Methotrexate serum concentration and histological response to multiagent primary chemotherapy for osteosarcoma of the limbs

The authors investigated the influence of methotrexate (MTX) serum concentration on (histologically evaluated) tumor necrosis, induced by a primary multiagent chemotherapy, including MTX, for osteosarcoma. MTX serum peaks in 151 patients, preoperatively treated with MTX (8-12 g/m(2)), cisplatin (120 mg/m(2)) and Adriamycin (60 mg/m(2)), were analyzed. Significantly (p < 0.01) higher serum MTX mean peaks were observed in patients with complete tumor necrosis (MTX 773.8 mu mol/l) compared to patients with 90-99% tumor necrosis (639.8 mu mol/l), 50-89% tumor necrosis (649.1 mu mol/l) or less than 50% tumor necrosis (610 mu mol/l). Complete tumor necrosis was observed in 9% of patients with MTX peaks of less than 600 mu mol/l, in 27% of patients with serum MTX peaks between 600 and 699 mu mol/l and in 37% of those with MTX peaks ranging from 700 to 799 mu mol/l. Higher MTX peaks (800-899, 900-999, > 1000 mu mol/l) were not associated with a further increase of cases with complete tumor necrosis. 40% of patients with an MTX peak greater than 700 mu mol/l had complete tumor necrosis, compared to 15.5% of patients who did not reach this value (p < 0.002). At a multivariant analysis including age, sex, tumor site and volume, pretreatment serum alkaline phosphatase and lactic dehydrogenase levels, MTX peaks of 700 mu mol/l and, less significantly, the histologic type (telangiectatic osteosarcoma), were independent factors influencing tumor necrosis. The authors conclude that MTX serum peaks significantly influence chemotherapy-induced tumor necrosis in osteosarcoma. In a primary treatment consisting of cisplatin, Adriamycin and MTX(, complete tumor necrosis can be obtained in 40% of patients with MTX peak concentrations greater than or equal to 700 mu mol/l.