Randomized comparison of VAC versus VAI chemotherapy (CT) as consolidation for standard risk (SR) Ewing sarcoma tumor (ES): Results of the Euro-EWING.99-R1 trial.

Abstract

9517 Background: Anthracyclines and alkylating agents are the main effective drugs known for ES. Ifosfamide and cyclophosphamide are widely used, have different toxicity profiles and unknown relative efficiency. The Euro-EWING.99-R1 trial compared, in SR localized ES, two consolidation regimens combining either ifosfamide or cyclophosphamide with vincristine and D-actinomycin (VAI vs VAC) given after an intense induction CT containing vincristine, ifosfamide, doxorubicin and etoposide (VIDE) (NCT00020566). Methods: SR tumors were localized ES with either a good histological response to VIDE chemo (<10% cells), or small tumors (< 200 ml) resected at diagnosis or receiving radiotherapy alone as local treatment. Pts entered the trial after 6 VIDE + 1 VAI courses. Allocated treatment was either 7 VAI courses with ifo = 6 g/m²/course or 7 VAC courses with cyclo = 1.5 g/m²/course. Randomization was stratified by gender, age, local treatment and data center. It was a non-inferiority trial comparing VAC to VAI with a limit of non-inferiority set at -8.5% for 3-y event-free survival rate (EFS). Overall, 806 pts were required to achieve 80%-power with 1-sided alpha = 5%. 91.4%-confidence intervals (CI) are given for this final analysis performed after 3 interim analyses. Results: 856 pts were recruited between 02/2000 and 08/2010 in 202 European pediatric and adult oncology centers in 11 countries: 424 VAI and 432 VAC. With a median FU of 4.6 y, the main results were: 3-y EFS = 77.1 and 76.0% respectively, 3-y EFS difference = -1.1% (-6.3; +4.2), hazard ratio (HR) of event = 1.06 (0.83; 1.36), HR of death = 1.05 (0.78; 1.41) (intention to treat). Results were stable on the per protocol population. Major modifications of CT were significantly more frequent in the VAI arm (13%) than in the VAC arm (6%) due to toxicity but also to an inferior compliance. We observed more thrombocytopenia in the VAC arm but more grade 2-4 acute tubular renal toxicity in the VAI arm (31 vs 16%). Conclusions: Cyclophosphamide and ifosfamide have a similar efficacy in consolidation treatment of standard risk Ewing sarcoma. Late effects studies are on-going to compare renal and gonadal toxicity of both arms.