Osteosarcoma: methotrexate & doxorubicin versus methotrexate, etoposide & ifosfamide

Study Type: Therapy
OE Level of Evidence: 2
Journal Level of Evidence: N/A
Synopsis
234 patients with nonmetastatic osteosarcoma were randomized to preoperative chemotherapy of high-dose methotrexate with either doxorubicin or with etoposide and ifosfamide. After a median of 77-month follow-up, patients who had received the etoposide-ifosfamide regimen exhibited a larger percentage of good histologic response. Three- and 5-year Please login to view the rest of this report. Please login to view the rest of this report.
Funding: Non-Industry funded
Sponsor: Association pour la Recherche sur le Cancer; Institut Gustave-Roussy, France
Conflicts: None disclosed
CONTENT IS LOCKED
Why was this study needed now?
Current strategies of chemotherapy in patients with osteosarcomas usually involve preoperative administration of high-dose methotrexate, doxorubicin, cisplatin, and ifosfamide; although, the multi-drug combinations can cause an increase in toxicity. In particular, cardiotoxicity and ototoxicity can be observed with doxorubicin and cisplatin use, respectively. Previous studies have looked at the combination of etoposide and ifosfamide, and have reported a high response rate. Accordingly, a study was required to determine which regimen was more effective.
What was the principal research question?
Was histologic response better with high-dose methotrexate plus etoposide and ifosfamide compared to high-dose methotrexate plus doxorubicin?
Population: 234 patients (<20 years of age) with high-grade, nonmetastatic limb osteosarcoma
Intervention: Etoposide-ifosfamide arm: Preoperative chemotherapy consisted of 7 courses of high-dose methotrexate (12 g/m^2; 4-hour infusion) and two 4-day courses of etoposide (75mg/m2 i.v. over 1 hour in 250-500mL saline serum) and ifosfamide (3g/m2/day i.v. over 3 hours in 250-500mL serum saline). High-dose methotrexate was administered during weeks 1, 2, 3, 7, 8, 12, and 13, and etoposide-ifosfamide were given daily for 4 days during weeks 4 and 9. Surgery was planned during week 14. Postoperative chemotherapy consisted of 12 courses of high-dose methotrexate and 3 courses of etoposide-ifosfamide in good responders, and 5 courses of cisplatin (120mg/m2) and doxorubicin (70mg/m2) in poor responders. (n=118)
Comparison: Doxorubicin arm: Preoperatve chemotherapy consisted of 7 courses of high-dose methotrexate (12g/m2; 4-hour infusion with 1L of 5% dextrose in water with 1mEq/kg sodium bicarbonate) and 2 courses of doxorubicin (70mg/m2; 6-hour infusion). Methotrexate was administered on weeks 1, 2, 3, 6, 7, 10, and 11, and doxorubicin was administered on weeks 4 and 8. Surgery was planned during week 12. Postoperative chemotherapy consisted of 12 courses of high-dose methotrexate and 3 courses of doxorubicin in good responders, and 5 courses of etoposide-ifosfamide in poor responders. (n=116)
Outcomes: Histologic analysis was performed according to the Huvos method, with good histologic response defined as total or almost total necrosis (5% or less of viable cells). Event-free survival and overall survival were calculated by Kaplan-Meier method. Treatment toxicity was also evaluated by World Health Organisation (WHO) toxicity scale for children.
Methods: RCT, Multicenter, Assessor-blinded
Time: Median follow-up was 77 months. Chest x-rays were obtained every 2-3 months for the first 3 years, every 4 months for years 4 and 5, and yearly thereafter. Bone scintigraphy was performed every 6 months for the first 3 years.
What were the important findings?
What should I remember most?
How will this affect the care of my patients?
The authors responsible for this critical appraisal and ACE Report indicate no potential conflicts of interest relating to the content in the original publication.