Active surveillance for clinical complete response after neoadjuvant treatment of locally advanced esophageal cancer

Neoadjuvant treatment of locally advanced, non-metastatic esophageal cancer consisting of neoadjuvant chemo(radio)therapy, followed by radical esophagectomy with subsequent adjuvant therapy is the international standard of care. Rates of 10% to 40% post-neoadjuvant complete remission after neoadjuvant chemo(radio)therapy in patients with locally advanced esophageal carcinoma are reported (1). Approaches for organ preservation after neoadjuvant therapy for locally advanced carcinoma of the gastrointestinal tract are primarily found in the treatment of rectal carcinoma (2). This approach receives increasing attention in the treatment of esophageal cancer and several studies are addressing this issue (3-5).

The challenge is on the one hand the accuracy of clinical response evaluations for adequate selection of this patient group and on the other hand the question, if this patient group will actually benefit from surgery or whether the obligatory surgery after neoadjuvant chemoradiotherapy (nCRT) can be dispensed with extended clinical response evaluation (CRE) and active surveillance (AS) under strict supervision.

To investigate whether AS is non-inferior in overall survival (OS) compared to surgery on principle after neoadjuvant nCRT, analogous to the CROSS protocol in patient with locally advanced esophageal carcinoma, van der Wilk et al. executed the national phase III SANO trial in The Netherlands. The primary endpoint was non-inferior 2-year OS (OS <15% below the expected OS in the surgery group). A total of 309 patients in 12 Dutch hospitals were divided into two groups using stepped-wedge cluster randomization. One hundred and ninety-eight patients underwent CRE/AS. One hundred and eleven patients underwent primary resection. The 2-year results show non-inferiority in OS in the AS group compared to the surgery on principle group.

In this trial, complete remission was determined during two different time points 6 and 12 weeks after completion of nCRT to define CRE. However, it can be observed a high rate of patients in the CRE/AS group with isolated residual tumors (96 of 198, 48%), which were detected at the third, fourth, or fifth follow-up visit after randomization and underwent salvage resection. Tumor persistence after nCRT and delayed resection did not appear to adversely affect OS in the CRE/AS group. The rate of postoperative complications was also comparable.

It should be noted that the accuracy of CRE is still limited in the population of SANO-trial and ways must be found to improve it. Contrary to expectations based on the pre-trial data, the specificity for accurate CRE appears to be significantly lower with 48% of the patients in the CRE/AS group developing isolated loco-regional regrowth. This underlines the importance of structured follow-up examinations, which were obviously effective in the SANO trial. Furthermore, the data shows for practice, that adherence to follow-up visits is essential and requires a high degree of patient compliance, which in turn can pose significant challenges outside of trial protocols.

Another aspect worth highlighting is the higher rate of distant metastases in the CRE/AS group (43% vs. 34%), which were detected during the second follow-up positron-emission computed tomography This could indicate that the delayed surgical treatment of residual tumors after nCRT may have clinical relevance and favored the occurrence of distant metastases in this group. The data from this patient cohort would need to be analyzed separately. However, due to the early detection of distant metastases after 30 days of follow-up, it must be assumed, that occult metastases already existed after completion of nCRT and only became clinically apparent during follow-up.

The stepped-wedge cluster randomization can be considered as a pragmatic study design and in addition to the obvious disadvantages of non-parallel and non-individual randomization, we would also like to mention the advantages. Originally, of the 274 patients who achieved a complete clinical response, 156 were assigned to the CRE/AS group and 118 to the surgery group. A further 35 patients were assigned to the surgery group from the preSANO trial. Since crossover between the groups was possible and 42 patients switched from the surgery group to the CRE/AS group, an imbalance ultimately occurred between the groups. Patient selection in a randomized controlled trial on this specific issue of surgical versus non-surgical treatment for locally advanced esophageal cancer presents a major challenge. The individual randomization often leads to the rejection of potential study patients due to personal concerns. In this context patients with complete remission after nCRT often specifically seek an option to avoid surgery. Randomization with the possibility of being assigned to the surgery-on-principle group is then rejected. The use of stepped-wedge cluster randomization, while accepting selection bias in favor of an adequate number of patients, is a pragmatic approach in this highly selective patient population. Despite the selection bias, we see in the SANO trial two balanced patient groups in terms of general patient characteristics, which could indicate a minor influence of this bias. A critical point is the shorter monitoring period in the CRE/AS group due to the study design, which particularly limits the interpretation of the 2-year data.

In the SANO trial, patients with both squamous cell carcinoma and adenocarcinoma were treated with nCRT. Future studies must determine, whether the use of the polychemotherapy FLOT (fluorouracil, leucovorin, oxaliplatin, docetaxel), which is now the standard treatment for patients with adenocarcinoma, has an impact on OS in locally advanced esophageal adenocarcinoma in this question (6). It has already been shown, that a reduction in distal tumor recurrences was achieved, particularly due to the better systemic tumor control in patients treated with FLOT. This finding could have a major impact on the long-term data of patients under AS (7).

In the SANO trial, the occurrence of distant metastases appears to be a relevant factor, particularly in the CRE/AS group. The non-inferiority endpoint for OS was achieved after 2 years; whether this will be confirmed after longer follow-up remains to be seen. After approximately 2 years, the OS curves of the two groups intersect. Since disease-free survival was higher in the surgery group, this effect could further negatively impact OS in the AS group, thus leveling off the non-inferiority endpoint in the AS group over time. This will be evident in the long-term data.

The SANO trial addresses the highly relevant question of whether organ preservation after neoadjuvant systemic therapy with complete remission in locally advanced esophageal cancer is safe and effective, as data from high-volume centers also show that esophageal resection can represent a significant burden of morbidity for some patients (8). Due to the study design and the aforementioned limitations of the study, the question of whether the CRE/AS approach represents a safe alternative to guideline-based therapy for patients with complete remission after nCRT cannot be conclusively answered. Nevertheless, the study provides evidence that a selective patient group appears to benefit from the AS treatment approach. Both the long-term data from the SANO trial as well as randomized controlled trials with parallel and individual randomization procedures must confirm this hypothesis.

Acknowledgments

None.

Footnote

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

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1614/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1614/coif). J.H. reports honoraria from AstraZeneca. The other author has no conflicts of interest to declare.

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