Phase I II M ulticenter R andomized T rial o f O xaliplatin Added t o C hronomodulated F luorouracil-Leu covorin a s First-Line T reatment o f M etastatic C olorectal C ancer

Purpose: To study how adding oxaliplatin (l-OHP) to chronomodulated fluorouracil (5-FU)‐leucovorin (LV) affected the objective response rate, as first-line treatment of metastatic colorectal cancer. Patients and Methods: Two hundred patients from 15 institutions in four countries were randomly assigned to receive a 5-day course of chronomodulated 5-FU and LV (700 and 300 mg/m 2 /d, respectively; peak delivery rate at 0400 hours) with or without l-OHP on the first day of each course (125 mg/m 2 , as a 6-hour infusion). Each course was repeated every 21 days. Response was assessed by extramural review of computed tomography scans. Results: Grade 3 to 4 toxicity from 5-FU‐LV occurred in < 5% of the patients (< 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given l-OHP (10% of the courses), and less than 2% of the patients had severe hematotoxicity. Thirteen percent of the patients had moderate functional impairment from peripheral sensory neuropathy. Sixteen percent of the patients receiving 5-FU‐LV had an objective response (95% confidence interval [CI], 9% to 24%), compared with 53% of those receiving additional l-OHP (95% CI, 42% to 63%) (P < .001). The median progression-free survival time was 6.1 months with 5-FU‐LV (range, 4.1 to 7.4 months) and 8.7 months (7.4 to 9.2 months) with l-OHP and 5-FU‐LV (P 5 .048). Median survival times were 19.9 and 19.4 months, respectively. Conclusion: By chronomodulating 5-FU‐LV, we were able to add l-OHP without compromising dose-intensities. l-OHP significantly improved the antitumor efficacy of this regimen. J Clin Oncol 18:136-147. © 2000 by American Society of Clinical Oncology.