Originally published as JCO Early Release 10.1200/JCO.2004.00.5785 on October 24 2005

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Neoadjuvant Chemotherapy With High-Dose Ifosfamide, High-Dose Methotrexate, Cisplatin, and Doxorubicin for Patients With Localized Osteosarcoma of the Extremity: A Joint Study by the Italian and Scandinavian Sarcoma Groups

From the Chemotherapy, Surgery, Pathology, and Basic Research Divisions of the Department of Musculoskeletal Oncology, Istituti Ortopedici Rizzoli, Bologna; Oncologic/Orthopaedic Surgery, Centro Traumatologico Ortopedico, Firenze; Department of Pediatric Oncology, Meyer Hospital, Firenze; Department of Medical Oncology, S Maria delle Croci Hospital, Ravenna; Department of Oncology, Gradenigo Hospital; Department of Pediatric Oncology, Ospedale Regina Margherita, Torino, Italy; Department of Medical Oncology, The Norwegian Radium Hospital, Oslo, Norway; Department of Cancer Epidemiology, and Paediatric Oncology, Lund University Hospital, Lund; Department of Orthopaedics, Karolinska Hospital, Stockholm, Sweden; and Department of Pathology, Haartman Institute, Helsinki, Finland.

Address reprint requests to Stefano Ferrari, MD, Chemotherapy, Istituti Ortopedici Rizzoli, Via C. Pupilli 1, 40136 Bologna, Italy; e-mail: stefano.ferrari{at}ior.it

PURPOSE: To explore the effect of high-dose ifosfamide in first-line treatment for patients 40 years of age with nonmetastatic osteosarcoma of the extremity.

PATIENTS AND METHODS: From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m²), methotrexate (12 g/m²), cisplatin (120 mg/m²), and doxorubicin (75 mg/m²). Postoperatively, patients received two cycles of doxorubicin (90 mg/m²), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m²). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination.

RESULTS: No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI, 57% to 71%) and overall survival was 77% (95% CI, 67% to 81%), whereas seven patients (4%) experienced local recurrence.

CONCLUSION: The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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