| Summary: | 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 micromol/L hr) 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 micromol/L hr, 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 micromol/L hr
(P=0.024), such that 4,000 micromol/L hr 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
micromol/L hr.
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