Impact of Severe Anastomotic Leak After Esophagectomy on Long-Term Survival: Insights from a Modern Multicenter Cohort

Highlight

• Anastomotic leak (AL) after esophagectomy occurs in approximately 14.6% of cases in a large European cohort.
• Severe leaks requiring surgical reintervention (ECCG type III) significantly increase 30- and 90-day mortality and nearly halve median overall survival.
• AL increases pulmonary complications and reduces the likelihood of receiving adjuvant therapy.
• Non-surgical or conservatively managed leaks do not significantly impact long-term survival.

Study Background

Esophagectomy remains a cornerstone curative treatment for esophageal and junctional cancers. Despite advancements in perioperative management and surgical techniques, anastomotic leak (AL), a disruption of the surgical connection between esophageal segments, remains a serious postoperative complication. Historically, AL has been associated with increased morbidity, mortality, cancer recurrence, and impaired long-term survival. However, previous studies were often limited by heterogeneity in AL definitions and outdated management protocols.

The Esophagectomy Complications Consensus Group (ECCG) has recently standardized the classification and grading of AL, enabling better comparison across centers and more precise risk stratification. Contemporary multimodal therapy, including neoadjuvant regimens like CROSS (chemoradiotherapy) and FLOT (chemotherapy), combined with improved perioperative care and innovative endoscopic salvage techniques, may mitigate previous risks associated with AL.

This multicenter study aimed to clarify the prognostic impact of AL severity graded by ECCG criteria on long-term survival in patients undergoing esophagectomy in the modern treatment era.

Study Design

The Anastomotic Leak After Esophagectomy on Long-term Survival (ALES) study is an international, retrospective cohort analysis involving 17 high-volume European centers, reflecting contemporary practice settings. Inclusion criteria were adult patients with esophageal or junctional cancers managed with neoadjuvant CROSS or FLOT regimens followed by esophagectomy from 2018 to 2023.

Postoperative AL was graded per ECCG guidelines: type I (conservative management), type II (requiring interventional but non-surgical treatment), and type III (requiring surgical reintervention). Primary endpoints were overall survival and short-term mortality (30 and 90 days). Secondary endpoints included postoperative complications, specifically pulmonary events, and adjuvant therapy administration rates.

Key Findings

This cohort included 2,905 patients, of whom 425 (14.6%) developed an AL. Stratification demonstrated notable differences based on AL severity:

Incidence and Complications

Overall AL incidence aligns with previously reported rates; however, this study’s granular categorization elucidates severity-dependent risks.

AL was significantly associated with pulmonary complications: 46.8% in AL patients versus 26.7% in those without leaks (P<0.001). Such complications contribute to heightened morbidity and potentially influence oncologic outcomes.

Mortality

Patients experiencing ECCG type III leaks requiring surgical reintervention exhibited substantially elevated mortality rates, with 30-day mortality of 7.3% versus 2.7% and 90-day mortality of 12.3% versus 4% when compared to no-leak patients (P<0.001 for both comparisons).

Survival Outcomes

Median overall survival was markedly compromised in the type III AL group (33.9 months) compared with the no-leak group (69.3 months; P<0.001). After multivariable adjustment for confounding factors, the hazard ratio for death in type III AL patients was 1.51 (95% CI: 1.04–2.18; P=0.029), demonstrating independent prognostic significance.

Importantly, AL managed conservatively (type I) or non-surgically (type II) did not significantly affect long-term survival, highlighting that severity and intervention strategy critically modulate outcomes.

Adjuvant Therapy Administration

AL patients were less likely to receive planned adjuvant therapy (33.9% vs. 43.3%; P=0.004), possibly reflecting prolonged recovery and diminished performance status, which may contribute indirectly to inferior oncologic outcomes.

Expert Commentary

This extensive multicenter cohort study offers robust contemporary evidence affirming that severe anastomotic leaks requiring surgical correction significantly impair survival after esophagectomy. The findings emphasize that AL is not merely a short-term postoperative event but has long-lasting oncologic repercussions.

The use of ECCG standardized definitions strengthens the validity and reproducibility of these results, addressing prior limitations linked to heterogeneous AL classification. Moreover, the study incorporates modern neoadjuvant chemotherapy protocols and perioperative care, reflecting the current standard of management.

Nevertheless, the retrospective design and potential center-specific variations in patient selection and management represent limitations. Additionally, the mechanisms by which AL adversely affects survival warrant further mechanistic and prospective studies. Possible hypotheses include systemic inflammation, delayed or omitted adjuvant therapy, and micro-metastatic seeding facilitated by leaks.

Clinically, these findings underscore the importance of early identification, aggressive management, and prevention strategies for AL, particularly type III leaks. Leveraging less invasive endoscopic techniques for leak closure and improved postoperative support may attenuate the adverse impact on survival.

Conclusion

The ALES study definitively demonstrates that severe anastomotic leaks requiring surgical reintervention after esophagectomy substantially increase postoperative mortality and reduce long-term survival. Non-surgical or conservatively managed leaks have a minimal impact on survival, indicating that severity and management approach are pivotal.

These results highlight the need for enhanced perioperative strategies aimed at leak prevention, prompt diagnosis, and effective management. Future research should focus on novel stabilization methods, personalized risk mitigation, and optimizing adjuvant therapy delivery to improve oncologic outcomes in this vulnerable population.

Funding and Clinical Trials Registration

Information on funding sources and clinical trial registration was not specified in the primary publication.

References

Giorgi L, Guidozzi N, Salem R, et al. The Impact of Anastomotic Leak After Esophagectomy on Long-term Survival in the Modern Era of Management (ALES Study): A Multicenter Cohort Study. Ann Surg. 2026 Sep 3. PMID: 42687130. https://pubmed.ncbi.nlm.nih.gov/42687130/

Low DE, Kuppusamy MK, Alderson D, et al. Benchmarking Complications Associated with Esophagectomy. Ann Surg. 2019;269(2):291-298.

van der Sluis PC, Ruurda JP, van Hillegersberg R. Anastomotic Leakage Following Esophagectomy: Risk Factors, Diagnosis, and Treatment. Dis Esophagus. 2017;30(10):1-7.