ESOPEC: targeting micro-metastatic disease combined with local control

Esophageal and gastric adenocarcinoma are global diseases with a combined annual incidence of approximately 1.5 million cases. They are the fifth and seventh highest causes of cancer mortality worldwide (1). While all gastric and gastroesophageal junction (GEJ) cancers are adenocarcinomas (GEAC), approximately 90% of cancers of the thoracic esophagus are squamous cell carcinomas [esophageal squamous cell carcinoma (ESCC)] (1). Worldwide, ESCC accounts for approximately 85% of esophageal cancers, though this varies considerably by region. While ESCC is by far the most predominant subtype in Asia and Africa, esophageal adenocarcinoma predominates in North America and Europe (2,3).

Among both ESCC and GEAC, cure and extension of life remain a challenge: approximately 50% of patients present with incurable stage disease (4). The cure rate for locally advanced disease is limited, and once metastatic, cure is rare. For patients with potentially curable stages of disease, definitive treatment includes surgery as the keystone component. However, given the limited cure rates with surgery alone, additional modalities—chemotherapy and radiation—were tested in combinations and sequences with surgery (5).

Based upon years of iteration and testing in clinical trials, two approaches became standards of care across the world. For GEAC, peri-operative chemotherapy was validated in the MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) and AIO (Arbeitsgemeinschaft Internistische Onkologie) studies as superior to surgery alone or surgery followed by adjuvant therapy (6,7). For locally advanced esophageal adenocarcinoma and squamous cell carcinoma, pre-operative concurrent chemoradiation is the preferred option based on the CROSS (ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study) trial (8).

One unifying feature of both approaches is the anatomic target of the GEJ—a physical, histologic, and likely biologic bridge between the stomach and the distal esophagus (9). In retrospect, there are mechanistic reasons to support both peri-operative chemotherapy and neoadjuvant chemoradiotherapy (CRT). Each combines therapies that maximize both loco-regional and distant disease control. Distant disease control is achieved via targeting of presumed micrometastases. In CRT, local control is enhanced by radiation at the risk of less systemic control due to lower doses of chemotherapy. In peri-operative therapy, local control depends on surgery alone while full doses of chemotherapy maximize control of distant disease. However, until each treatment paradigm was tested head-to-head, the fractional contributions of local and systemic control to overall survival (OS) were not known.

The ESOPEC trial aimed to answer this question by comparing OS in locally advanced, resectable esophageal and GEJ adenocarcinomas in 438 patients treated with peri-operative FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel) or neoadjuvant CRT (10). OS was higher with peri-operative FLOT [hazard ratio (HR) 0.70; P=0.01], therefore answering the question of which approach is superior. However, in the initial publication, follow-up was relatively short, limiting the ability to explain why FLOT was superior. The subsequent Journal of Clinical Oncology publication by Hoeppner et al. with longer-term follow-up provides additional data on recurrence patterns, allowing assessment of whether improved local or distant control explains the OS benefit (11).

Local control, measured by pathologic complete response (pCR), was superior in the CROSS arm of ESOPEC (16.8% vs. 10%) despite inferior OS. The explanation for the superiority of FLOT lies in reduced distant and metastatic recurrence across all sites: distant lymphatic (9.3% vs. 15.6%; HR 0.60), hematogenous (17.2% vs. 26.1%; HR 0.59), and pleural/peritoneal recurrence (12.0% vs. 16.4%; HR 0.63, not statistically significant) (11). These findings suggest that the improved OS with FLOT is primarily driven by improved systemic disease control, which outweighs the superior local control achieved with CRT. Based on these data, peri-operative FLOT represents the preferred standard of care for locally advanced GEAC.

There are several differences between the CRT arm of the original CROSS trial and the CRT arm of the ESOPEC trial that may influence interpretation of OS differences. Median OS for the CROSS regimen was lower in ESOPEC (39 vs. 44 months), and the pCR rate for adenocarcinoma was lower in ESOPEC (10% vs. 23%) (8,10). Relatedly, in CROSS-CRT 91% of patients completed all five cycles chemotherapy and 92% completed all radiotherapy. Contrastingly, in ESOPEC-CRT only 67% of patients completed all chemotherapy and 89% completed all radiotherapy. Surgical resection status was comparable across both studies: R0 resection was achieved in 92% of patients in the CROSS-CRT and 95% in ESOPEC-CRT. While these differences may contribute to the observed OS advantage of FLOT, cross-trial comparisons should be interpreted with caution.

The ESOPEC results simplify and unify the treatment paradigm for locally advanced GEAC: peri-operative FLOT is superior to neoadjuvant CRT across anatomic sites. Longer-term recurrence data from Hoeppner et al. further explain this benefit through improved systemic disease control with full-dose peri-operative chemotherapy (11). This unified approach establishes a new therapeutic backbone upon which future strategies for GEAC may be built. It is unclear to what extent ESOPEC’s findings apply to medical practice where ESCC predominates, as ESOPEC only included patients with GEAC. However, recent trials in Asia have also supported a shift towards pre- and postoperative chemotherapy as opposed to adjuvant chemotherapy (12,13). Given that FLOT likely represents the upper limit of tolerability for cytotoxic therapy, ongoing trials are evaluating the addition of immunotherapy and targeted agents. One such study, MATTERHORN, reported OS data at the 2025 European Society for Medical Oncology (ESMO) meeting, demonstrating improved survival with the addition of the immune checkpoint inhibitor (ICI) durvalumab to peri-operative FLOT compared with chemotherapy alone (14). Additionally, CHECKMATE-577 demonstrated improved disease-free survival with the addition of nivolumab in patients without a pCR to CROSS (15).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0045/prf

Funding: This work was supported by the VUMC Cancer Center Support Grant - 4P30CA068485-30.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0045/coif). M.K.G. received consulting fees from AMCA. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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