A PHASE-I STUDY OF 5-DAY CONTINUOUS VENOUS INFUSION OF CARBOPLATIN ATCIRCADIAN RHYTHM-MODULATED RATE COMPARED WITH CONSTANT RATE

The circadian rhythm-modulated delivery of anticancer drugs has shown to reduce toxicity and improve anticancer efficacy. The aim of this ph ase I trial was to compare the feasibility and tolerability of carbopl atin (CBDCA) administered at circadian-modulated or flat infusion rate in 24 patients with advanced cancer. Each treatment cycle consisted o f a 5-day continuous intravenous infusion of CBDCA, to be repeated at 28-day intervals. Three dose levels were determined, with a CBDCA dose 15%, 40% and 60% over that calculated using Calvert's formula. Two sc hedules were compared: schedule A (forty-four courses), with a at circ adian rhythm-modulated rate (peak at 16.00 hr) and schedule B (fifty c ourses), at a constant rate. At the first and second dose level neithe r of the administered cycles were accompanied by hematologic toxicity higher than Grade 3. At the third dose level, two cycles out of 15 for schedule A and two out of 20 for schedule B were accompanied by Grade 4 thrombocytopenia. The repeat cycles were delayed from day 28 to 42 in some patients, with no difference between circadian-modulated and f lat infusion. Three partial responses out of 9 evaluable patients were observed in schedule A and 2 out of 10 evaluable patients in schedule B. We showed no potential advantage of the chronomodulated 5-day CBDC A continous infusion method over the flat rate method. Although antitu mor effects were observed in this pilot study, the treatment cannot be assessed for efficacy relative to other schedules.