Serum Methotrexate (MTX) Concentrations and Prognosis in Patients with Osteosarcoma of the Extremities Treated with a Multidrug Neoadjuvant Regimen

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Abstract
The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital. The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 μmol/1) than in the patients who relapsed (571.9 μmol/1) ( p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 μmol/1. In fact, according to the mean MTX concentrations, the patients with less than 700 μmol/1 showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700μmol/1 MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed. These data suggest that in neoadjuvant chemotherapy of osteosarcoma there is a correlation, even in patients treated with multidrug regimens, between serum concentrations of MTX and the prognosis; for this reason the patients who show low MTX serum concentrations should be treated with increased amounts of MTX to achieve upper 700 μmol/1 MTX serum levels.

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