Association between surgical timing and postoperative outcome in patients with residual esophageal cancer after neoadjuvant chemoradiotherapy

Introduction

Esophagectomy remains the standard treatment for resectable esophageal cancer. However, it is associated with a mortality rate of 1–5%, a complication rate of 59%, persistent symptoms, and deterioration in quality of life (1). The CROSS trial demonstrated that neoadjuvant chemoradiotherapy (nCRT) improved survival, with 29% of patients achieving pathological complete response (pCR) after nCRT (2). These findings highlight a clinical dilemma regarding post-nCRT management: whether routine esophagectomy is indicated for all patients, or whether active surveillance (AS) is indicated as an organ-preserving strategy. The PreSANO and SANO trials were conducted to address this dilemma (3,4). In patients with esophageal cancer who demonstrated a clinical complete response (cCR) after nCRT based on multimodal assessment, AS was shown to be non-inferior to surgery with respect to 2-year overall survival (OS) (4); AS was associated with better quality-adjusted survival rates (4). Therefore, AS is considered a viable alternative to surgery. However, substantial uncertainty remains regarding the optimal timing of surgery (TTS) after completion of neoadjuvant therapy in patients with confirmed residual cancer. Overtoom et al. performed a multicenter retrospective cohort study using data from the pre-SANO and SANO trials in The Netherlands (3-5). A key strength is the exclusive focus on patients with post-neoadjuvant residual disease (5). Patients were selected if a biopsy obtained via endoscopy 4–6 weeks after completion of nCRT demonstrated residual disease on histological analysis. Forty patients were excluded because of refusal to undergo surgery, surgery performed abroad, unresectability, death before surgery, or lack of preoperative positron emission tomography/computed tomography (PET/CT), leaving a final cohort of 167 patients. This editorial discusses short-term postoperative morbidity and long-term outcomes in relation to differences in TTS after nCRT, and places these findings in the context of prior studies. We believe timely surgery should generally remain the preferred approach in patients with biopsy-confirmed residual disease after nCRT. Although postponement may occasionally be necessary, it should be supported by a structured reassessment and optimization of the patient’s condition before surgery.

Short-term postoperative morbidity

In the Overtoom study, patients with TTS >12 weeks were at a higher risk of postoperative respiratory complications and chyle leakage than those who underwent surgery within 12 weeks (5). Specifically, the odds of respiratory complications and chyle leakage increased approximately 3.66-fold and 3.75-fold, respectively (5). A study using a large nationwide Dutch dataset reported that patients operated at 11–17 weeks and ≥17 weeks after completion of nCRT had significantly higher rates of overall postoperative complications and a higher risk of anastomotic leakage than those undergoing surgery at 5–11 weeks (6). In an international multicenter cohort study, a longer interval between the completion of nCRT and surgery was associated with increased short-term mortality (7). When the interval was 101–200 days (approximately ≥14 weeks), the 90-day mortality was approximately two-fold higher, and when the interval was >200 days, it increased to approximately three-fold (7). These studies have demonstrated that a longer interval before surgery is associated with an increased risk of postoperative complications. In fact, in a study by Overtoom et al., postponement beyond 12 weeks was frequently attributable to patient-related factors such as temporary physical unfitness (13/40 in the >12-week group) (5). Thus, maintaining functional status during the waiting period through nutritional support and prehabilitation may be important for improving short-term postoperative morbidity (8,9).

Long-term outcomes

Previous studies investigating long-term outcomes of prolonged TTS after nCRT have reported inconsistent results. In the Overtoom study, which was limited to patients with histologically confirmed residual disease, patients who underwent surgery after a prolonged interval (>12 weeks) had better disease-free survival (DFS) (adjusted hazard ratio, 0.48) (5). In contrast, a prolonged interval to surgery did not significantly affect the 5-year recurrence-free survival in the DICE and NeoRes II trials (7,10).

Several methodological and biological factors have been proposed as explanations for these discrepancies. One explanation for these discrepancies is selection bias. Patients who develop distant metastases during the waiting period are typically excluded from surgery (5). Consequently, the population that ultimately undergoes delayed surgery may be selectively enriched with individuals exhibiting less aggressive tumor biology, potentially leading to an overestimation of survival outcomes. Generally, prolonged TTS may allow tumor progression, which may increase the likelihood of positive resection margins and compromise long-term oncological outcomes. This possibility is supported by previous studies that reported increased recurrence and reduced survival following extended surgical delays (6,7).

Another contributing factor is the immortal time bias. In retrospective cohort studies, this bias occurs when patients must survive a certain period before being classified into a particular treatment group, which can lead to overestimation of survival (11). Therefore, deaths occurring between the completion of neoadjuvant therapy and resection were not captured within that group, which can artificially inflate survival estimates associated with a longer TTS and favor delayed surgery in survival analyses. This may partly explain why delayed surgery does not always compromise long-term outcomes in retrospective cohorts, including the study by Overtoom et al. (5). Simultaneously, excessive delays may entail genuine biological risks, including interval progression and loss of resectability.

Consequently, longer intervals may reflect patient selection, rather than treatment-related harm. In this context, cancer recurrence affects OS and is associated with increased short-term mortality due to postoperative complications and the compromised general condition of the patient.

AS after achieving cCR following nCRT

Surgical resection remains the preferred management strategy in patients with biopsy-confirmed residual disease when technically and physiologically feasible. In contrast, AS is primarily intended for patients who achieve a cCR after nCRT. In a meta-analysis of patients with a cCR, no significant difference in progression-free survival was observed between AS and standard surgery (12). However, local recurrence occurred in 40% of patients in the surveillance group at 5 years. In the DUCA study, when the overall waiting period was >25 weeks, the ypT stage increased, and the pCR rate decreased (6).

AS can still allow salvage surgery after recurrence, with an R0 resection rate of approximately 95% (12). Thus, an appropriate and reliable follow-up infrastructure is essential for safely implementing AS in patients who achieve cCR following nCRT. Bayley et al. defined cCR using four clinicopathologic parameters derived from restaging studies: absence of dysphagia and stricture, low tumoral fluorodeoxyglucose uptake (standardized uptake value max ≤4), and a negative post-treatment endoscopic biopsy for carcinoma (13). After achieving cCR following nCRT, esophagectomy should be considered in patients with strictures, positive biopsy findings, or signet ring cell histology because cCR and pCR may be discordant (13). Importantly, AS adoption effectively prolonged the interval between surgeries in a subset of patients. Therefore, any extension of the TTS should be actively managed using AS, which requires stringent restaging and rapid access for salvage esophagectomy to avoid missed progression and maintain operability.

Perioperative treatment for resectable esophageal, gastric, and gastroesophageal junction adenocarcinoma

The perioperative treatment landscape of esophageal adenocarcinoma is rapidly evolving. The ESOPEC trial showed better OS with perioperative FLOT than with nCRT using the CROSS regimen in patients with resectable esophageal adenocarcinoma (3-year OS: 57.4% vs. 50.7%) (14). Additionally, the MATTERHORN trial reported improved outcomes with durvalumab plus perioperative FLOT for resectable gastric and gastroesophageal junction adenocarcinomas, including a higher pCR rate (19.2% vs. 7.2%) and better event-free survival (15). Although MATTERHORN focused on gastric and gastroesophageal junction adenocarcinomas rather than esophageal adenocarcinomas, these findings suggest that perioperative treatment strategies for gastroesophageal adenocarcinomas are changing. This evolving context may affect response patterns, post-treatment assessments, and the future role of AS. Therefore, conclusions derived from the SANO/preSANO framework should be interpreted with caution.

Our perspective

Overall, we believe that the current evidence suggests that a longer TTS may increase the incidence of short-term postoperative complications. In certain subsets, a longer TTS in patients with histologically proven residual disease after completion of nCRT was not associated with worse OS or DFS, although residual confounding and immortal time bias remain a concern. If delay is unavoidable, it should be implemented as an active strategy with stringent restaging and proactive optimization through prehabilitation and nutritional support, along with a predefined pathway for timely surgery. Importantly, postponement of nCRT is unlikely to be equally safe for all patients with esophageal cancer. Future studies should determine who can safely defer surgery and who should proceed without delay.

Conclusions

In conclusion, an optimized multidisciplinary decision-making process is needed to determine whether surgery should proceed and tailor surgical scheduling in patients with residual disease after neoadjuvant therapy for esophageal cancer. Timely surgery should generally remain the preferred approach. In contrast, unavoidable postponement should be accompanied by structured restaging, nutritional support, and prehabilitation, with a clear strategy for resection to preserve operability and minimize postoperative morbidity.

Acknowledgments

We would like to thank Editage (www.editage.jp) for the English language editing.

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-2026-1-0065/prf

Funding: The study was supported by JSPS Grant-in-Aid for Scientific Research C (grant No. 24K11935).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0065/coif). The authors have 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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