Reconsidering the role of esophagectomy in selected patients with stage IV esophageal adenocarcinoma

Stage IV esophageal adenocarcinoma (EAC) is generally regarded as a systemic disease. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for esophageal and esophagogastric junction cancers recommend systemic therapy as the primary treatment modality for metastatic disease, with local interventions considered only for highly selected patients following multidisciplinary evaluation (1). Similarly, the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines underscore the central role of systemic therapy in metastatic disease, while limiting the use of local treatments to specific circumstances, such as symptom palliation or within strictly selected multimodality or investigational frameworks (2).

Sewell and colleagues analyzed 66 patients with clinically diagnosed stage IV esophageal adenocarcinoma, including both stage IVA and IVB disease, who underwent esophagectomy after systemic therapy (3). Authors suggest that, in highly selected patients with stage IVB disease, particularly those with oligometastatic features, aggressive local treatment including resection of the primary tumor may contribute to long-term survival. This observation is clinically relevant in light of recent advances in systemic therapy. In advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma, immune checkpoint inhibitors combined with chemotherapy have become a standard first-line option, and durable disease control is increasingly observed. Long-term follow-up of the CheckMate 649 trial demonstrated sustained survival benefit with nivolumab plus chemotherapy, indicating that a subset of patients achieves prolonged disease control with modern systemic therapy (4,5). As a result, clinicians have been increasingly confronted with the question of whether additional local treatment should be reconsidered in selected patients.

In this study, the contrast in 3-year overall survival (OS) between stage IVA and IVB patients is striking, reported as 57% versus 85%, but likely influenced by strong selection bias. Patients in the IVB group were those who remained fit and progression free for a prolonged period before surgery, reflecting patient selection and sustained disease control enabling surgery, rather than the intrinsic survival benefit of esophagectomy itself. In addition, OS was measured from treatment initiation, and the interval between treatment initiation and surgery was markedly longer in the IVB cohort, with a median of 854 days. Consequently, survival time required to reach surgery is inherently incorporated into the analysis, raising concern for immortal time bias. Therefore, a direct comparison of survival between stage IVA and IVB disease may be of limited clinical meaning, as these groups differ not only in disease extent but also in treatment strategy, surgical approach, and post-treatment fitness.

Nevertheless, to address these limitations from a methodological perspective, landmark analyses restricting comparison to patients who remain progression free at predefined time points, such as six or twelve months after treatment initiation, or analyses using time-dependent covariates, would allow more accurate estimation of the contribution of esophagectomy for stage IV esophageal adenocarcinoma. Further refinement using objective measures of disease control, including Response Evaluation Criteria in Solid Tumors (RECIST) response, metabolic response on positron emission tomography, or circulating tumor DNA dynamics, may clarify the optimal indications, timing, and patient selection for surgical intervention in each group. In stage IVB patients, the definition of oligometastatic disease remains inconsistent, although European groups have attempted to standardize the definition, diagnosis, and treatment of oligometastatic esophagogastric cancer through consensus initiatives such as the OligoMetastatic Esophagogastric Cancer (OMEC) project, underscoring the importance of biologically informed patient selection rather than anatomical staging alone (6). Stratified analyses according to oligometastatic patterns and treatment era, particularly before and after the introduction of immune checkpoint inhibitors, would further enhance interpretability.

Postoperative complications after esophagectomy, including anastomotic leakage, have been shown to be independently associated with worse long-term survival in a large multicenter cohort study, underscoring the oncologic consequences of surgical morbidity (7). In this study, postoperative complications occurred at an alarmingly high rate of approximately 55%, with Clavien-Dindo grade III to V complications observed in 13 patients, in-hospital mortality in three patients, and an anastomotic leakage rate of approximately 30% among patients with stage IVA disease. Notably, the surgical approach differed substantially between disease groups, with a markedly higher rate of open esophagectomy in patients with stage IVA disease. This imbalance represents a clinically relevant, yet unadjusted, confounder and raises the possibility that differences in surgical invasiveness, rather than disease stage itself, may have contributed to the observed survival disparity. A higher proportion of minimally invasive procedures in stage IVB patients may have facilitated reduced postoperative morbidity, better preservation of performance status, and a smoother transition to long-term systemic therapy, thereby indirectly influencing survival outcomes.

Surgical safety emerges as a critical issue in this study. In recent years, minimally invasive surgical techniques have contributed to reductions in postoperative complications and improved recovery after esophagectomy. The TIME trial demonstrated reduced pulmonary complications with totally minimally invasive esophagectomy compared with open surgery (8), while the MIRO trial showed lower major morbidity with a hybrid minimally invasive approach (9). In Japan, a multicenter phase III randomized controlled trial (JCOG1409) further demonstrated that thoracoscopic esophagectomy was associated with a significantly lower incidence of postoperative pulmonary complications compared with open esophagectomy, without compromising OS (10). In addition, transmediastinal esophagectomy using a mediastinoscopic approach avoids transthoracic manipulation (11) and may further reduce cardiopulmonary and nerve related complications (12). By minimizing postoperative morbidity, less invasive approaches tailored to disease extent may facilitate timely continuation of systemic therapy and potentially improve long-term outcomes.

Taken together, this study makes a meaningful contribution to the evolving discussion on the role of esophagectomy in stage IV esophageal adenocarcinoma. While esophagectomy should not be regarded as standard treatment for metastatic disease, it may represent a therapeutic option for a small, biologically selected subset of patients. Careful patient selection following systemic chemotherapy including immunotherapy, rigorous methodological evaluation, and continued efforts to reduce surgical morbidity through minimally invasive techniques might be essential. Ultimately, the clinical value of this approach should be clarified within multidisciplinary frameworks and, ideally, through prospective trials or well-designed registries.

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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.