MAPIE vs MAP as postoperative chemotherapy in patients with a poor response to preoperative chemotherapy for newly-diagnosed osteosarcoma: results from EURAMOS-1 (Paper 032)

Objects: EURAMOS-1 is an international randomized controlled trial investigating treatment optimization in osteosarcoma on the basis of histological response to preoperative chemotherapy (CT). We investigated the efficacy and safety of an intensified CT regimen for patients (pts) with a “poor response” (PoR; ≥10% viable tumor at surgery). Methods: Pts ≤40yrs with localized or primary metastatic high-grade extremity or axial osteosarcoma deemed resectable were eligible for registration at diagnosis. Eligibility for randomization included: [a] receipt of two cycles preoperative methotrexate, doxorubicin, cisplatin (MAP); [b] complete macroscopic resection of primary tumor; and [c] no disease progression. PoR pts were randomized (1:1) after surgery to continuation with MAP or intensification with MAPIE, which included the same total doses of M, A and P, plus ifosfamide and etoposide. The primary outcome measure was event free survival (EFS); secondary: overall survival, toxicity. The trial design sought improved 3yr EFS from 45% to 55% (80% power, 2-sided alpha 5%). The final analysis was planned after 378 EFS events. Following a routine annual review of emerging data (Jun-14), the Independent Data Monitoring Committee recommended early release of results. This was ratified by the Trial Steering Committee (25-Jul-14). Results: 2,260 pts were registered (Apr-05 to Jun-11) from 17 countries (326 sites). PoR was reported in 1,059 pts and 618 consented to randomization (310 MAP, 308 MAPIE). Baseline characteristics were balanced by arm: median age 14yr, 59% male, 13% confirmed metastases. At Mar-14, with a median follow-up of 4.5 years, there were 300 EFS events and 182 deaths. Fewer patients allocated MAPIE received the intended dose of each drug. Toxicity (acute and long-term) was greater with MAPIE, and there were more secondary malignancies. There was no evidence of an advantage in terms of EFS: hazard ratio 1.01 (95% CI 0.80-1.26), nor in survival: hazard ratio 0.99 (95% CI 0.74-1.32). There was evidence of non-proportionality of hazards in EFS; the restricted mean EFS time also showed no difference. Conclusions: We found that adding ifosfamide and etoposide to MAP is associated with additional morbidity and has no effect on survival outcomes. Evidence from EURAMOS-1 does not support adaptation of postoperative chemotherapy based on histological response.