PHASE-I TRIAL OF A 5-DAY INFUSION OF L-LEUCOVORIN PLUS DAILY BOLUS 5-FLUOROURACIL IN PATIENTS WITH ADVANCED GASTROINTESTINAL MALIGNANCIES

The combination of leucovorin [(6d,l)-5-formyltetrahydrofolate] and 5- fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as t reatment of advanced colorectal cancer. Leucovorin is metabolized to m ethylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxy uridine and methylene tetrahydrofolate. Only l-leucovorin is metaboliz ed to methylene tetrahydrofolate and forms this ternary complex. Howev er, d-leucovorin may not be inert. d-Leucovorin may impair cellular up take and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectivenes s of racemic leucovorin, we have begun to explore the effects of the p ure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of 1-leucovorin and daily intravenous bol uses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in g roups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 pe r day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeate d every 28 days. Seventeen patients with advanced gastrointestinal can cers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The mo st common severe toxicities (and the number of patents affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/recta l pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 p er day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears activ e for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective t han d,l-leucovorin for modulating the effectiveness of 5-FU.