The authors evaluated the combination of etoposide/cyclophosphamide (VP/CY) as initial, presurgical therapy for patients with osteosarcoma and found an 88% response rate for the primary tumor and any metastases. After definitive, limb-salvage surgery and adjuvant chemotherapy with etoposide, cyclophosphamide, cisplatin, and doxorubicin, patients without metastases at diagnosis whose cases were followed for a median of 2 years from diagnosis achieved a relapse-free survival (RFS) probability of 78% +/- 9%. This result is equivalent to the best adjuvant chemotherapy results reported to date. Patients without metastases at diagnosis had significantly better RFS probability (78% +/- 9%) than those with metastases at diagnosis (0%). Transient, severe myelosuppression has been the only major toxicity of the VP/CY courses. No irreversible organ damage or toxic deaths have been seen in patients enrolled in this study. The authors conclude that the combination of VP/CY is effective treatment for osteosarcoma, and when combined with cisplatin/doxorubicin (CIS/DOX), is as effective as any previously reported chemotherapy for osteosarcoma.