Adjuvant Oral Uracil-Tegafur with Leucovorin for Colorectal Cancer Liver Metastases: A Randomized Controlled Trial.

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

Safety analysis of FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies.

PURPOSE: Oxaliplatin-based therapy, notably FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin), is a standard regimen approved globally for the treatment of metastatic colorectal cancer, and as adjuvant treatment of colon cancer. As part of the Japanese submission for the adjuvant indication, the safety profile of FOLFOX4 regimen was compared in Asian and Western patients. PATIENTS AND METHODS: A total of 3359 patients with colorectal cancer treated with the FOLFOX4 regimen were included in the analyses: 1515 from 2 Asian studies (Japanese Post Marketing Surveillance and Multicenter Asia Study in Adjuvant Treatment of Colon Cancer with Oxaliplatin/5-FU/LV), and 1844 from 4 Western studies (EFC2962, N9741, EFC4584, and Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer). Doses administered and safety parameters were analyzed by using common definitions and programs. RESULTS: Demographic and baseline characteristics were comparable between Asian and Western patients. Patients received FOLFOX4 for a median of 6-12 cycles, which ranged from 16 to 28 weeks. Median dose intensities of oxaliplatin and of 5-fluorouracil, bolus and infusion, were within the ranges of 33 to 36 mg/m(2)/week, 297 to 338 mg/m(2)/week, and 467 to 510 mg/m(2)/week, respectively. Most frequently reported adverse events (AE) included hematologic, gastrointestinal, and neurosensory adverse events (NSAE). The incidence of grade ≥3 neutropenia ranged from 37% (422 of 1134) to 52% (83 of 159) in Asian and 41% (455 of 1108) to 56% (144 of 259) in Western studies; of diarrhea, ranged from 1.4% (3 of 222) to 6.3% (10 of 159) and 11% (30 of 268 or 120 of 1108) to 14% (36 of 259); of NSAEs, from 1.9% (21 of 1134) to 4.4% (7 of 159) and 9.3% (25 of 268) to 19% (39 of 209); and of allergic reactions, from 0.6% (7 of 1134) to 3.1% (5 of 159) and 1.1% (3 of 268) to 3.0% (33 of 1108), respectively. The probability of grade ≥3 NSAEs and diarrhea was statistically significantly lower in Asian than in Western studies by using a log-rank test. CONCLUSION: There was no evidence that Asian patients experienced worse toxicity than did Western patients when treated with FOLFOX4, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed.

How do we apply adjuvant FOLFOX to Japanese patients with curatively resected colorectal cancer?

AIM: In Japan the combination of fluorouracil (5-FU), leucovorin and oxaliplatin (FOLFOX) was approved as adjuvant therapy for stage III or high-risk stage II colon cancer only in September 2009. In this study we evaluated the safety and efficacy of FOLFOX as adjuvant chemotherapy for stage IIIb or IV colorectal cancer (CRC) patients in a Japanese group at a single institute. METHODS: A total of 45 consecutive patients received 12 cycles of adjuvant FOLFOX for stage IIIb (n = 31) or IV (n = 14) CRC. Toxicity and disease-free survival (DFS) were analyzed retrospectively. RESULTS: The median dose intensities of oxaliplatin and 5-FU were 0.7 and 0.74, respectively. Oxaliplatin was discontinued in 10 (22%) patients due to an allergic reaction in five, neurotoxicity in four and gastrointestinal toxicity in one. No severe neurotoxicity occurred. The median duration from completion of treatment until complete recovery from peripheral neuropathy was 582 days (95% CI, 486-678). Two-year DFS for stages IIIb and IV was 56.9% and 56.3%, respectively (log-rank, P = 0.533). Univariate analysis revealed that severe vessel invasion, liver metastasis and higher baseline levels of CA19-9 were associated with shorter DFS in stage IV patients. Multivariate analysis including the selected biomarkers revealed none as a significant prognostic factor. CONCLUSION: Adjuvant FOLFOX was well tolerated in a Japanese cohort of both stage IIIb and IV CRC patients.