Phase I evaluation and pharmacokinetic study of weekly iv thymidine and 5-FU in patients with advanced colorectal carcinoma.

Overview

A phase I study of weekly iv thymidine (TdR) and 5-FU was carried out in patients with advanced colorectal carcinoma using two dosage schedules. Schedule 1 employed a 3-hour infusion of TdR (6-8 g/m2/hour) followed immediately by a bolus of 5-FU (100-200 mg/m2). Schedule 2 used a slightly larger dose of TdR (18 g/m2/hour for 1.5 hours), with 5-FU given 30 minutes after the TdR infusion was started. Myelosuppression was observed erratically at the higher doses of 5-FU. Diarrhea and severe fatigue were seen frequently with Schedule 1. CNS side effects were the dose-limiting effects for both schedules. For long-term use the maximally tolerated 5-FU doses were 100 mg/m2/week for Schedule 1 and 175 mg/m2/week for Schedule 2. In pharmacokinetic studies in five patients, both schedules produced prolonged plasma beta-half-lives of 5-FU (96-189 minutes). Extensive formation of floxuridine was seen with both schedules. It appears likely that CNS toxic effects are characteristic of TdR-containing 5-FU regimens and would limit the therapeutic potential of this approach.