Biochemical modulation of 5-fluorouracil: A randomized comparison of sequential methotrexate, 5-fluorouracil and leucovorin versus sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic colorectal cancer

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Abstract
The optimal chemotherapy for advanced colorectal carcinoma is not known. Two regimens, both based upon biochemical modulation of 5-FU, were compared in a randomized multicenter trial. A total of 202 symptomatic patients were randomly allocated to receive either 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 × 8) (MFL) or sequential 5-FU 500 mg/m2 followed by leucovorin 60 mg/m2 30–40 minutes later, on days 1 and 2 (FLv). Treatments were repeated every 14 days for eight courses and then every 3 to 4 weeks. Four patients were unevaluable. The two treatments were equally effective with respect to objective response rates (complete (CR) + partial (PR), MFL 17%, FLv 21%), subjective response rates (symptom relief in the absence of severe adverse effects, 45% vs. 37%), and survival (median 7.5 vs. 9 months). All responses lasted at least 4 months. Overall, toxicity was low and comparable between the groups, but serious toxicity was more common in the MFL group. Since FLv is easier to administer and carries less risk for serious toxicity, it should be recommended as a first-line treatment before MFL. On either regimen, about 40% of symptomatic patients can expect palliation, i.e., symptomatic relief without severe adverse effects, for at least 4 months.