Beyond the <scp>SANO</scp> Trial: Reshaping Organ Preservation for Esophageal Cancer in the Era of Potent Neoadjuvant Therapies

We read the article by van der Wilk and colleagues on the SANO trial with great interest [1], a landmark study and the first phase 3 randomized controlled trial to demonstrate that for patients with esophageal cancer who achieve a clinical complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT), an active surveillance strategy offers non-inferior 2-year overall survival compared to standard surgery. We concur with the study's conclusion that organ preservation is a viable option for this specific patient population. The SANO trial has profound implications, trying to open a new chapter in the management of resectable esophageal carcinoma. However, as noted in various commentaries, the design and results of the SANO trial also highlight the core challenges facing current organ preservation strategies. The high local recurrence rate of 48% in the active surveillance group serves as a stark warning that relying solely on conventional endoscopic biopsy and imaging to assess cCR is far from adequate. This approach not only risks missing minimal residual disease (MRD) but also exposes patients to the dangers of delayed treatment and the potential loss of an opportunity for salvage surgery. Therefore, prior to the widespread implementation of organ preservation strategies, it is crucial to establish and explore more precise, multimodal systems for response assessment. The future direction lies in integrating novel technologies to overcome the deficiencies of traditional methods. The preSINO trial had provided preliminary evidence that circulating tumor DNA (ctDNA) demonstrated high specificity in monitoring MRD and could effectively identify patients at high risk for tumor recurrence [2]. Furthermore, emerging technologies such as radiomics and artificial intelligence could offer new possibilities for the non-invasive and accurate prediction of pathological complete response (pCR). In China, the predominant pathological subtype of esophageal cancer is squamous cell carcinoma (ESCC), which is considered more sensitive to chemoradiotherapy. This implies that a potentially higher proportion of patients with ESCC may achieve a cCR or pCR with nCRT, and the benefits of the organ preservation strategy for this population warrant greater attention. The JCOG 0909 studies have already confirmed that for early-stage and selected locally advanced ESCC, definitive chemoradiotherapy combined with salvage therapy can achieve long-term efficacy comparable to surgery [3]. However, the results of the SANO trial have attracted great attention and debate worldwide; this indicates that there is nothing in nature perfect. The preSANO study had already shown that the diagnostic regimen used could miss a substantial proportion of active residual tumors [4]. In addition, the accuracy of cCR assessment, controversies regarding statistical methods, the short duration of follow-up, and the low proportion of ESCC cases in the SANO trial (26% in the active surveillance group and 24% in the surgery group) all have raised worries and skepticism among thoracic surgeons. We believe the value of the SANO trial lies not only in its conclusion but, more importantly, in its illumination of future research directions—how to more safely select candidates for organ preservation. The solution requires not only improving the accuracy of cCR assessment but also enhancing the efficacy of neoadjuvant therapy to pCR rates from the outset. In recent years, immunotherapy, represented by PD-1/PD-L1 inhibitors, has achieved breakthrough progress. The prospective phase 3 ESCORT-NEO trial conducted in China confirmed that neoadjuvant chemoimmunotherapy significantly increased the pCR rate in ESCC to 15.4% and 28% [5]. More recently, the results from the SCIENCE trial were even more encouraging, showing that an investigational regimen of neoadjuvant chemoradiotherapy with Sintilimab pushed the pCR rate to an impressive 60% for ESCC patients [6]. Such a high pCR rate suggests that, in the future, more than half of patients will have achieved complete tumor eradication before their scheduled operation. This would fundamentally shift the therapeutic balance compared to the nCRT era. With a highly effective neoadjuvant immunochemoradiotherapy strategy, perhaps six out of ten patients with ESCC being tumor-free, subjecting all complete responders to “standard” surgery might cause more detriment than benefit for the majority of the ESCC patients. In conclusion, we should not “hypercritically” focus on the limitations of the organ preservation strategy in the SANO trial, but rather view it as a pivotal starting point. It has validated a long-held clinical hypothesis and now incites us to solve the remaining challenges. We are in an exciting era where more effective systemic treatments (e.g., immunochemoradiotherapy) combined with more precise response assessment tools (e.g., ctDNA), which will enable us to more confidently select the optimal, individualized treatment pathway for each patient. When there is a higher “stake” demand, and the accurate appraisal will be even more stringent. The future of organ preservation will not be a simple “watch and wait” approach but an active, scientific management model based on precision diagnostics and highly effective treatment, ultimately achieving the dual goals of eradicating the tumor and preserving quality of life. Jun Wang: conceptualization, funding acquisition, writing – original draft, writing – review and editing, project administration, data curation, supervision, resources, formal analysis, investigation. Zhouguang Hui: conceptualization, investigation, writing – review and editing. Qingsong Pang: conceptualization, investigation, writing – review and editing. The authors declare no conflicts of interest. The authors have nothing to report.