5-Methyltetrahydrofolate for biochemical modulation of fluorouracil (FU) in patients with advanced colorectal cancer: A randomized phase I–II study of two different FU administration schedules

Abstract

To determine the maximum tolerable dose (MTD) and therapeutic activity of MTHF-modulated FU using two different administration schedules of the antimetabolite (bolus vs. two-hour infusion), the present randomized study using a 'pick-the-winner' design was undertaken in patients with advanced colorectal cancer. Eighty-two patients with previously untreated advanced measurable colorectal cancer were randomly assigned to treatment with MTHF (100 mg/m2 days 1-5 i.v. bolus) plus FU (400 mg/m2 days 1-5) given either as i.v. bolus injection or as a two-hour infusion every four weeks. In the absence of dose-limiting toxicity (DLT, defined as > or = WHO grade 3 hematotoxicity and/or > or = WHO grade 2 nonhematologic side effects) and evidence of progressive disease, the FU dose was escalated by 50 mg/m2/day during each subsequent cycle until the individual maximum tolerable dose (MTD) was reached. Forty patients were randomized to the FU bolus arm and 42 patients to the FU two-hour infusion arm. The median MTD was 475 mg/m2/day (95% CI: 450-500) in the FU bolus arm with stomatitis +/- diarrhea being the most common DLT. Gastrointestinal side effects were also dose-limiting in the two-hour infusion arm; however, the median MTD was 600 mg/m2/day (95% CI: 568-632). Myelosuppression was more pronounced in the FU bolus arm than in the two-hour infusion arm. The overall response rates were 27.5% (95% CI: 15-44%; 1 CR and 10 PR) for patients treated in the bolus arm and 14.5% (95% CI: 5-28%; 1 CR and 5 PR) for those treated in the two-hour infusion arm. Analogous to recorded response, median time to progression (8.5 vs. 6.25) and overall survival time (14.0 vs. 11.0) tended to be superior in the FU bolus arm. The observed differences in tolerable drug dose and toxicity between the two treatment arms might be explained by the administration schedule-dependent clinical pharmacokinetics of FU and/or the difference in extent of biochemical modulation of the antimetabolite through MTHF. The fact that the two regimens were not equitoxic probably also helps to explain the favourable response activity noted in the MTHF/FU bolus arm. Whether MTHF is as effective as leucovorin for biochemical modulation of FU remains to be determined in a randomized trial, for which we would recommend its combined use with bolus FU ('winner arm') using a starting dose of 400 mg/m2/day x5.