Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every two weeks (LV5FU2 regimen): A clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer

Purpose: To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT- 11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC). Patients and Methods: All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m²). LV5FU2 was started I hour after the end of the biweekly CPT-11 infusion and was also administered on day 2. Results: Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m², and a dose level of 300 mg/m² was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m². Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months. Conclusion: The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT- 11 at 180 to 200 mg/m² in combination with LV5FU2 has been selected as the recommended dose for further studies.