Methotrexate pharmacokinetics and survival in osteosarcoma

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Abstract
Background The aim of this study was to analyze the relationship between exposure to high‐dose methotrexate (HDMTX) and tumor response in terms of survival in children with osteosarcoma. Procedure This study included 44 patients (479 courses) who received a median dose of 5.92 g/m2 of MTX (interquartile range (IQR) 2.37 g/m2) in a 4‐hr infusion. The mean area under the concentration–time curve (AUC) estimated by parametric methods (non‐parametric expectation maximization, NPEM), and the mean concentration at the end of the infusion were considered to be the exposure parameters. Tumor response was recorded as disease‐free survival (DFS), overall survival (OS), and histologic tumor response. The relationship between MTX exposure and survival parameters was analyzed by Cox regression. Results The group of 11 patients who were the least exposed to MTX (AUC < 2,400 μmol/Lhr) presented a high DFS, probably due to the shorter interval of time between MTX courses that led to a higher dose density. In patients with AUC > 2,400 μmol/Lhr, an increase in the AUC was related to an increase in the DFS. Significant differences were observed in the DFS between patients whose mean AUC was below or above 4,000 μmol/Lhr (P = 0.024), such that 4,000 μmol/Lhr was considered as the minimum AUC to be aimed at for future patients. Conclusions Dose density seems to be an important factor in osteosarcoma response, but this must be confirmed in further studies. In order to improve the response to osteosarcoma in children, it is recommended that the dose of MTX to be increased such as to obtain an AUC higher than 4,000 μmol/Lhr.