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 I-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 less than or equal to 5% of the patients (less than or equal to 1% of the courses). Grade 3 to 4 diarrhea occurred in 43% of the patients given I-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 I-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 I-OHP and 5-FU-LV (P = .048). Median survival times were 19.9 and 19.4 months, respectively.

Conclusion: By chronomodulating 5-FU-LV,we were able to add I-OHP without compromising dose-intensities. I-OHP significantly improved the antitumor efficacy of this regimen. (C) 2000 by American Society of Clinical Oncology.