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Erschienen in:
01.10.2012 | Original Paper
Clinical relations of methotrexate pharmacokinetics in the treatment for pediatric osteosarcoma
Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 10/2012
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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.