Irinotecan: a review of the initial phase I trials

The unique mechanism of action of irinotecan (CPT-11 [Camptosar]), topoisomerase I inhibition, together with the results of preclinical studies, suggest that the drug's antitumor and toxicologic effects may be schedule-dependent. To further explore this possibility, we reviewed the initial phase I studies of various administration schedules that have been conducted in Japan, France, and the United States. This review showed toxicities to be fairly consistent across dosing schedules, although the severity and extent of diarrhea and neutropenia differed somewhat. The institution of intensive loperamide therapy and perhaps myeloid growth factors may have allowed for further dose escalation on some schedules, although it is unclear whether dosing intensity should be pursued without regard to dosing frequency. Preliminary antitumor activity of irinotecan noted in a study of leukemia and lymphoma supports the theory that the drug may exhibit schedule-dependent antitumor activity. The results of these early studies of irinotecan should be taken into account when designing subsequent trials of the agent alone or in combination with other chemotherapeutics in specific tumor types.