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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

From the Department of Internal Medicine (Cancer Research), West German Cancer Center, University Medical School, Essen, Germany; Department of Hematology and Oncology, Charité, Campus Berlin-Buch, Humboldt University, Berlin, Germany; Department of Clinical Research, Oncology-New Technology, Rhône-Poulenc Rorer, Cologne, Germany; and Department of Pharmacology and Experimental Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, NY.

Address reprint requests to U. Vanhoefer, MD, Department of Internal Medicine (Cancer Research), West German Cancer Center, University Medical School, Hufelandstr 55, 45122 Essen, Germany

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU_24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity.

PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m²) and LV (500 mg/m²) in combination with escalated doses of 5-FU_24h ranging from 1.8 to 2.6 g/m² were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m² (dose level 7).

RESULTS: Seventy-nine cycles of 5-FU_24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m² (dose level 7), diarrhea of grade 3 or 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/m², LV 500 mg/m², and 5-FU_24h 2.6 g/m² given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU_24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

U.V. is recipient of the Bristol-Myers Squibb Young Investigator Award of the American Association for Cancer Research, New Orleans, LA, March 28, 1998.

Presented in part at the 34th Annual Meeting of the American Society for Clinical Oncology, Los Angeles, CA, May 16-19, 1998, and at the 89th Annual Meeting of the American Association for Cancer Research, New Orleans, LA, March 28-April 1, 1998.

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