Phase I study of a weekly schedule of irinotecan, high-dose leucovorin, and infusional fluorouracil as first-line chemotherapy in patients with advanced colorectal cancer

Purpose: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorou racil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer an d to assess preliminary data on the antitumor activity. Patients and Methods: Twenty-six patients with measurable metastatic colore ctal cancer were entered onto this phase I study. In the first six dose lev els, fixed doses of CPT-11 (80 mg/m(2)) and LV (500 mg/m(2)) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m(2) were admini stered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dos e levers 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/ m(2) (dose level 7), Results: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during th e first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Canc er Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Of her nonhematologic and hematologic side effe cts, specifically alopecia and neutropenia, did not exceed grade 2, With th e escalation of CPT-11 to 100 mg/m(2) (dose level 7), diarrhea of grade 3 o r higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. Conclusion: The recommended doses for further studies are CPT-11 80 mg/m(2) , LV 500 mg/m(2), and 5-FU24h 2.6 g/m(2) given on a weekly-times-six schedu le followed by a 1-week rest period. The addition of CPT- 11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with m anageable toxicity. (C) 1999 by American of Clinical Oncology.