PREDICTIVE FACTORS OF HISTOLOGIC RESPONSE TO PRIMARY CHEMOTHERAPY IN OSTEOSARCOMA OF THE EXTREMITY - STUDY OF 272 PATIENTS PREOPERATIVELY TREATED WITH HIGH-DOSE METHOTREXATE, DOXORUBICIN, AND CISPLATIN

Purpose: In osteosarcoma of the extremity, a strong correlation betwee n chemotherapy-induced necrosis and prognosis has been reported. The a im of this study was to investigate the possible factors that influenc e histologic response to primary chemotherapy. Patients and Methods: I n 272 patients with high-grade osteosarcoma of the extremity preoperat ively treated with high-dose methotrexate (HDMTX), cisplatin (CDP), an d doxorubicin (ADM), the histologic response to chemotherapy was evalu ated and graded as complete (no viable tumor cells) or incomplete (per sistence of viable tumor cells). Several factors, such as metastatic d isease to the lung at diagnosis, sex, age, sire and tumor volume, hist ologic subtype, serum alkaline phosphatase, lactate dehydrogenase (LDH ), and methotrexate (MTX) pharmacokinetics were investigated to test t heir predictive significance on histologic response. Results: Fifty-on e patients with localized disease (20.6%) and none of the 25 patients with metastatic disease at presentation had a complete histologic resp onse (P = .006). After multivariate analysis, performed on patients wi th localized disease only, MTX serum peak (greater than or equal to 70 0 mu mol/L) and histologic subtype were proven to be significant predi ctive factors of histologic response. A complete response was seen in 28.8% of patients with 700 mu mol/L or greater MTX serum levels and in 9.9% of those patients with lower levels (P = .001). The chondroblast ic subtype was less responsive (6.1% of complete response), compared w ith the osteoblastic (16.3%), fibroblastic (33.3%), and telangiectatic (42.3%). Conclusion: Patients with metastatic osteosarcoma and locali zed chondroblastic osteosarcoma have a reduced chemosensitivity to pri mary chemotherapy with MTX, CDP, and ADM. MTX serum peak significantly influences tumor necrosis. A dose adaptation of MTX is recommended to obtain a serum peak of 700 mu mol/L or greater when MTX is infused in 6 hours. (C) 1998 by American Society of Clinical Oncology.