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

Authors

  • Kristine R. Crews Pharm.D.,

    Corresponding author
    1. Department of Pharmaceutical Sciences, St. Judes Children's Research Hospital, Memphis, Tennessee
    2. University of Tennessee Health Science Center College of Pharmacy, Memphis, Tennessee
    • Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Mail Stop 313, 332 N. Lauderdale, Memphis, TN 38105-2794
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    • Fax: (901) 525-6869

  • Tiebin Liu M.S.P.H.,

    1. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
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  • Carlos Rodriguez-Galindo M.D.,

    1. Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee
    2. University of Tennesse Health Science Center College of Medicine, Memphis, Tennesse
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  • Ming Tan Ph.D.,

    1. University of Tennesse Health Science Center College of Medicine, Memphis, Tennesse
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  • William H. Meyer M.D.,

    1. University of Tennesse Health Science Center College of Medicine, Memphis, Tennesse
    2. Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
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  • J. Carl Panetta Ph.D.,

    1. Department of Pharmaceutical Sciences, St. Judes Children's Research Hospital, Memphis, Tennessee
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  • Michael P. Link M.D.,

    1. Department of Pediatrics, Stanford University School of Medicine, Stanford, California
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  • Najat C. Daw M.D.

    1. University of Tennesse Health Science Center College of Medicine, Memphis, Tennesse
    2. Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee
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Abstract

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 ≥ 1000 μM 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 μM), 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 μM were found to have a worse outcome (estimated 5-year EFS, 58.5% ± 6.7%) compared with patients who had a mean peak concentration ≤ 1500 μM (estimated 5-year EFS, 75.5% ± 6.6%; P = 0.02).

CONCLUSIONS

When HDMTX (12 g/m2) was used with multiagent therapy for patients with osteosarcoma, very high MTX exposures were associated with poorer outcome. The prospective evaluation of MTX pharmacokinetics and their relation to outcome in a large study is warranted to further substantiate the current findings and to elucidate the causative mechanism. Cancer 2004. © 2004 American Cancer Society.

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