Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer.

Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC. PATIENTS AND METHODS: Forty-eight patients entered the trial and received irinotecan 350 mg/m2 d.1 and raltitrexed 3 mg/m2 d.2, every three weeks. After recruitment of the first 16 patients, grade III-IV toxicity was observed in 6 patients (38%). Therefore, an amendment reduced by 15% the dose of both drugs (irinotecan 300 mg/m2, raltitrexed 2.6 mg/m2). RESULTS: A total of 290 cycles were administered (range 1-18, median number 6). According to intention-to-treat analysis, the overall response rate was 27% (95% confidence interval 16%-42%), including 3 complete responses and 10 partial responses. The median duration of response was 10 months, while median progression-free survival and overall survival were 5 and 14 months, respectively. In the first 16 patients, the main toxicities were grade III-IV diarrhea in 25% and grade III-IV neutropenia in 13%. In the subsequent 32 patients, they were grade III-IV diarrhea in 34% and grade III neutropenia in 6%. Two toxic deaths occurred. CONCLUSION: The combination irinotecan-raltitrexed is an active regimen, but the significant incidence of side-effects requires accurate patient selection and, eventually, new schedules.