Methotrexate Serum Concentration and Histological Response to Multiagent Primary Chemotherapy for Osteosarcoma of the Limbs

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Abstract
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.