PHASE-I CLINICAL AND PHARMACOKINETIC STUDY OF LEUCOVORIN AND INFUSIONAL HEPATIC ARTERIAL FLUOROURACIL

Purpose: A phase I and pharmacokinetic trial wets performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer. Patients and Methods: Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks, The regimen consisted of FA 200 mg/m(2) by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m(2) by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m(2), with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-stare plasma concentrations (C-ss) of 5-FU. Results: Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m(2), The recommended dose for the 22-hour component of the schedule was 1.6 g/m(2) and wets associated with tolerable toxicity. A C-ss of 2.2 +/- 0.8 mu mol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens, Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy. Conclusion: A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer, The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy py has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases. (C) 1995 by American Society of Clinical Oncology.