Relationship of peak serum methotrexate concentration to prognosis and drug tolerance in non-metastatic extremity osteosarcomas

Abstract

Purpose

This study aimed to explore whether peak serum methotrexate concentration (C_max) correlated with adverse events, overall survival (OS) and event-free survival (EFS) in patients with primary extremity osteosarcoma.

Methods

Patients with extremity osteosarcoma who were treated at our center between 2005 and 2015 were retrospectively studied. All the patients were Enneking stage II and had received standard perioperative chemotherapy composed of high-dose methotrexate, doxorubicin, cisplatin and ifosfamide. C_max and treatment-associated toxicities of each cycle were recorded. OS and EFS were estimated and compared by Kaplan–Meier survival analysis, and Cox regression models were performed for univariate comparisons.

Results

In total, 567 patients were followed for an average of 53 months (24–104 months). The estimated 3- and 5-year EFS were 71.7 and 63.1%, and the 3- and 5-year OS were 78.2 and 72.9%, respectively. C_max ranged from 527 to 2495 µmol/L with a mean value of 931 ± 106 µmol/L. No significant differences in EFS and OS (p = 0.18 and p = 0.28) were observed among patients with a mean C_max > 1500, > 1000, > 700 and < 700 µmol/L. However, patients with a mean C_max > 1500 µmol/L had significantly increased rates of grade 3–5 toxicity. In the univariate analysis, C_max was not a prognostic factor for EFS (p = 0.08) or OS (p = 0.16).

Conclusions

C_max did not correlate significantly with the oncologic prognosis of non-metastatic extremity osteosarcoma patients treated by multi-agent chemotherapy; however, C_max correlated closely with toxicities and complications. The persistent inclusion of methotrexate in classical multidisciplinary chemotherapy was questioned and should be examined in future trials.

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