Toxic and therapeutic effects of methotrexate-folinic acid (Leucovorin) in advanced cancer and leukemia.

Abstract

Recent studies suggest that a therapeutic advantage with reduced toxicity can be achieved by the administration of intensive high doses of methotrexate in malignant disease. The action of methotrexate can be reversed by the administration of folinic acid (Leucovorin) which bypasses the major site of methotrexate action, the binding of dihydrofolic reductase, preventing the formation of tetrahydrofolic acid. Thus, the duration of exposure of sensitive cells to lethal doses of methotrexate can be accurately controlled. Patients with metastatic cancer or acute leukemia were treated with oral methotrexate administered in 4 equally divided doses totalling 100, 200, or 300 mg/m2 over a 24-hour period once weekly. Leucovorin, in doses of 5 mg every 6 hours for 6, 9, or 12 doses depending upon the creatinine clearance, was begun on a randomized basis at 24 or 36 hours after methotrexate to determine if there were any differences in response or toxicity by the delay in “rescue.” Objective and/or subjective responses were observed in 25% of 93 patients with metastatic cancer and remissions (3 complete and 5 partial) in 23% of 35 evaluable patients with acute leukemia. The highest response rates were obtained in head and neck carcinomas (22%) and breast carcinomas (45%). Responses were also seen in other carcinomas, including ovary, cervix, and choriocarcinoma. Toxicity was Minimal and similar in all combinations of schedules of methotrexate and Leucovorin. This approach warrants further study alone or in combination with other drugs in carcinoma of the breast and head and neck, and in acute leukemia.