Neoadjuvant Chemoradiotherapy Versus Chemotherapy for the Treatment of Locally Advanced Esophageal Adenocarcinoma in the European Multicenter ENSURE Study

Objective: This study aimed to compare clinicopathologic, oncologic, and health-related quality of life (HRQL) outcomes following neoadjuvant chemoradiation (nCRT) and chemotherapy (nCT) in the ENSURE international multicenter study. Background: nCT and nCRT are the standards of care for locally advanced esophageal cancer (LAEC) treated with curative intent. However, no published randomized controlled trial to date has demonstrated the superiority of either approach. Methods: ENSURE is an international multicenter study of consecutive patients undergoing surgery for LAEC (2009-2015) across 20 high-volume centers (NCT03461341). The primary outcome measure was overall survival (OS), secondary outcomes included histopathologic response, recurrence pattern, oncologic outcome, and HRQL in survivorship. Results: A total of 2211 patients were studied (48% nCT, 52% nCRT). pCR was observed in 4.9% and 14.7% (P<0.001), with R0 in 78.2% and 94.2% (P<0.001) post nCT and nCRT, respectively. Postoperative morbidity was equivalent, but in-hospital mortality was independently increased [hazard ratio (HR)=2.73, 95% CI: 1.43-5.21, P=0.002] following nCRT versus nCT. Probability of local recurrence was reduced (odds ratio=0.71, 95% CI: 0.54-0.93, P=0.012), and distant recurrence-free survival time reduced (HR=1.18, 95% CI: 1.02-1.37, P=0.023) after nCRT versus nCT, with no difference in OS among all patients (HR=1.10, 95% CI: 0.98-1.25, P=0.113). On subgroup analysis, patients who underwent R0 resection following nCT as compared with nCRT had improved OS (median: 60.7 months, 95% CI: 49.5-71.8 vs 40.8 months, 95% CI: 42.8-53.4, P<0.001). Conclusions: In this European multicenter study, nCRT compared with nCT was associated with reduced probability of local recurrence but reduced distant recurrence-free survival for patients with LAEC, without differences in OS. These data support tailored patient-specific decision-making in the overall approach to achieving optimum outcomes in LAEC.