BIWEEKLY INTENSIFIED AMBULATORY CHRONOMODULATED CHEMOTHERAPY WITH OXALIPLATIN, FLUOROURACIL, AND LEUCOVORIN IN PATIENTS WITH METASTATIC COLORECTAL-CANCER

Purpose: This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with max imum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic a cid [FA]) and at 4:00 PM for oxaliplatin (I-OHP). Patients and Methods : Fifty patients with metastatic coloretal cancer were enrolled in the trial. The first treatment course consisted of daily administration o f 5-FU (700 mg/m(2)/d), FA (300 mg/m(2)/d), and L-OHP (25 mg/m(2)/d) f or 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m(2)/d if toxicity was less than grade 2. Results: World Health Organization (WHO)-modified g rade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting, Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, resp ectively, as compared with our previous 5 days on-16 days off schedule , The overall objective response rate was 48% (95% confidence limits [ CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated pati ents and 69% (48% to 90%) in 13 chemotherapy-naive patients, A 5-FU DI >1,400 mg/m(2)/wk over four courses was associated with a near doubli ng of the response rate, Residual metastases were surgically removed i n 13 patients (26%). Median progression-free survival and survival dur ations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively. Conclusion: This highly effective fully a mbulatory outpatient regimen deserves further testing in randomised tr ials both in chemotherapy-naive patients and before surgery to remove metastases. (C) 1996 American Society of Clinical Oncology.