Mega doses of methotrexate in the treatment of osteosarcoma.

High-dose-methotrexate therapy with eitrovorum factor (leucovorin) rescue has been widely used in the treatment of many solid tumors and lymphomas. This therapy plays an important role in the management of osteosarcoma. The rationale behind using high doses of this drug is to achieve high plasma levels (10 to 10-5 M)for prolonged periods. This probably facilitates the passive entry of methotrexate (MTX) into the tumor cells having defective transport systems. It has also been suggested that increased intracellular levels of free MTX can over come drug resistance caused by increased levels of dihydrofolate reductase (DHFR) or presence of a DHFR having low affinity for MTX Moreover, such high doses facilitate MTX polyglutamate formation within the tumor cells and hence prolong its cytotoxie effects. On these basis, such therapy has been advocated for base in osteosarcoma. The treatment has been shown to reduce regression of primary and metastatic tumors and response rates seem to increase with more frequent and intense treatments. More recently, some workers have used 12 g/m of MTX which results in improved response rate and survival. Previously we have reported the treatment of two cases of metastatic osteosarcoma with high doses (5 g/m) of MTX. Mega doses, however, have not been attempted in Pakistan due to its prohibitive cost and toxicity. We recently treated a case of osteosarcoma with 12 g/m of MTX on four different occasions. We monitored the MTX levels in the plasma as well as RBCs and evaluated the toxicity and clinical outcome of this patient.