Nonmetastatic Osteosarcoma of the Extremity: Results of a Neoadjuvant Chemotherapy Protocol (IOR/OS-3) with High-dose Methotrexate, Intraarterial or Intravenous Cisplatin, Doxorubicin, and Salvage Chemotherapy Based on Histologic Tumor Response

Abstract

Aims and Background: From 1986 to 1989, a study for the treatment of nonmetastatic osteosarcoma of the extremity (IOR/OS-2) was carried out at the Rizzoli Institute. The cumulative dose of doxorubicin delivered was 480 mg/m², and severe heart failure developed in 5 (3%) of the 164 treated patients. The specific aim of the subsequent study was to assess the efficacy of a protocol, similar to IOR/OS-2, but with a reduced cumulative dose of doxorubicin (390 mg/m²). Additional aims were to assess the role of the route of infusion (intraarterial or intravenous) of cisplatin on histologic response of the primary tumor and the use of ifosfamide as salvage chemotherapy in poor responders. Methods: The new chemotherapy regimen (IOR/OS-3) was comprised of a preoperative phase with methotrexate (10 g/m²), cisplatin (120 mg/m² intraarterially or intravenously), and doxorubicin (60 mg/m²). After surgery, the same drugs were administered, with the addition of ifosfamide (10 g/m²) in patients who had a poor histologic response to primary chemotherapy. Results: Ninety-five patients entered the study. The rate of good histologic response was 64% with intraarterial cisplatin and 43% with intravenous cisplatin (P = 0.05). The 8-year event-free survival and overall survival were 54% and 61%, respectively, with no significant difference according to the histologic response. No cases of clinical doxorubicin-induced cardiopathy were recorded. Event-free and overall survival did not significantly differ from those achieved with IOR/OS-2 (8-year disease-free and overall survival, respectively 63% and 72%). Conclusions: The reduction in the doxorubicin cumulative dose avoided episodes of cardiotoxicity, without consequences on the efficacy of treatment. The addition of ifosfamide was an effective “salvage” therapy for poor responders. A better histologic response with intraarterial cisplatin was observed, but owing to the availability of an effective salvage therapy for poor responders, the advantages in terms of histologic response did not compensate for the cost and discomfort for the patients of this modality of infusion of cisplatin.