METHOTREXATE PHARMACOKINETICS AND PROGNOSIS IN OSTEOSARCOMA

Purpose: The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed. Patients and Methods: MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated. Results: A mean threshold peak level of ≥ 1,000 μmol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values ≥ 1,000 μmol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 μmol/L, P = .011; 6,684 v 5,820 h · μmol/L, P ≤ .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t( 1/2 )) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h · μmol/L, respectively, P ≤ .002). Conclusion: MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level ≥ 1,000 μmol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.