CHRONOMODULATED VERSUS FIXED-INFUSION-RATE DELIVERY OF AMBULATORY CHEMOTHERAPY WITH OXALIPLATIN, FLUOROURACIL, AND FOLINIC ACID (LEUCOVORIN) IN PATIENTS WITH COLORECTAL-CANCER METASTASES - A RANDOMIZED MULTIINSTITUTIONAL TRIAL

Background: In a previous phase II trial, circadian (chronomodulated) delivery of fluorouracil (5-FU), folinic acid (FA; leucovorin), and ox aliplatin (1-OHP; a new platinum complex with no renal and minor hemat ologic toxic effects) produced an objective response rate of 58% in 93 patients with metastatic colorectal cancer. Purpose: To determine whe ther chronomodulated drug delivery affects therapeutic activity, we ag ain tested this regimen in another trial in patients with previously u ntreated metastatic colorectal cancer, this time comparing chronomodul ated with constantrate drug delivery. Methods: Seven European centers participated in this trial. Ninety-two patients with metastatic colore ctal cancer were enrolled and assigned to a treatment schedule by cent ral randomization. Treatment courses consisted of the daily administra tion of 5-FU (600 mg/m(2) per day), FA (300 mg/m(2) per day), and 1-OH P (20 mg/m(2) per day) for 5 days and were repeated every 21 days (16- day intermission) in ambulatory patients with the use of a programmabl e in-time pump. Drug delivery was kept constant over a 5-day period in schedule A (47 patients). It was chronomodulated in schedule B (maxim um delivery of 5-FU and FA infusions at 0400 hours and maximum deliver y of 1-OHP at 1600 hours; 45 patients). A risk of partial chemical ina ctivation of 1-OHP by its 2-hour exposure to the basic pH of the 5-FU solution in the catheter was documented in schedule A. Results: Severe stomatitis (grade 3 or 4, World Health Organization [WHO] grading sys tem), the dose-limiting toxic effect of 5-FU, occurred in five times a s many patients on schedule A than on schedule B (89% versus 18%; chi( 2) = 46; P<.001). The cumulative dose-limiting toxicity of schedule B was peripheral sensitive neuropathy (WHO grade 2). This side effect wa s reversible following 1-OHP withdrawal. Higher doses of 5-FU were adm inistered in schedule B (median: 700 mg/m(2) per day) compared with sc hedule A (median: 500 mg/m(2) per day) (P<.0001; Mann-Whitney U test). On schedule B, 24 of 45 patients (53%; 95% confidence interval [CI] = 38%-68%) exhibited an objective response compared with 15 of 47 patie nts (32%; 95% CI = 18%-46%) on schedule A (chi(2) = 4.3; P = .038). Th e median progression-free survival was, respectively, 11 and 8 months (P = .19; logrank). The median survival was 19 months (95% CI = 14.8-2 3.2) on schedule B and 14.9 months (95% CI = 12.1-17.8) on schedule A (P = .03; logrank). Conclusion: This ambulatory treatment modality was both more effective and less toxic if drug delivery was chronomodulat ed rather than constant over time. Implication: The respective roles o f 1-OHP dose and schedule and circadian peak time of drug delivery are being investigated with regard to the high activity of this three-dru g, chronomodulated chemotherapeutic regimen.