High-Dose Methotrexate in Osteosarcoma: Let the Questions Surcease—Time for Final Acceptance

Osteosarcoma is the most common primary malignant bone tumor affecting children and adults. The etiology is unknown, although a higher incidence occurs in patients with bilateral retinoblastoma, Paget’s disease of bone, the Li Fraumeni syndrome, and those who have received therapeutic radiation. The biologic behavior is consistent with the premise that silent pulmonary micrometastases are present in at least 80% of patients at diagnosis. These metastases are not visible on imaging studies, but in the absence of effective systemic therapy, they generally surface 6 to 9 months after surgical ablation of the primary tumor. If untreated, they will be responsible for the patients demise within 2 to 3 years of their appearance. Historical controls reveal a survival of 5% to 20%. There are currently four major classes of chemotherapeutic agents with established efficacy that are used in the therapy of this malignancy: doxorubicin, cisplatin, ifosfamide/high-dose cyclophosphamide, and high-dose methotrexate with leucovorin rescue (MTXL). Doxorubicin and MTX-L were discovered first in the early 1970s. Doxorubicin, and the other agents when discovered later, were accepted without query; not so for MTX-L. It was initially subjected to intense scrutiny, 1,2 rebuffed intermittently, 3 and later incorporated with variable degrees of indifference or enthusiasm into therapeutic regimens seemingly for want of a more effective agent. During this interminable period of probation (still extant 4 ), support for its efficacy and confirmation of its activity emanated from various publications. It was shown to be effective in eliminating overt pulmonary metastases, improving the opportunity for limb salvage, healing pathologic fractures, and enhancing the effect of radiation therapy for palliation and control of inoperable tumors. 5 When administered postoperatively as the sole agent after ablation of the primary tumor, it increased survival to 40%, 6 and in combination with other agents (pre- and postoperative therapy), it increased survival to 65% to 75%. 6-12