A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue.

the treatment of neoplastic diseases (9). Early preclinical studies by Goldin et al. (4) demonstrated that the toxicity of high doses of methotrexate could be minimized without loss of therapeutic activity by the administration of the reduced folate, calcium leucovorin. Clinical studies in the treatment of metastatic osteogenic sarcoma (7) and other solid tumors (2, 8) have since demonstrated the activity of such high-dose methotrexate-leucovorin rescue regimens. To date, the dosage of methotrexate used, the length of the methotrexate infusion, and the scheme for leucovorin mes cue vary widely among protocols and have been established largely on an empirical basis. Studies by Pinedo et al. (12) have clearly shown a relationship between extracelluhar concentrations of methotmexate and leucovorin and the effectiveness of †̃ †̃ rescue―in tissue culture and laboratory animals. Furthermore, recent studies by Sirotnak, et al. (13) suggest that the clinical efficacy of high-dose methotrexate leuocovomin rescue therapy in both L1210 leukemiaand Sarcoma 180-bearing mice can be optimized by minimizing the dose of reduced folate. A Phase 1 clinical trial by Jacobs and Santicky (6) using 3 fixed-dosage regimens of leucovo rin demonstrated that, indeed, leucovorin dosages could be reduced without undue host toxicity. The aim of this investigation was to confirm the clinical relationship be tween plasma methotrexate concentration and dosage of leucovorin needed to prevent toxocity. The dose of leuco vorin was individualized based upon each patient's plasma methotrexate clearance in an effort to minimize the dose of leucovorin administered, avoid host toxicity, and maximize therapeutic efficacy.