No correlation between methotrexate serum level and histologic response in the pre-operative treatment of extremity osteosarcoma

Our objectives were to evaluate the behavior of different doses of pre-operative methotrexate (MTX) pharmacokinetics, and assess correlations between the osteosarcoma histologic response and MTX serum peak concentrations. In total, 336 patients with osteosarcoma of the extremities were treated with three neoadjuvant protocols of chemotherapy including high-dose MTX (different doses for each protocol), cisplatin and doxorubicin (same doses in all protocols). The doses of MTX were 8 g/m(2) in 124 patients, 10 g/m(2) in 110 patients and 12 g/m(2) in 102 patients. The mean value of peak serum MTX was 801 mu mol/l (range 298-1831) with significant intra- and inter-patient variability. For patients treated with 8, 10 and 12 g/m(2) it was 587, 735 and 1114 mu mol/l, respectively (P < 0.0001). The histologic response to pre-operative chemotherapy was 90% or above tumor necrosis in 62.8% of patients and less than 90% in 37.2%. The grade of histologic response significantly correlated with the histologic subtype of the tumor, whereas no significant association was found between the mean peak of serum MTX and the histologic response. Thus, increasing the dose of MTX increases the MTX serum peaks, but does not correlate with the histologic response of the tumor.