Esophageal adenocarcinoma is an aggressive malignancy with rising incidence and high mortality, for which multimodal treatment is standard in resectable disease. Surgery alone is insufficient, and combined systemic and locoregional approaches are required to improve long-term outcomes.
Two strategies dominate current practice. Perioperative chemotherapy with the FLOT regimen focuses on systemic disease control, while neoadjuvant chemoradiotherapy using the CROSS protocol aims to improve locoregional control and pathological response before surgery. Both approaches have demonstrated survival benefit, but they differ in intensity, toxicity, and therapeutic emphasis.
The article titled “Understanding Divergent Outcomes: A Comparative Analysis of ESOPEC and CROSS Real-World Studies in Esophageal Adenocarcinoma”, published in the European Journal of Surgical Oncology on December 27, 2025, highlights how outcomes observed in randomized controlled trials may diverge from those seen in real-world clinical practice. By comparing survival, pathological response, treatment completion, and safety between the ESOPEC trial and a large real-world CROSS cohort, the analysis provides important context for interpreting evidence and supports more individualized treatment decision-making in resectable esophageal adenocarcinoma.
Authors: Pascal Burri, MD ∙ Stavros Chatziisaak, MD ∙ Sebastian Wolf, MD ∙ Dimitrios Chatziisaak, MD, MSc
Methods and Endpoints
This analysis is based on two complementary data sources evaluating multimodal treatment strategies for resectable esophageal adenocarcinoma.
First, real-world outcomes of neoadjuvant chemoradiotherapy using the CROSS protocol were derived from a nationwide observational cohort reported in the Netherlands Cancer Registry. This cohort reflects routine clinical practice, encompassing a broader and more heterogeneous patient population, including older patients, wider variation in tumor location, and less restrictive staging criteria. Real-world data were used to assess overall survival, pathological response, treatment completion, and postoperative outcomes outside the controlled setting of a randomized trial.
Second, comparative trial-based evidence was obtained from the ESOPEC phase III randomized controlled trial, presented at ESTRO 2025. ESOPEC enrolled a highly selected population of patients with resectable esophageal or gastroesophageal junction adenocarcinoma and directly compared perioperative FLOT chemotherapy with neoadjuvant chemoradiotherapy according to the CROSS protocol under standardized treatment conditions.
A retrospective PICO framework was applied to systematically compare study design, patient characteristics, and outcome reporting across the real-world cohort and the ESOPEC trial. Key endpoints included overall survival, progression-free survival, pathological complete response, treatment completion rates, postoperative mortality, and treatment-related toxicity.
You can read about ESOPEC trial updates from ESTRO 2025: Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer on OncoDaily.
Results
A total of 438 patients were included in the ESOPEC trial, compared with 4,765 patients in the real-world CROSS cohort. Patients enrolled in ESOPEC were younger and more frequently presented with advanced T stage and nodal involvement, reflecting the trial’s selective enrollment criteria.
Survival outcomes favored perioperative chemotherapy. In ESOPEC, FLOT achieved a median overall survival of 66 months versus 37 months with CROSS, corresponding to a significant reduction in mortality risk.Progression-free survival favored FLOT. In contrast, the real-world CROSS cohort demonstrated a median overall survival of 33.7 months, closely aligning with the CROSS arm of ESOPEC but substantially inferior to FLOT.
Pathological complete response rates showed a different pattern.
- FLOT achieved a pCR rate of 16.7% in ESOPEC
- CROSS achieved 10.1% pCR within ESOPEC
- real-world CROSS demonstrated a higher pCR rate of 20.5%
This discrepancy may reflect differences in patient selection, pathological evaluation, and reporting practices rather than superior systemic disease control in routine care.
Treatment delivery and safety differed between strategies. FLOT was associated with higher rates of grade ≥3 systemic toxicity, while CROSS demonstrated favorable tolerability and high treatment completion rates in the real-world setting, noting that adverse events were not systematically captured in registry data. Differences in postoperative outcomes were observed between treatment strategies, while real-world CROSS outcomes were comparable to those reported in the ESOPEC CROSS arm, with no unexpected safety signals.
Conclusion
This comparative analysis supports perioperative FLOT chemotherapy as the strategy associated with improved survival outcomes in resectable esophageal adenocarcinoma when delivered in a randomized trial setting. At the same time, it demonstrates that neoadjuvant chemoradiotherapy with CROSS remains an effective, reproducible, and well-tolerated option in real-world clinical practice.
Key clinical implications include:
- FLOT offers improved systemic disease control and survival in fit patients
- CROSS remains a valid alternative for patients unsuitable for intensive chemotherapy
- variability in pCR highlights the need for standardized pathological response assessment
Overall, treatment selection should be individualized, integrating tumor location, patient fitness, toxicity tolerance, and therapeutic goals. Bridging the gap between trial evidence and real-world outcomes will be essential as multimodal and organ-preserving strategies continue to evolve in esophageal adenocarcinoma.
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