A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated coldrectal carcinoma

BACKGROUND. This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5- fluorouracil (5-FU)based chemotherapy. METHODS. CPT-11 was given as a 90- minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS. A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m². An additional 102 patients were enrolled at a starting dose of 100 mg/m² to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m² starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m², the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicides between the 125 mg/m² and 100 mg/m² starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age ≥ 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS. CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicides. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m² has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.