Adjuvant chemotherapy in osteosarcoma: An odyssey of rejection and vindication

Abstract

Osteosarcoma is the most common malignant bone tumor affecting children and adolescents. The biological behavior is consistent with the premise that pulmonary micrometastases are present at diagnosis in the majority of patients. These are silent and undetected on imaging studies. They usually surface six to twelve months following amputation of the primary tumor and if untreated are responsible for the patients demise. Until the 1970s the tumor was generally considered to be chemoresistant. However, in the early 1970's, two chemotherapeutic agents were found to be active in osteosarcoma. These comprised Adriamycin (doxorubicin) and high-dose Methotrexate with Citrovorin factor rescue (Leucovorin rescue). The administration of high-dose Methotrexate following amputation alone or in combination with other agents yielded a cure rate of 40-65 percent. This was attributed to the destruction of the pulmonary micrometastases. The improved survival due chemotherapy did not go unchallenged. The Mayo Clinic adduced data to suggest that there had been a "natural improvement" in the cure rate over several years and that it should not necessarily be assumed that chemotherapy, particularly high-dose Methotrexate, was responsible for the improvement. The veracity of historical controls and the efficacy of high dose Methotrexate were also disputed by additional claims from the Mayo Clinic. Principal among these was recent advances in diagnostic techniques i.e. CT lung and radionuclide bone scans. To resolve the problem a multi-institutional randomized osteosarcoma trial (MIOS) was launched. A series of patients was treated by amputation and postoperatively with multiagent chemotherapy comprising high-dose Methotrexate Adriamycin, Cisplatin, Bleomycin, Cyclophosphamide and Dactinomycin. A second series of patients was treated with amputation only (concurrent controls). Treatment by amputation and postoperative adjuvant chemotherapy achieved a 66 percent two-year disease-free survival. In contrast, patients treated by amputation alone garnered a significantly worse outcome: less than 20 percent survival. The latter was comparable to survival in the historical control series. Chemotherapy was thus found to be effective and comparison of the results with historical controls was validated. The above experience was further substantiated by an additional concurrent randomized trial. An editorial by James Holland in the Journal of Clinical Oncology commented on the results of the randomized trial(s) and offered suggestions for the conduct of future trials. The acceptance of chemotherapy as an integral and essential component for the treatment of osteosarcoma launched a new era in the conquest of this disease. © 2010 Springer Science+Business Media, LLC.