Introduction: The Dilemma of the Complete Responder
For patients with locally advanced esophageal cancer, the standard of care has long been defined by the CROSS trial protocol: neoadjuvant chemoradiation (nCRT) followed by mandatory surgical resection. However, a significant subset of patients—approximately 20% to 30%—exhibit a clinical complete response (cCR) after nCRT, meaning no residual tumor is detectable by endoscopy, biopsy, or imaging. This observation has ignited a fierce debate in the surgical oncology community: if the cancer appears to be gone, is a morbid, life-altering esophagectomy truly necessary?
The Surgery as Needed for Oesophageal Cancer (SANO) trial sought to answer this by comparing active surveillance (with surgery reserved only for recurrence) against immediate esophagectomy. While early results suggested noninferiority in the short term, the long-term trade-offs between organ preservation and oncologic safety remained opaque. A new decision analytical model, published in JAMA Surgery, now provides a rigorous 5-year perspective on this clinical crossroads, revealing that the choice between surveillance and surgery is heavily dependent on the time horizon and individual recurrence risk.
Background: The SANO Trial and the Paradigm Shift
Active surveillance in esophageal cancer is modeled after successful strategies in rectal cancer, where “watch and wait” has become an option for complete responders. The appeal is obvious: esophagectomy is associated with significant perioperative mortality, long-term gastrointestinal dysfunction, and a permanent reduction in quality of life (QoL).
The SANO trial was a landmark multicenter study that randomized patients who achieved cCR after nCRT to either standard surgery or active surveillance. The initial findings indicated that active surveillance did not compromise 2-year survival. However, many clinicians remained skeptical, noting that esophageal cancer is notoriously aggressive and that the sensitivity of current clinical staging tools (PET-CT and endoscopy) for detecting microscopic residual disease is imperfect. This uncertainty necessitated a deeper look at the long-term effectiveness of these strategies through the lens of quality-adjusted life-years (QALYs), which account for both the quantity and the quality of survival.
Study Design: Modeling the Long-Term Horizon
To address the limitations of short-term trial data, Bondzi-Simpson and colleagues developed a Markov decision analytical model. This model simulated the clinical trajectory of a 60-year-old male with cT3N1M0 esophageal cancer—a typical presentation—who achieved a cCR after receiving the CROSS regimen.
The model utilized transition probabilities and utility inputs derived directly from the SANO trial data and supplemented by high-quality literature. Patients in the model could transition between several health states: clinical complete response, local recurrence (resectable or unresectable), distant recurrence, post-esophagectomy (immediate or salvage), and death.
The primary outcome was QALYs over a 5-year period, with secondary outcomes including total life-years. The researchers also performed sensitivity analyses to determine at what point the risks of surgery outweigh the risks of recurrence, and vice versa.
Key Findings: The 5-Year Advantage of Surgery
When looking at a 5-year horizon, the model’s findings were definitive: standard esophagectomy was the superior strategy for maximizing both survival and quality-adjusted survival.
Survival and QALY Gains
At the 5-year mark, patients who underwent immediate esophagectomy gained an average of 3.11 life-years, compared to 2.41 life-years for those in the active surveillance group. This represents an incremental gain of 0.70 life-years, or approximately 8.4 months of additional life.
When adjusted for quality of life, the benefit of surgery remained significant. The surgery group yielded 1.74 QALYs, while the surveillance group yielded 1.34 QALYs. The incremental gain of 0.40 QALYs translates to roughly 4.8 months of life in perfect health. These results suggest that despite the initial morbidity and the persistent functional changes following esophagectomy, the long-term protection against fatal recurrence provided by surgery outweighs the quality-of-life benefits of keeping the esophagus.
The 2-Year Horizon Paradox
Interestingly, when the model was restricted to a 2-year horizon—aligning with the primary endpoint of the SANO trial—the preference flipped. At 2 years, active surveillance was the preferred strategy for QALYs, providing an incremental gain of approximately 15 days of perfect health. This explains why the early SANO results were so favorable toward surveillance; the short-term avoidance of surgical recovery and its associated complications dominates the early data, while the consequences of late recurrences only become apparent in later years.
Subgroup and Sensitivity Analyses: Finding the Threshold
One of the most valuable aspects of this study is its identification of specific “tipping points” where active surveillance might become the preferred long-term option.
Recurrence Probability
Sensitivity analysis revealed that the model favored active surveillance only when the probability of recurrence was less than 43%. In current clinical practice, the recurrence rate for cCR patients is often estimated to be higher than this threshold, reinforcing surgery as the default for most fit patients.
Resectability of Recurrences
Active surveillance relies on the assumption that if the cancer returns locally, it can still be cured with “salvage” surgery. The model showed that for surveillance to be the superior QALY strategy, the likelihood of a local recurrence being resectable must be greater than 94%. In reality, many recurrences are either distant (metastatic) or locally advanced by the time they are detected, making salvage surgery difficult or impossible.
Quality-of-Life Impact
If a patient places an extremely high value on avoiding the specific complications of esophagectomy (such as reflux, dumping syndrome, or strictures), the model shifts. When the negative QoL impact of esophagectomy was modeled as severe and permanent, active surveillance became more attractive. However, when the model accounted for the fact that many patients adapt to their post-esophagectomy status over time (time-varying covariate), the long-term benefit of surgery was further strengthened.
Expert Commentary: Balancing Organ Preservation and Cure
The findings of this study provide a necessary reality check for the growing enthusiasm for organ preservation in esophageal cancer. While “watch and wait” is a seductive prospect for both patients and clinicians, the Markov model suggests that the oncologic risk of leaving the esophagus in place is substantial over a 5-year period.
Clinicians must weigh the “front-loaded” risk of surgery (perioperative mortality and immediate QoL drop) against the “back-loaded” risk of surveillance (late recurrence and lost opportunity for cure). For a young, fit patient, the 8.4-month survival advantage offered by surgery is likely to be the deciding factor. Conversely, for an elderly patient with significant comorbidities or a limited life expectancy, the short-term QoL benefits of active surveillance—as seen in the 2-year horizon data—may be more relevant.
One limitation of the model is its reliance on the accuracy of cCR assessment. As imaging technology (such as radiomics or circulating tumor DNA) improves, our ability to identify true complete responders will improve, potentially lowering the recurrence probability below the 43% threshold and making surveillance a safer bet for a larger number of patients.
Conclusion: A Nuanced, Individualized Approach
This decision analytical model clarifies the long-term implications of the SANO trial. While active surveillance is a viable and potentially preferred short-term strategy for maintaining quality of life, standard esophagectomy remains the most effective way to maximize long-term survival and quality-adjusted life-years in the majority of patients.
The choice should not be binary. Instead, these findings support a nuanced, individualized approach to post-nCRT management. Patients with a high tolerance for surgical risk and a primary goal of long-term cure should be encouraged toward esophagectomy. Those with high surgical frailty or a profound preference for organ preservation may reasonably choose surveillance, provided they understand the trade-off in long-term survival probability. Ultimately, the goal of modern esophageal cancer care is to move beyond a one-size-fits-all model, using data like these to guide shared decision-making.
References
1. Bondzi-Simpson A, Gupta V, Ribeiro T, et al. Esophagectomy vs Active Surveillance in Clinical Complete Responders After Neoadjuvant Chemoradiation. JAMA Surg. 2026;e255890. doi:10.1001/jamasurg.2025.5890.
2. van der Wilk BJ, Eyck BM, Lagarde SM, et al. Neoadjuvant chemoradiotherapy followed by surgery versus active surveillance for oesophageal cancer (SANO-trial): a phase 3, multicentre, non-inferiority, randomised controlled trial. Lancet Oncol. 2023;24(6):662-673.
3. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084. (The CROSS Trial).
