Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma

Marta Hegyi, Ágnes Gulácsi, Edit Cságoly, Katalin Csordás, Olivér T. Eipel, Dániel J. Erdélyi, Judit Müller, Karolina Nemes, Orsolya Lautner-Csorba, Gábor T. Kovács

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Abstract

Purpose: High-dose methotrexate (HD-MTX) with leuco-vorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacoki-netic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity. Methods: Pharmacokinetic data of 105 patients with oste-osarcoma treated with 989 HD-MTX courses were evaluated. Pharmacokinetic parameters (clearance, half-life and AUC) were calculated based on methotrexate (MTX) serum levels measured at 6, 24, 36, 48 h after the initiation of the infusion. Clinical data were collected by retrospective chart review. Hepato-, nephro- and bone marrow toxicity parameters were categorized according to Common Toxicity Criteria v.3.0, and MTX dose intensity was calculated. Event-free survival (EFS) and overall survival (OS) were estimated according to the Kaplan-Meier method. Results: Patients with serious hepatotoxicity had higher mean peak MTX concentrations (p<0.0001), 24-h (p = 0.001) and 48-h MTX serum levels (p = 0.008) and AUC0-48 (p<0.0001), and lower MTX clearance (p = 0.0002). No significant association was found between toxicity and age, gender, presence of metastases or histological tumor response. Patients with higher 48-h MTX serum levels had significantly better OS and EFS. Higher dose intensity was associated with better EFS (p = 0.0504). There was no association between presence of toxicity and survival. Conclusion: There was correlation between MTX exposure and the incidence of toxicity. Higher serum concentrations at 48 h were associated with a better 5-year OS and EFS. These results suggest that higher MTX exposure may lead to serious side effects, but it also improves treatment outcome.

Original languageEnglish
Pages (from-to)1697-1702
Number of pages6
JournalJournal of cancer research and clinical oncology
Volume138
Issue number10
DOIs
Publication statusPublished - Oct 1 2012

Keywords

  • Methotrexate
  • Osteosarcoma
  • Pharmacokinetics
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hegyi, M., Gulácsi, Á., Cságoly, E., Csordás, K., Eipel, O. T., Erdélyi, D. J., Müller, J., Nemes, K., Lautner-Csorba, O., & Kovács, G. T. (2012). Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma. Journal of cancer research and clinical oncology, 138(10), 1697-1702. https://doi.org/10.1007/s00432-012-1214-2