SEQUENTIAL METHOTREXATE, 5-FLUOROURACIL (5-FU), AND HIGH-DOSE LEUCOVORIN VERSUS 5-FU AND HIGH-DOSE LEUCOVORIN VERSUS 5-FU ALONE FOR ADVANCED COLORECTAL-CANCER - A MULTIINSTITUTIONAL RANDOMIZED TRIAL

Background. The primary objective of this study was to compare the sin gle-biochemical modulation of 5-fluorouracil (5-FU) and leucovorin wit h that of the double-biochemical modulation of methotrexate and leucov orin. Because of the Martin et al. study in which an experimental mode l showed similar effects of 5-FU at maximum tolerated doses to the mod ulation with leucovorin at standard doses, a third treatment arm of 5- FU alone was also studied. Methods. A randomized trial was performed u sing a 500-mg/m(2) intravenous (i.v,) 1-hour infusion of methotrexate, and 12 hours later, a 600-mg/m(2) i.v. bolus of 5-FU plus a 200-mg/m( 2) i.v. 1-hour infusion of leucovorin (MFL) every 2 weeks versus 5-FU plus leucovorin at an equal dose and schedule (FL), versus a 1200-mg/m (2) i.v dose of 5-FU every 2 weeks. Of 186 patients included in the st udy, 178 were evaluable. Results. In a preliminary analysis with 94 ev aluable patients, two significant statistical differences were shown. First, the toxicity rate of the 5-FU-alone (F) treatment arm was highe r than that of the other arms (MFL vs. F, P = 0.0002; FL vs. F, P = 0. 00001). Second, the median survival was worse in the F treatment arm w ith a rate of 12.6 months for the MFL and FL arms and 7.5 months for t he F arm (P < 0.05). Considering these results, the F treatment arm wa s discontinued. The final results included 70 evaluable patients for M FL and 74 patients for FL. No difference was found in the distribution of prognostic factors. The response rates were 25.7% for MFL (95% CI, 16-37.5) and 14.8% for FL (95% CI, 7.6-25), (P = 0.1). The median sur vival was 14.3 months for patients treated with MFL and 12.3 months fo r those treated with FL. The hematologic toxicity was mild, with no gr ade 3/4 leukopenia in either treatment arm. The major nonhematologic t oxicity in the MFL and FL treatment arms was ocular; nongrade 3/4 diar rhea also was observed. Conclusions. The results of MFL double-biochem ical modulation failed to show a significant statistical difference fr om that of single-biochemical modulation for this dose and schedule.