A. RANDOMIZED CLINICAL TRIAL of three different schedules of methotrexate administration was conducted in 281 patients with advanced squamous cell carcinoma of the head and neck, and adenocarcinoma of breast and colon. Methotrexate was administered once weekly according to the following regimens: A) 125 mg/m2 by mouth every 6 hours for four doses followed by citrovorum factor, 5 mg every 6 hours for six to 12 doses beginning 36 hours after the first dose of methotrexate; B) 15 mg/m2 by mouth every 6 hours for four doses; or C) 60 mg/m2 intravenously as a single dose. Courses were continued weekly unless hematologic or oral toxicity occurred. Patients were evaluated at the end of 12 weeks. Dose escalations were permitted every 4 weeks if neither toxicity nor tumor regression occurred. Responses were seen in 21% of patients treated on Regimen A (27% head and neck, 17% breast, 12% colon), 20% on Regimen B (27% head and neck, 20% breast and 7% colon) and 26% on Regimen C (34% head and neck, 28% breast, and 7% colon). None of these schedules was significantly different. There was no difference among the schedules in median duration of response (6.3 months on Regimen A, 5.8 months on Regimen B, and 5.4 months on Regimen C) or survival. Hematologic toxicity was less on Regimen B and similar on Regimens A and C.
These results indicate that no therapeutic advantage is gained by weekly administration of higher doses of methotrexate followed by citrovorum factor, when compared to lower doses of methotrexate given on the same schedule.