Phase I Trial of 5-Day Continuous Venous Infusion of Oxaliplatin at Circadian Rhythm-Modulated Rate Compared With Constant Rate

作者：J. P. Caussanel, Francis Albert Lévi, Silvano Brienza, J.L. Misset, Moshe Itzhaki, René Adam, Gerard A. Milano, B Hecquet, Georges Mathé · 发表于：JNCI Journal of the National Cancer Institute · 年份：1990 · DOI：10.1093/jnci/82.12.1046 · 被引用次数：254 · 研究领域：Cancer Treatment and Pharmacology、Chemotherapy-related skin toxicity、Central Venous Catheters and Hemodialysis

The toxic effects and tissue uptake of both cisplatin and oxaliplatin--[(1R, 2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O']platinum--were previously shown to vary similarly according to dosing time in mice. A 4-hour infusion of cisplatin resulted in fewer side effects and allowed administration of higher doses at 16 hours than at 4 hours in patients with cancer. We hypothesized that the continuous venous infusion of oxaliplatin for 5 days would be less toxic and would deliver a higher dose to the patient if the drug were infused at a circadian rhythm-modulated rate (peak at 16 hr; schedule B) rather than at a constant rate (schedule A). We tested this hypothesis in a randomized phase I trial. We escalated the dose of oxaliplatin to the patient by 25 mg/m2 per course. Courses were repeated every 3 weeks. An external, multichannel, programmable-in-time pump was used for the infusions. Toxicity was assessable for 94 courses in 23 patients (12 patients with breast carcinoma, nine with hepatocellular carcinoma, and two with cholangiocarcinoma). The incidence of neutropenia of World Health Organization grades II-IV and the incidence of distal paresthesias were 10 or more times higher (P less than .05) with schedule A than with schedule B. In addition, vomiting was 55% higher (P = .15) with schedule A than with schedule B. Furthermore, with schedule B, the mean dose of oxaliplatin (P less than .001) and its maximum tolerated dose (P = .06) could be increased by 15% over those d...