A dose-finding study of irinotecan (CPT-11) plus a four-day continuous 5-fluorouracil infusion in advanced colorectal cancer

Objective: Irinotecan (CPT-11) has shown considerable activity in colorecta l cancer, and its combination with 5-fluorouracil (5-FU) represents an attr active approach. A phase I study was conducted to determine the maximum tol erated dose (MTD) and the dose-limiting toxicities (DLTs) of CPT-11 in comb ination with a continuous infusion of 5-FU for 4 days. Methods: Forty-two p atients with histologically confirmed metastatic colorectal cancer who had not received prior treatment for advanced disease were enrolled. The patien ts' median age was 64 years; 26 (62%) patients were men, and the performanc e status (WHO) was 0 in 26 (62%) patients, 1 in 15 (36%) and 2 in 1 (2%), T wenty-two (52%) patients had 2 or more metastatic sites. CPT-11 (starting d ose 200 mg/m(2)) was administered as a 30-min intravenous infusion with inc rements of 50 mg/m(2) on day 4. 5-FU (starting dose 400 mg/m(2)) was admini stered as a 4-day continuous intravenous infusion with increments of 50 mg/ m(2) on days 1-4. Treatment was repeated every 4 weeks. Results: The MTD of the combination was found to be 600 mg/m(2) for 5-FU and 350 mg/m(2) for C PT-11. Neutropenia, febrile neutropenia and delayed diarrhea were the DLTs. Grade 3/4 neutropenia was observed in 22 (13%) out of 169 administered tre atment cycles, febrile neutropenia in 7 (4%) and grade 3/4 diarrhea in 20 ( 12%). Other toxicities were mild. Among 36 patients evaluable for response, partial response was achieved in 8 (22%), stable disease in 12 (33%) and p rogressive disease in 16(44%) patients. Responses were mostly seen at the h igher dose levels. Conclusions: The combination of a 4-day continuous infus ion of 5-FU followed by CPT-11 represents an active and well-tolerated regi men for patients with colorectal cancer. This regimen merits further evalua tion in phase II studies. Copyright (C) 2001 S.Karger AG, Basel.