The treatment of nonmetastatic high grade osteosarcoma of the extremity: Review of the Italian Rizzoli experience. Impact on the future

The Bone Tumor Center of the "Istituto Ortopedico Rizzoli" was established in 1955 with the aim of studying and treating the musculoskeletal tumors. Between 1959 and 2006, 1245 patients with high grade nonmetastatic osteosarcoma of the extremity were treated at our Institute. Most of them were enrolled in study protocols. In the "prechemotherapy era", the cure rate was 11%, with an amputation rate of 90%. Our first experience with adjuvant chemotherapy was in 1972. A total of 223 patients received adjuvant chemotherapy, with a disease-free survival (DFS) ranging from 45% to 53%, according to the chemotherapy protocol used. With the introduction of neoadjuvant chemotherapy, the resection rate increased and reached 94%, when high dose fosfamide was added to standard doses of methotrexate, cisplatin, and adriamycin. In the last few years, the results of treatment of nonmetastatic osteosarcoma of the extremity have reached a plateau (64% five-year DFS), and strategies of dose intensification are not able to improve the prognosis. Not only new active drugs, but also different approaches to the disease, are needed. In this regard, we are now investigating tumor microenvironment-targeted agents and chemotherapy protocols based on prospective biological stratification of patients. Collaborative projects with international groups and institutions are crucial for this rare disease.