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 toxicities 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 > or = 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 toxicities. 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.