Osteosarcoma: review of the past, impact on the future. The American experience.

Major advances have been achieved in the treatment of osteosarcoma with the discovery of several chemotherapeutic agents that were active in the disease. These agents comprise high-dose methotrexate with leucovorin rescue, Adriamycin, cisplatin, ifosfamide and cyclophosphamide. The agents were integrated into various regimens and administered in an effort to destroy silent pulmonary micrometastases which are considered to be present in at least 80% of patients at the time of diagnosis. Their efficacy in achieving this goal was realized and their use was further extended to the application of preoperative (neoadjuvant) chemotherapy to destroy the primary tumor and achieve safe surgical resections. Disease free survival was escalated from <20% prior to the introduction of effective chemotherapy to 55-75% and overall survival to 85%. Further, the opportunity to perform limb salvage was expanded to 80% of patients. Of interest also was an attempt in one series to treat the primary tumor exclusively with chemotherapy, and abrogation of surgery. Adding to these advances, varieties of subsequently discovered agents are currently undergoing investigations in patients who have relapsed and/or failed conventional therapy. The agents include Gemcitabine, Docetaxel, novel antifolate compounds, and a liposome formulation of adriamycin (Doxil). A biological agent, muramyl tripeptide phosphatidyl ethanolamine (MTPPE) was also recently investigated in a 2x2 factorial design to determine its efficacy in combination with chemotherapy (methotrexate, cisplatin, Adriamycin and ifosfamide).In circumstances where the tumor was considered inoperable, chemotherapy and radiotherapy were advocated for local control. High dose methotrexate, Adriamycin and cisplatin and Gemcitabine interact with radiation therapy and potentiate its therapeutic effect. This combination is also particularly useful in palliation. Occasionally, the combination of radiation and chemotherapy may render a tumor suitable for surgical ablation. Samarium153, a radio active agent, is also used as palliative therapy for bone metastases.However, despite the advances achieved with the multidisciplinary application of chemotherapy, radiotherapy and surgical ablation of the primary tumor over the past 3(1/2) decades, the improved cure rate reported initially has not altered. Particularly vexing is the problem of rescuing patients who develop pulmonary metastases after receiving seemingly effective multidisciplinary treatment. Approximately 15-25% of such patients only are rendered free of disease with the reintroduction of chemotherapy and resection of metastases. Extrapulmonary metastases and multifocal osteosarcoma also constitute a major problem. The arsenal of available agents to treat such patients has not made any substantial impact in improving their survival. New chemotherapeutic agents are urgently required to improve treatment and outcome. Additional strategies to be considered are targeted tumor therapy, anti tumor angiogenesis, biotherapy and therapy based upon molecular profiles. This communication outlines sequential discoveries in the chemotherapeutic research of osteosarcoma in the United States of America. It also describes the principles regulating the therapeutic application of the regimens and considers the impact of their results on the conduct in the design of future investigations and treatment.