Chemotherapy for osteosarcoma with high-dose methotrexate is effective and outpatient therapy is now possible

Background In phase 11 trials, combinations of methotrexate with agents such as doxorubicin, cisplatin, etoposide and ifosfamide have been shown to be more effective than methotrexate alone, as neoadjuvant or adjuvant treatments for osteosarcoma. Doxorubicin, however, is associated with long-term cardiotoxicity, while cisplatin is associated with ototoxicity. The Societe Francaise d'Oncologie Pediatrique (SFOP) Osteosarcoma group, therefore, compared the efficacy of two regimens without cisplatin as neoadjuvant treatment for osteosarcoma: methotrexate plus etoposide and ifosfamide versus methotrexate plus doxorubicin. Objective To compare the efficacy of high-dose methotrexate plus etoposide and ifosfamide with that of high-dose methotrexate plus doxorubicin as preoperative chemotherapy in pediatric patients with osteosarcoma. Design and intervention This multicenter randomized trial enrolled patients aged <20 years who had high-grade nonmetastatic limb osteosarcoma proven by biopsy. Patients in the doxorubicin arm received seven courses of high-dose methotrexate (12g/m(2)) and two courses of doxorubicin (70mg/m(2)). Methotrexate was given in weeks 1, 2, 3, 6, 7, 10 and 11, and doxorubicin in weeks 4 and 8. Patients in the etoposide-ifosfamide arm received seven courses of methotrexate, administered in weeks 1, 2, 3, 7, 8, 12 and 13, and, in addition, received etoposide (75mg/m(2)) and ifosfamide (3g/M-2) daily for 4 days in weeks 4 and 9. After surgical excision of the primary tumor, postoperative chemotherapy was given according to the histologic response as assessed by a pathologist blinded to group assignment. In the doxorubicin arm, good responders received 12 courses of methotrexate and 3 courses of doxorubicin, while poor responders received 5 courses of etoposide-ifosfamide. In the etoposide-ifosfamicle arm, good responders received 12 courses of methotrexate and 3 courses of etoposide-ifosfamicle, while poor responders received 5 courses of cisplatin (120mg/m(2)) and doxorubicin (70mg/m(2)). A good histologic response was defined as total or almost total tumor necrosis (i.e. the presence of <= 5% viable cells). Outcome measures The primary end point was a good histologic response after neoadjuvant chemotherapy. Secondary end points were event-free survival, overall survival and toxicity. Results The analysis included 234 patients from 28 centers, 116 of whom were randomized to the doxorubicin arm and 118 to the etoposide-ifosfamide arm. Median follow-up was 77 months. The full course of preoperative chemotherapy was completed by 86 patients (74%) in the doxorubicin arm and by 94 patients (80%) in the etoposide-ifosfamicle arm. A good response was obtained by 56% of patients in the etoposide-ifosfamicle arm and 39% in the doxorubicin arm (P=0.009). The 3-year EFS rates were 69% in the etoposide-ifosfamicle arm and 62% in the doxorubicin arm. Acute toxic effects were reported as manageable, with no acute-toxicity-related deaths. Conclusion In combination with seven cycles of high-dose methotrexate, two cycles of etoposide-ifosfamicle is superior to two cycles of doxorubicin as preoperative treatment for osteosarcoma.