[Irinotecan: various administration schedules, study of drug combinations, phase I experience]

Irinotecan (CPT11) is a synthetic camptothecin-derived DNA topoisomerase I inhibitor. Based on phase I clinical trials, several schedules have been recommended for phase I studies including 350 mg/m2 every 3 weeks in Europe, 125 mg/m2 for 4 weeks every 6 weeks in the USA, and 100 mg/m2 weekly or delayed until recovery in case of grade > 2 toxicity in Japan. The principal dose-limiting toxicities in those schedules are neutropenia and delayed diarrhea. Early treatment with high doses of loperamide has made diarrhea a manageable toxicity and allowed dose escalation up to 500 mg/m2. Recently, two very interesting schedules have been investigated allowing to increase dose-intensity: every other week infusion and protracted infusion. With those schedules, it appears that the diarrhea occurred more frequently with the weekly schedule. In addition, authors have observed interpatients variations in terms of toxicity and pharmacokinetics. Those variations may be related to modifications in the hepatic metabolism of the drug that may occur in patients with hepatic dysfunction and/or in patients with concomitant medications. The understanding of the individual metabolism of the drug would help to determine individual dose adaptation. Based on synergistic preclinical interaction with several drugs, combinations of irinotecan with other cytotoxic drugs such as thymidylate synthethase inhibitors and platinum salts are currently investigated in phase I-II studies.