Active surveillance for esophageal cancer after clinically complete response: relevant considerations of the SANO-trial

With interest we read the editorial commentary on active surveillance for patients with locally advanced esophageal cancer and a clinically complete response to neoadjuvant chemoradiotherapy (1). Some relevant aspects of the Surgery As Needed for Oesophageal cancer (SANO)-trial were highlighted (2). In this response letter we will highlight and provide some additional information.

The authors point out correctly that one of the biggest challenges in active surveillance is the accuracy of clinical response evaluations (CREs). Higher sensitivity and specificity of diagnostic tests will result in earlier detection of residual tumor after neoadjuvant chemoradiotherapy to identify non-clinically complete responders. In the preSANO-trial, all patients underwent two CREs followed by esophagectomy (3). We reported that 90% of patients with >10% residual tumor cells [i.e., tumor regression grade (TRG) 3–4] were detected, calculated by dividing the rate of false negative CREs with the rate of false negative plus true positive CREs. The results were considered sufficient to proceed with the SANO-trial. Since the primary goal of the SANO-trial was to assess the efficacy of active surveillance, and not to report on the accuracy of CREs, we did not report on the rate of true positive CREs or information concerning TRG status in patients with positive CREs. Therefore, the results of the accuracy of CREs in the present phase III study inevitably cannot be compared with the preSANO-trial.

The authors are correct that CREs are not perfect, resulting in a substantial proportion of patients developing locoregional recurrence during follow-up. The central question is, however, if these locoregional recurrences are detected in time to accomplish radical esophagectomy and arrive at comparable overall survival compared to patients undergoing standard surgery.

In the SANO-trial, active surveillance was noninferior to standard surgery in terms of 2-year overall survival. When considering the entire follow-up, overall survival was comparable as well. However, a non-significant difference was seen for the rate of distant dissemination in favor of standard surgery. Although this did not result in worse overall survival, we must acknowledge that we cannot rule out a possible statistically or clinically relevant difference in distant dissemination after longer follow-up. This may then result in a worse overall survival for patients undergoing active surveillance. Hence, we agree with the authors that the long-term results of the SANO-trial will show whether there will be an effect on overall survival. These data are to be expected soon.

In the majority of patients, residual tumor is detected 6 or 12 weeks after completion of neoadjuvant chemoradiotherapy. These patients do not have a clinically complete response and surgery is indicated. In the Neores-2 trial, outcomes were compared between patients undergoing surgery at 6 weeks, versus 12 weeks after completion of neoadjuvant chemoradiotherapy. In this trial, no differences were reported between both groups. However, in a post-hoc analysis comparing 46 patients in total with TRG4 residual tumor, postponement of surgery to twelve weeks compared to 6 weeks resulted in worse overall survival (4). This could raise concerns on the safety of postponing surgery in patients with a non-clinically complete response. Previously, numerous studies were published by us and other research groups, stating surgery can be safely postponed to 12 weeks, even with proven residual tumor (5,6). We believe that the results from the post-hoc analysis in the Neores-2 trial do not outweigh scientifically the numerous retrospective studies and the meta-analysis published previously.

The authors notice that the adherence of patients to the strict surveillance protocol is of vital importance for the outcomes of these patients. It is known that treatment effects observed in clinical trials often are less favorable in patients outside clinical trials. Therefore, we started the SANO-2 trial to assess the safety and effectiveness of active surveillance in a cohort outside of the original SANO-trial.

During the course of the SANO-trial the ESOPEC-trial was published. In that trial, 438 patients with adenocarcinoma of the esophagus or esophagogastric junction were included. Patients were randomized between preoperative chemoradiotherapy according to CROSS or perioperative chemotherapy according to FLOT-4 (7). Patients undergoing perioperative chemotherapy had improved overall survival compared to patients undergoing preoperative chemoradiotherapy. Notably, the outcomes of the chemoradiotherapy arm in the ESOPEC-trial were poor. The pathologically complete response rate was only 10% and only 75% of patients completed the full course of neoadjuvant chemoradiotherapy (compared to 23% and 91% respectively in the CROSS-trial). Furthermore, the high rates of pathologically complete response rates reached in the FLOT-4 trial were not accomplished in several international cohort studies using this regimen (8). Although we do not believe that the results of the ESOPEC-trial will result in total abandonment of neoadjuvant chemoradiotherapy, we acknowledge the changing landscape of neoadjuvant therapies in the field of esophageal cancer treatment. The promising rates of pathologically complete response after chemotherapy reinforce the concept of active surveillance for patients with locally advanced esophageal cancer.

The primary report of the SANO-trial has limitations. It should be acknowledged, however, that a substantial fraction of patients (46%) with clinically complete response after neoadjuvant chemoradiotherapy did not undergo esophagectomy due to persisting clinically complete response or early detection of distant metastases, resulting in futility of a high-risk procedure. This strategy resulted in improved health-related quality of life. The long-term follow-up of the SANO-trial will clarify whether the trend towards higher distant dissemination rates results in worse overall survival. Until then, pros and cons on active surveillance strategy should be discussed with the patient. We are looking forward to additional clinical trials on active surveillance in esophageal cancer patients, including the NEEDS trial and the ESORES trial (9,10).

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Thoracic Disease. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1-0282/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.

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References

1. Hoeppner J, Nimczewski F. Active surveillance for clinical complete response after neoadjuvant treatment of locally advanced esophageal cancer. J Thorac Dis 2025;17:9257-9. [Crossref] [PubMed]
2. van der Wilk BJ, Eyck BM, Wijnhoven BPL, et al. Neoadjuvant chemoradiotherapy followed by active surveillance versus standard surgery for oesophageal cancer (SANO trial): a multicentre, stepped-wedge, cluster-randomised, non-inferiority, phase 3 trial. Lancet Oncol 2025;26:425-36. [Crossref] [PubMed]
3. Noordman BJ, Spaander MCW, Valkema R, et al. Detection of residual disease after neoadjuvant chemoradiotherapy for oesophageal cancer (preSANO): a prospective multicentre, diagnostic cohort study. Lancet Oncol 2018;19:965-74. [Crossref] [PubMed]
4. Nilsson K, Klevebro F, Sunde B, et al. Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial. Ann Oncol 2023;34:1015-24. [Crossref] [PubMed]
5. Karthyarth MN, Mathew A, Ramachandra D, et al. Early versus delayed surgery following neoadjuvant chemoradiation for esophageal cancer: a systematic review and meta-analysis. Esophagus 2023;20:390-401. [Crossref] [PubMed]
6. Overtoom HCG, Eyck BM, van der Wilk BJ, et al. Prolonged Time to Surgery in Patients With Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer. Ann Surg 2026;283:268-76. [Crossref] [PubMed]
7. Hoeppner J, Brunner T, Schmoor C, et al. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med 2025;392:323-35. [Crossref] [PubMed]
8. Postoperative and Pathological Outcomes of CROSS and FLOT as Neoadjuvant Therapy for Esophageal and Junctional Adenocarcinoma: An International Cohort Study From the Oesophagogastric Anastomosis Audit (OGAA). Ann Surg 2023;277:e1026-34.
9. Nilsson M, Olafsdottir H, Alexandersson von Döbeln G, et al. Neoadjuvant Chemoradiotherapy and Surgery for Esophageal Squamous Cell Carcinoma Versus Definitive Chemoradiotherapy With Salvage Surgery as Needed: The Study Protocol for the Randomized Controlled NEEDS Trial. Front Oncol 2022;12:917961. [Crossref] [PubMed]
10. Weis J, Kiemen A, Schmoor C, et al. Study Protocol of a Prospective Multicenter Study on Patient Participation for the Clinical Trial: Surgery as Needed Versus Surgery on Principle in Post-Neoadjuvant Complete Tumor Response of Esophageal Cancer (ESORES). Front Oncol 2021;11:789155. [Crossref] [PubMed]