Comparison of two chemotherapy regimens in Ewing sarcoma (ES): Overall and subgroup results of the Euro Ewing 2012 randomized trial (EE2012).

Abstract

11500 Background: In 2010, different chemotherapy regimens were standard in Europe and the USA for newly diagnosed ES. In the absence of novel agents to investigate, comparison of these two strategies was considered worthwhile. Methods: Newly diagnosed localised or metastatic ES patients aged 5-50 were eligible. Patients were randomized to receive either the European regimen (Arm A) of VIDE (vincristine [V], ifosfamide [I], doxorubicin [D] and etoposide [E]) induction and VAI or VAC (V, actinomycin D and I or cyclophosphamide [C]) consolidation or the USA regimen (Arm B) of compressed VDC/IE induction and IE/VC consolidation. The primary outcome measure was event-free survival (EFS); secondary outcomes included overall survival (OS) and toxicity. The design was Bayesian with interpretation based on posterior probabilities (with non-informative priors) – i.e. probability that true hazard ratio (HR) < 1.0 given the data [Pr(HR<1.0|data)], with 95% credible intervals (CrI) reported. HRs were obtained from Cox models adjusted for baseline stratification parameters. Heterogeneity tests (HT) were used to investigate whether the treatment effect differed according to baseline parameters. Analysis was intention-to-treat. Results: Between December 2013 and May 2019, 640 patients were randomised (320 to each arm) from 10 European countries. Baseline stratification factors were: sex (58% male; 42% female); age (41% <14 years; 59% 14+ years); disease type (74% localised, 17% lung/pleural metastasis, 9% other metastasis); tumour volume (56% <200 ml, 44% >200 ml); country (37% UK, 31% France, 32% other). Median follow-up was 1.7 years. The HRs (95% CrI) were 0.70 (0.51, 0.95) for EFS and 0.64 (0.42, 0.96) for OS in favour of Arm B, with posterior probabilities of 98% for both that Arm B was better. Subgroup analyses showed no evidence that this benefit differed depending the baseline features, with no HT being close to significance (table). There were no major differences in acute toxicity: 68% of patients in Arm A experienced serious adverse events and 67% in Arm B. Conclusions: VDC/IE chemotherapy is superior to VIDE for both EFS and OS, with no excess toxicity. This benefit is consistent across all baseline stratification parameters. Clinical trial information: ISRCTN92192408 . [Table: see text]