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Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma

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Abstract

Purpose

High-dose methotrexate (HD-MTX) with leucovorin rescue is widely used to treat osteosarcoma. Our objectives were to assess correlations between pharmacokinetic parameters and the outcome of osteosarcoma and to analyze the relation between HD-MTX exposure and toxicity.

Methods

Pharmacokinetic data of 105 patients with osteosarcoma 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.

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Acknowledgments

We are grateful to all the nurses, doctors and patients who took part in the study.

Conflict of interest

There are no competing financial interests in relation to the work described.

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Correspondence to Marta Hegyi.

Additional information

Marta Hegyi and Ágnes Gulácsi contributed equally to this work and are co-first authors.

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Hegyi, M., Gulácsi, Á., Cságoly, E. et al. Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma. J Cancer Res Clin Oncol 138, 1697–1702 (2012). https://doi.org/10.1007/s00432-012-1214-2

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  • DOI: https://doi.org/10.1007/s00432-012-1214-2

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