High-dose methotrexate pharmacokinetics and outcome of children and young adults with osteosarcoma

BACKGROUND. High-dose methotrexate (HDMTX) is used frequently in combination regimens that include nephrotoxic chemotherapy. The authors evaluated the impact of factors such as age and prior nephrotoxic agents on MTX pharmacokinetics in children and young adults with osteosarcoma and examined whether MTX pharmacokinetic parameters were associated with outcome. METHODS. The authors evaluated MTX pharmacokinetics in 140 patients who were treated with 1083 courses of HDMTX on 3 consecutive studies of multiagent chemotherapy at a single institution. The influence of MTX pharmacokinetics on the outcome of 107 patients with localized disease was examined. RESULTS. Mean peak MTX concentrations greater than or equal to 1000 muM were achieved in 135 patients (96%). MTX clearance was decreased after cisplatin therapy (P = 0.01), after cisplatin in combination with ifosfamide therapy (P < 0.0001), and after MTX therapy (P = 0.003). In patients with localized osteosarcoma, a higher mean MTX area under the curve, a higher mean peak concentration of MTX, a longer mean time above a threshold concentration (500 muM), and a lower mean MTX clearance were associated with lower probability of event-free survival (EFS). Patients who had a mean peak MTX plasma concentration > 1500 muM were found to have a worse outcome (estimated 5-year EFS, 58.5% +/- 6.7%) compared with patients who had a mean peak concentration less than or equal to 1500 muM (estimated 5-year EFS, 75.5% +/- 6.6%; P = 0.02). CONCLUSIONS. When HDMTX (12 g/m(2)) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer 6 outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current San findings and to elucidate the causative mechanism. (C) 2004 American Cancer Society.