Understanding divergent outcomes: A comparative analysis of ESOPEC and CROSS real-world studies in esophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma is an aggressive malignancy with increasing incidence and high mortality. Two established treatment strategies for resectable disease are perioperative chemotherapy with FLOT and neoadjuvant chemoradiotherapy (nCRT) using the CROSS protocol. The ESOPEC trial demonstrated a survival advantage of FLOT over CROSS, while real-world data on CROSS suggest broad applicability in clinical practice. This study compares outcomes of the recently published ESOPEC trial with a large real-world cohort to inform treatment decisions METHODS: We conducted a comparative analysis of the ESOPEC randomized controlled trial and the nationwide real-world cohort study by van Laarhoven et al. Patient characteristics, pathological complete response (pCR), overall survival (OS), progression-free survival (PFS), treatment completion, and adverse events were analyzed. A retrospective PICO framework was applied to systematically compare study designs and populations RESULTS: The ESOPEC trial (n = 438) showed a median OS of 66.0 months in the FLOT arm versus 37.0 months with CROSS (HR: 0.70, p = 0.01), while the real-world CROSS cohort (n = 4765) showed a median OS of 33.7 months. The pCR rate was higher in the real-world CROSS study (20.5 %) than in ESOPEC's CROSS arm (10.1 %) and exceeded the pCR of ESOPEC's FLOT arm (16.7 %) CONCLUSION: FLOT demonstrates superior survival outcomes compared to CROSS in controlled settings, supporting its use in fit patients. However, CROSS remains an effective and tolerable real-world strategy. Treatment selection should consider tumor location, patient fitness, and toxicity. Standardized pCR assessment is essential to bridge clinical trial and real-world data.

Keywords: Comparative outcome analysis; Esophageal adenocarcinoma; Neoadjuvant chemoradiotherapy; Pathological complete response (pCR); Perioperative FLOT chemotherapy; Real-world evidence.