies as Topic; Humans; Intestinal Neoplasms; Leucovorin; Quinazolines; Thiophenes; Thymidine; Thymidylate Synthase; Tumor Cells, Cultured

The response of liver metastases to chemotherapy relies mainly on quantitative US and CT investigations, the two techniques being indifferently used. The morphologic changes of metastatic lesions during treatment have received little attention and their significance is still questionable. Based on the review of 53 US and 41 CT examinations of 15 patients treated with hepatic arterial chemotherapy for colorectal liver metastasis, our study was aimed at assessing: 1) the relationship between US and CT measurements of metastasis response to chemotherapy and 2) changes in the US and CT patterns of liver metastases during treatment and the existence of specific patterns of favorable response to chemotherapy or of disease progression. We concluded that: 1) as to quantitative response to chemotherapy, US and CT, performed on 13 patients within 1 month, were in agreement in all but 1 case, 2) US and CT patterns of treated liver metastases were different in case of favorable response and of disease progression; lesion outline, homogeneity and calcifications are useful diagnostic criteria to this purpose, 3) liver perfusion abnormalities may occur at various times during and after chemotherapy; these ischemic lesions must be differentiated from new metastases.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Floxuridine; Fluorouracil; Follow-Up Studies; Humans; Infusions, Intra-Arterial; Italy; Leucovorin; Liver; Liver Neoplasms; Remission Induction; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography

Phase II studies involving novel chemotherapy treatment are often first reported to the scientific community as a published abstract. This study was designed to determine how authors report their phase II abstract data and what types of conclusions are made. All 1992 phase II colorectal cancer abstracts from the 1992 Proceedings of the American Society of Clinical Oncology were reviewed and analyzed for descriptive and quantitative data and conclusions. The response rate was the most commonly reported response statistic (28/29), with few studies reporting confidence intervals (4/29), median duration of response (5/29), or median survival (9/29). Toxicity data was quantitative in 21 trials and qualitative or absent in 8 trials. Conclusions about the toxicity data were ambiguous or absent in five trials. Conclusions about the response data included inappropriate use of terms, indirect or ambiguous language, or no conclusion. These results indicate that the reporting of phase II trials in abstract form is highly variable and plagued by problems that make data interpretation difficult. Recommendations for change are suggested.

Topics: Abstracting and Indexing; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Clinical Protocols; Clinical Trials, Phase II as Topic; Colonic Neoplasms; Communication; Fluorouracil; Humans; Interferons; Leucovorin; Rectal Neoplasms; Remission Induction; Research; Research Design

A group of 60 patients with advanced head/neck cancer were treated with high-dose folinic acid (500 mg/m-2/week-1) plus 5-fluorouracil (400 mg/m-2/week-1 on day 1, and cisplatin (20 mg/m-2/week-1) 24 h after folinic acid infusion was completed. Out of 55 evaluable patients, 10 patients (18%) experienced a complete response with a mean duration of 11.4+ months, 25 patients had a partial response (45%) of 6.7+ months, 6 patients (11%) showed a stabilization of 4.8+ months, and 14 (25%) progressed. The overall response rate was 63.6% (95% confidence limits 56.5%-69.5%). Patients pretreated with radiotherapy had a 67% overall response rate, while those pretreated with chemotherapy showed a 54% overall response rate. All patients with cancer of the oropharynx had a major response, while patients with cancer of the oral cavity had the lowest response rate. The mean survival of patients who attained a complete response was 14.5+ months. Partial responders had a mean survival of 10.6+ months, while patients who progresses survived a mean of 3.6+ months. The treatment has been very well tolerated with few cases of grade 3 gastrointestinal toxicity. Grade 1-2 leukopenia was recorded in 64% of cases, grade 1-2 nausea/vomiting in 85%. In one case therapy was stopped because of persistent diarrhoea.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Carcinoma, Squamous Cell; Cisplatin; Cystadenocarcinoma; Drug Administration Schedule; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Leucovorin; Male; Middle Aged; Neoplasm Metastasis

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Colorectal Neoplasms; Fluorouracil; Humans; Leucovorin; Methotrexate; Prognosis

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Clinical Trials as Topic; Colonic Neoplasms; Combined Modality Therapy; Drug Synergism; Fluorouracil; Humans; Interferon-gamma; Leucovorin; Levamisole; Somatostatin

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (5-FU) by stabilizing the 5-fluoro-2'-deoxyuridine-5'-monophosphate-thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay, we tested the effects of 5-FU and 5-fluoro-2'-deoxyuridine (FdUrd) with and without leucovorin (LV) on a panel of 11 human colorectal carcinoma cell lines. The effect of LV on 5-FU and FdUrd was quantitatively similar. A clinically achievable level of LV (20 microM) increased the cytotoxicity in all three replicate experiments in 10 of the 11 cell lines (P less than .05, binomial test). LV alone at a concentration of 20 microM had no effect on cell survival. In three cell lines, 50% inhibition of growth occurred at a clinically achievable area under the curve of 5-FU alone. With the addition of LV, one additional cell line showed 50% growth inhibition at a clinically achievable level of 5-FU. Hence large clinical trials may be necessary to detect a significant improvement in survival as a result of adding LV to the fluorinated pyrimidines.

Topics: Carcinoma; Cell Survival; Colorectal Neoplasms; Drug Synergism; Floxuridine; Fluorouracil; Humans; Leucovorin; Tumor Cells, Cultured

In this study (GI 6384), regimens are compared which, in phase II investigations, produced 2-fold increases in the historical rates of objective and minor responses. These regimens were associated with overall survival exceeding 1 year. In arm 1, 5-fluorouracil (FUra) alone, 500 mg/m2 on days 1 through 5 was escalated in 25-mg/m2 increments in monthly courses to produce mild to moderate toxicity. This allows an examination of dose-response relationships and comparisons of therapeutic index. In arm 2, leucovorin (LV), was escalated from 25 to 250 to 500 mg/m2 beginning 1 hour before a bolus FUra (30 mg/kg) every 3 weeks. Arm 3 (not previously tested) employed LV (25 mg/m2) 1 hour before FUra (600 mg/m2) given weekly for 6 weeks. It tested the efficacy of low-dose LV. Arm 4 tested high-dose LV (500 mg/m2) as a 2-hour infusion beginning 1 hour before a bolus FUra (600 mg/m2) weekly for 6 weeks. In a preliminary analysis of this study, findings are statistically consistent with the anticipated high frequencies of objective response. It also finds evidence of biological activity across the wide range of LV dosages and that LV produces an apparent favorable change in FUra side effects from hematological to gastrointestinal toxicities. One or more regimens may favorably change the anticipated prognosis of patients with measurable cancer of the colon and rectum.

Topics: Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluorouracil; Gastrointestinal Neoplasms; Humans; Leucovorin

Twenty-five patients with advanced measurable gastric carcinoma were treated with D,L-leucovorin (CF) (500 mg/m2) administered as a 2-hour infusion and FUra (600 mg/m2) iv push midinfusion. Patients were treated weekly for 6 weeks followed by a 2-week rest. Median age was 57 (range 32 to 82). Median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0 to 4). Thirteen patients had progressed on previous combination chemotherapy that included FUra. At the time of this report, 19 patients were evaluable for response: 3 patients had partial responses, 8 had stable disease, and 8 progressed (but 3 of these received only 3 or fewer treatments before early disease-related death). Two of the responders were previously treated with FUra. Four patients were too early to evaluate. Measurable responses of greater than 50% were seen in bone, liver, lung, and an abdominal mass. Diarrhea occurred in 9 patients and FUra dose reduction was necessary in 8 of them. Other toxicities included lacrimation, rash, nausea, and mucositis. One toxic death occurred. Nine patients with gastrointestinal tumors confined primarily to the intra-abdominal space were treated with ip FUra in escalating doses (2 mM to 4 mM) in combination with D,L-CF in a 2-liter volume, either by 8 consecutive 4-hour dwells (7 patients) or once daily for 5 days (2 patients). The D,L-CF dose was 20.8 microM except for the first day of the 5-day schedule when it was 104 microM. Toxicity included leukopenia, mucositis, nausea and vomiting, skin rash, and abdominal pain. Three episodes of peritonitis resolved with antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Dose-Response Relationship, Drug; Drug Evaluation; Fluorouracil; Humans; Injections, Intraperitoneal; Leucovorin; Middle Aged; Stomach Neoplasms

The purpose of this study was to compare the pools of free FdUMP derived from 5-fluorouracil (FUra) and of dUMP synthesized de novo in Hep-2 and S-180 cells, their relationship to inhibition of thymidylate synthase (dTMP synthase; EC 2.1.1.45), and the effect of excess folinic acid (CF) on these parameters. These cells differ 50-fold in their sensitivity to FUra and, in the absence of thymidine, dTMP synthase is the growth-limiting site of action of FUra in S-180 cells, but in Hep-2 cells this site becomes growth-limiting only in the presence of excess folates. In both cells after a 3-hr incubation with varied concentrations of FUra, FdUMP comprised only 0.1-0.2% of the total acid-soluble pools derived from FUra. The changes in dUMP and FdUMP pools paralleled each other, dUMP being 1000-2000 times higher than FdUMP. The pools of dUMP increased only when dTMP synthase was significantly inhibited. This occurred in S-180 cells above 3 microM FUra and in Hep-2 cells above 30 microM, where the residual dTMP synthase was similar in both cells. Under these conditions, the dUMP and FdUMP pools in Hep-2 cells were 2 and 4 times higher, respectively, than in S-180 cells. After FUra removal, both pools continued to increase, dUMP and FdUMP pools in Hep-2 cells rising 6-fold and 10-fold higher, respectively, than in S-180 cells. The dTMP synthase inhibition and the high nucleotide pools in Hep-2 were short-lived, whereas in S-180 cells the inhibition and the pools were maintained longer. Excess CF retarded the recovery of dTMP synthase after FUra removal only in Hep-2 cells and led to a further increase in dUMP and FdUMP pools in these cells, while having no effect in S-180 cells. These data indicate that a high capacity of cells to accumulate free FdUMP does not alone guarantee that dTMP synthase inhibition will be growth-limiting. The relationship shown here between excess CF, dTMP synthase recovery, and the nucleotide pools suggests that some cell types, such as Hep-2, in spite of high levels of FdUMP, require in addition an excess of folates to retard dTMP synthase recovery and make it growth-limiting.

Topics: Animals; Carcinoma; Cell Line; Deoxyuracil Nucleotides; Fluorodeoxyuridylate; Fluorouracil; Humans; Kinetics; Leucovorin; Methyltransferases; Sarcoma, Experimental; Thymidylate Synthase

Serum and cerebrospinal fluid (CSF) concentrations of citrovorum factor (CF) and 5-methyltetrahydrofolic acid (5-MTHFA) were measured after i.v. infusion of leucovorin (50 or 100 mg/sq m) in seven patients undergoing treatment for meningeal carcinomatosis by intra-Ommaya reservoir injection of methotrexate (MTX). Serum CF levels rapidly rose after leucovorin administration as did 5-MTHFA, its conversion product. A small amount of CF entered the CSF, but peak CSF 5-MTHFA increased about 10-fold. The concentration X time (C X t) of additional 5-MTHFA in the CSF was greater [114.4 +/- 36.1 (S.E.) microgram/ml X min] after 100-mg/sq m doses of leucovorin than after 50 mg/sq m [14.2 +/- 4.3 micrograms/ml X min] (p less than 0.05). The CSF MTX concentration exceeded CSF 5-MTHFA by 2 to 3 logs throughout the 48 hr of observation, while serum 5-MTHFA and CF exceeded serum MTX by 0.5 to 2 logs. This study demonstrates that leucovorin administered i.v. to patients receiving intra-Ommaya MTX does not increase CSF concentrations of "rescue" folate above those of CSF MTX and are unlikely to interfere with MTX action against meningeal tumor. On the other hand, i.v. leucovorin does permit serum "rescue" folate to operate, thus reducing the systemic toxicity that may follow intraventricular administration of MTX.

Topics: Aged; Carcinoma; Female; Humans; Injections, Intravenous; Injections, Intraventricular; Leucovorin; Male; Meningeal Neoplasms; Methotrexate; Middle Aged; Tetrahydrofolates; Time Factors

Forty breast cancer patients with meningeal carcinomatosis were treated with a combined program of whole brain irradiation therapy with intrathecal and intraventricular methotrexate and citrovorum factor rescue. Responses were seen in 26 patients (65%); 13 patients (35%) failed to respond. The median survival time for the responding patients was six months, and for the nonresponders, one month. Factors affecting response and survival included pretreatment spinal fluid glucose, protein, and duration of CNS-related symptomatology prior to onset of therapy. In contrast, pretreatment CSF tumor cell count, CEA and initial CNS functional status did not appear to have prognostic significance. The authors conclude that following intensive therapy there can be much improvement in the quality of life and disease-free survival in breast cancer patients with meningeal carcinomatosis.

Topics: Brain; Breast Neoplasms; Carcinoma; Female; Humans; Injections, Intraventricular; Injections, Spinal; Leucovorin; Meningeal Neoplasms; Methotrexate; Palliative Care; Prognosis; Quality of Life

Since 1973 75 patients with carcinoma of the oropharynx were treated with regional cytostatic chemotherapy as an initial step of a combined therapy which consists of an follow-up operation and/or radiation. Methotrexate was used in intraarterial short infusions with Leucovorin rescue. The tumor response to i.a. chemotherapy was definite in 80% of the cases, without any negative side effects in the patients who are usually in a reduced general condition. After i.a. chemotherapy to reach a partial remission of the tumor and to create better conditions for the following therapy, we always tried to perform an operation and radiation. With this combination-therapy we reached, in the 1 year NED results as well as in the 3 year survival rate, with 60% resp. 54% better results than in patients who were only radiated after i.a. chemotherapy (43% 1 year NED results resp. 43% 3 year survival rate). A chemotherapy of oropharynx carcinoma is only justified, if other therapy forms follow up, if possible, composed of an operation and radiation. Because of the high rate of response of tumors seen in our patients, the low rate of side effects and the noticeable remission of the tumor-caused complaints it seems to us that the i.a. infusion therapy with methotrexate is a suitable form of chemotherapy for carcinoma of the oropharynx.

Topics: Antineoplastic Agents; Carcinoma; Female; Humans; Injections, Intra-Arterial; Leucovorin; Male; Methotrexate; Oropharynx; Pharyngeal Neoplasms

Topics: Animals; Carcinoma; Cell Line; Deoxyribonucleosides; Deoxyribose; Deoxyuridine; Drug Synergism; Fluorouracil; Humans; Inosine; Leucovorin; Mice; Sarcoma, Experimental; Thymidine; Thymidylate Synthase

We reviewed 33 cases of meningeal carcinomatosis seen at the Mount Sinai Hospital, New York, from 1970 through 1979. The major sources of meningeal disease were carcinoma of the breast (21 cases), carcinoma of the lung (five), and malignant melanoma (five). Seventy-eight percent of the patients had widespread metastases at the time of neurologic diagnosis. A combination of radiotherapy and intrathecal administration of methotrexate was the most successful treatment, and 14 of 22 treated patients showed at least symptomatic improvement; however, mean survival in the most improved group was still less than six months.

Topics: Adrenal Cortex Hormones; Carcinoma; Female; Humans; Leucovorin; Meningeal Neoplasms; Methotrexate; Outcome and Process Assessment, Health Care; Radiotherapy; Time Factors

The ectopic production of the beta-subunit of human chorionic gonadotropin (hCG) is described in a patient with an anaplastic carcinoma. After chemotherapy the marker decreased in a logarithmic fashion to undetectable levels but the neoplasm progressed and the patient died. The specificity of the beta-subunit of hCG is discussed. Discordance of the marker and clinical disease is pointed out, and several possible explanations are outlined. The lack of specificity of the beta-subunit of hCG and the discordance that it may exhibit means that its use in diagnosing and following disease progression may be limited.

Topics: Adult; Carcinoma; Chorionic Gonadotropin; Female; Hormones, Ectopic; Humans; Leucovorin; Methotrexate

Topics: Antineoplastic Agents; Carcinoma; Chemotherapy, Cancer, Regional Perfusion; Fluorouracil; Head; Head and Neck Neoplasms; Humans; Leucovorin; Melanoma; Melphalan; Methotrexate; Mouth Neoplasms; Nasopharyngeal Neoplasms; Paranasal Sinus Neoplasms; Sarcoma; Thiotepa; Vinblastine

Topics: Adenocarcinoma; Blood Cell Count; Blood Chemical Analysis; Bone Marrow Examination; Carcinoma; Carcinoma, Papillary; Carcinoma, Squamous Cell; Drug Therapy; Facial Neoplasms; Hematopoiesis; Hemoglobinometry; Infusions, Intra-Arterial; Injections, Intra-Arterial; Injections, Intramuscular; Intestinal Neoplasms; Leucovorin; Methotrexate; Mouth Neoplasms; Myxosarcoma; Toxicology; Urine; Urogenital Neoplasms

Topics: Carcinoma; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Geriatrics; Head and Neck Neoplasms; Humans; Infusions, Parenteral; Laryngeal Neoplasms; Leucovorin; Maxillary Neoplasms; Methotrexate; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasms; Orbital Neoplasms; Palatal Neoplasms; Temporal Arteries; Tongue Neoplasms; Toxicology

Topics: Carcinoma; Female; Humans; Injections, Intramuscular; Leucovorin; Methotrexate; Uterine Cervical Neoplasms

Topics: Animals; Ascites; Carcinoma; Folic Acid; Folic Acid Antagonists; Leucovorin; Methotrexate; Neoplasms, Experimental

Topics: Carcinoma; Female; Folic Acid; Folic Acid Antagonists; Humans; Leucovorin; Methotrexate; Uterine Cervical Neoplasms

Topics: Carcinoma; Female; Folic Acid; Folic Acid Antagonists; Humans; Injections, Intramuscular; Leucovorin; Methotrexate; Uterine Cervical Neoplasms