Superiority of sequential methotrexate, fluorouracil, and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma: a randomized trial.

Abstract

A total of 249 patients with advanced, symptomatic colorectal cancer who received no previous cytostatic therapy were randomly allocated to receive either fluorouracil (5-FU), 600 mg/m2, for 2 days or the following regimen: sequential methotrexate, 250 mg/m2, during the first 2 hours and 5-FU, 500 mg/m2, at hours 3 and 23 followed by leucovorin rescue initiated at hour 24 (15 mg x 8) (MFL). Treatment was repeated every 14 days for eight courses and then continued every 3 to 4 weeks. Five patients were unevaluable. In these groups the objective response could be evaluated in 69% and 73%, respectively, of the patients who received at least four treatment courses, whereas other outcomes were assessed in all randomized patients. The sequential MFL treatment was more effective than 5-FU alone, as indicated by the former's clinically and statistically highly significant advantage regarding the objective (complete [CR] plus partial [PR]) response rates (24% v 3%; P less than .001), subjective response rate (45% v 23%; P less than .001), and survival (median, 8.5 v 6 months; P less than .02). If all patients were considered for objective response, the figures were lower, 17% v 2%, but the difference was still statistically significant (P less than .001). All responses had a minimum duration of 4 months. Overall, the toxicity was low and comparable between the groups, but stomatitis and conjunctivitis were more common after sequential treatment. Our data suggest that the experimentally observed synergistic cell kill between methotrexate and 5-FU has clinical relevance and that the sequential MFL regimen is a superior alternative to 5-FU alone in the treatment of patients with advanced symptomatic colorectal cancer.