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 tox icities (DLT) of oxaliplatin (L-OHP) given on a weekly schedule including f ixed doses of leucovorin (LV) and infusional 5-fluorouracil (5-FU), to defi ne the toxicity profile of this regimen and to find preliminary evidence of its activity in pretreated patients with metastatic colorectal cancer (MCR C). Patients and methods: Twenty-one patients with progressive disease, treated with fluoropyrimidines and with histologically measurable MCRC entered int o 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 dos es 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 onc e 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 devel oped neutropenia during the first cycle of chemotherapy. Most patients comp lained of mild peripheral sensitive neurotoxicity, which was related to the cumulative dose of L-OHP. Treatment delays were necessary for a total of 4 2 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 (3 3%; 95% confidence interval (CI): 14.6%-57.0%) were considered to show a ma jor response (one complete), six showed a stable disease, and in addition p rogressive disease was observed in three patients. Conclusions: Our results show that L-OHP, LV and 5-FU can be administered s afely and repetitively using a weekly schedule. Diarrhea and neutropenia ar e 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.