Phase I study of a weekly schedule of oxaliplatin, high-dose leucovorin, and infusional fluorouracil in pretreated patients with advanced colorectal cancer

Purpose: To identify the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including fixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to define the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCRC). Patients and methods: Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered into this phase I study. Fixed doses of LV (500 mg/m(2)) followed by a 48-hour 5-FU 2600 mg/m(2) infusion (5-FU48h) were administered with escalating doses of L-OHP, starting from 60 mg/m(2) and with stepwise increments of 5 mg/m(2). No intra-patient dose escalation was allowed. Treatment was given once a week for four consecutive weeks, followed by a one-week rest period. Results: Three dose levels were tested. The MTD was L-OHP 70 mg/m(2) since two of the three patients showed dose-limiting diarrhea and the third developed neutropenia during the first cycle of chemotherapy. Most patients complained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 42 cases, but only in 11 of 42 after the pre-arranged 10% dose reduction of 5-FU (2300 mg/m(2)). Sixteen patients were evaluable for response: seven (33%; 95% confidence interval (CI): 14.6%-57.0%) were considered to show a major response (one complete), six showed a stable disease, and in addition progressive disease was observed in three patients. Conclusions: Our results show that L-OHP, LV and 5-FU can be administered safely and repetitively using a weekly schedule. Diarrhea and neutropenia are the DLT of this regimen. Its activity and its manageable toxicity profile deserve further evaluation in chemotherapy-naive MCRC patients. The doses recommended for phase II trials are: L-OHP 65 mg/m(2), LV 500 mg/m(2) and 5-FU48h 2300 mg/m(2) infusion given on a weekly-times-four schedule followed by a one-week rest period.