A phase I trial of CPT-11 in combination with 5-fluorouracil plus leucovorin chemotherapy for patients with metastatic colorectal cancer

Background/Aims: To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with 5-FU plus leucovorin (5-FU/LV) for patients with metastatic colorectal cancer in an outpatient setting, a phase I clinical trial was conducted. Methdology: Eligible patients received the RPMI regimen of 1-LV (200mg/m(2), for 2 hours) plus 5-FU (333mg/m(2), bolus) weekly for 4 weeks followed by a 2-week rest. CPT-11 was administered over the 5-FU/LV therapy at the 1st and 3rd week of every treatment cycle before the bolus 5-FU. Dose escalation of CPT-11 from 25 to 100 mg/m(2) was done for every cohort consisting of at least 3 patients to define a dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) for a phase 11 trial. Results: Twenty-one patients with metastatic colorectal cancer were enrolled. Hematologic toxicity was very infrequently observed. One patient enrolled at level 1 (25mg/m(2) CPT-11), but not the other patients, had muscle weakness at grade 3 and needed to be hospitalized. Hair loss at grade 1 was observed in 3 of 21 patients. Gastrointestinal toxicity, including nausea, was commonly observed throughout the dose levels. Diarrhea was frequently observed at doses higher than level 4 (60mg/m(2) CPT-11), and 2 of the 3 patients at dose level 6 (100mg/m(2) CPT-11) experienced diarrhea at grade 3 and needed to be hospitalized. As for the overall tumor responses, 3 partial responses (PR), 10 stable diseases, and 6 progressive diseases were observed, with 2 of the PRs occurring at dose level 5 (80mg/m(2) CPT-11). Conclusions: These results suggest that our treatment regimen using CPT-11 in combination with 5-FU/LV is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at the MTD of 100mg/m(2) Of CPT-11, and 80mg/m(2) CPT-11 is recommended for the next phase II trial.