Esophagus to Small Intestine
Lancet Oncol. 2025;26(4):425-436
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
Background: A substantial proportion of individuals with oesophageal cancer have a pathological complete response after neoadjuvant chemoradiotherapy and oesophagectomy. The authors aimed to investigate whether active surveillance could be an alternative for individuals with a clinical complete response after neoadjuvant chemoradiotherapy.
Methods: A multicentre, stepped-wedge, cluster-randomised, non-inferiority, phase 3 trial in 12 Dutch hospitals was performed. Individuals with locally advanced oesophageal cancer and a clinical complete response after neoadjuvant chemoradiotherapy (i.e., no tumour detected with endoscopic biopsies, ultrasound, and PET-CT) underwent active surveillance or standard surgery (i.e., oesophagectomy within 2 weeks after reaching clinical complete response). There were no inclusion restrictions regarding comorbidities or performance status, but participants had carcinoma, were age 18 years or older, and were treated with curative intent. Randomisation of hospitals was performed using computer-generated sequences without stratification methods, after an initial phase of all hospitals performing standard surgery. The primary endpoint was overall survival, analysed according to a modified intention-to-treat principle (allowing crossover at time of clinical complete response) and an intention-to-treat principle. Non-inferiority was defined as 2-year survival rate for active surveillance of 15% or less below that for standard surgery. The inclusion phase of the trial has been completed.
Findings: Between November 8, 2017, and January 17, 2021, 1115 individuals were screened, of whom 309 were included. 198 underwent active surveillance and 111 underwent standard surgery. 242 (78%) participants were male and 67 (22%) were female. Median follow-up was 38 months (interquartile range [IQR], 32–48). Two-year overall survival for active surveillance (74% [95% confidence interval {CI}: 69–78]) was non-inferior to standard surgery (71% [62–78]) after modified intention-to-treat analysis (1-sided 95% boundary: 7% lower). It remained non-inferior in the intention-to-treat analysis (75% [68–80] vs. 70% [63–77], 1-sided 95% boundary: 6% lower). There were no significant differences in overall survival according to modified intention-to-treat analysis (hazard ratio = 1.14, 2-sided 95% CI: 0.74–1.78) or intention-to-treat analysis (0.83, 0.53–1.31). The frequency of postoperative complications and postoperative mortality after standard surgery or postponed surgery after active surveillance was similar between groups.
Interpretation: Overall survival after active surveillance for oesophageal cancer was non-inferior compared with standard surgery after 2 years. For the long-term efficacy of active surveillance, extended follow-up is required. The results of the present trial could be used for patient counselling and shared decision making.
DOI: 10.1016/s1470-2045(25)00027-0
Prof. Dr. Michael Quante
Head of Gastrointestinal Oncology, University Medical Center Freiburg, Department of Internal Medicine II, Hugstetter Str. 55, 79106 Freiburg, Germany
From standard therapy to selectivity: Do the SANO trial findings herald a paradigm shift in esophageal surgery?
The SANO trial, recently published in The Lancet Oncology, investigated whether active surveillance (AS) after neoadjuvant chemoradiotherapy (nCRT, CROSS protocol) in patients with esophageal cancer who achieve a clinical complete response (cCR) is non-inferior to immediate surgery with respect to overall survival (OS). This multicenter, cluster-randomized, non-inferiority phase 3 trial allocated patients with cCR either to close surveillance with surgery only upon suspected tumor regrowth, or to standard surgery after completion of nCRT.
The results demonstrate that 2-year OS in the AS group (74%) was not inferior to that of the surgical control group (71%, hazard ratio = 1.14; p = 0.55). Moreover, health-related quality of life (HRQoL) was significantly better in the AS group, particularly within the first months following treatment (Cohen’s d > 0.50). Around 48% of patients in the AS group experienced local tumor regrowth, and 83 underwent successful salvage esophagectomy. Most regrowths occurred within 24 months, underlining the importance of structured follow-up.
The SANO trial thus provides the most compelling evidence to date that, in carefully selected patients with cCR after CROSS-based nCRT, a non-surgical strategy can be pursued with comparable survival outcomes and improved quality of life. However, it must be noted that stratified results by histology are not yet available. As squamous cell carcinomas (SCC) respond significantly better to chemoradiotherapy than adenocarcinomas, implementation of the SANO algorithm currently appears most appropriate for SCC.
In the context of other recent trials in neoadjuvant treatment for esophageal and gastroesophageal junction (GEJ) cancer, the SANO study enables a valuable reassessment of treatment strategies:
The ESOPEC trial compared perioperative FLOT chemotherapy (5-FU, leucovorin, oxaliplatin, docetaxel) with CROSS-based nCRT in patients with resectable esophageal or GEJ adenocarcinoma. It showed a significant survival benefit in favor of FLOT. Notably, the rate of pathological complete response (pCR) was slightly higher in the FLOT arm compared to CROSS, despite historical associations of CROSS with higher pCR rates. Surgical outcomes were comparable, but grade ≥ 3 adverse events were more frequent in the FLOT group. Nonetheless, this study established FLOT as the new standard of care for fit patients with adenocarcinoma, especially those with advanced-stage disease.
The TOPGEAR trial, which also assessed perioperative chemotherapy (in part FLOT) with or without the addition of preoperative chemoradiotherapy, showed no survival benefit from adding radiotherapy, despite improved pCR rates. Thus, in gastric and GEJ adenocarcinoma, radiotherapy appears to have limited added value. The NEO-AEGIS trial also confirmed that while chemoradiotherapy improved pCR, it did not translate into overall survival benefit.
The ongoing ESORES trial builds on these findings, aiming to determine whether surgery can also be safely omitted in patients who achieve a cCR after either nCRT or chemotherapy (e.g., FLOT). Unlike SANO, ESORES includes patients following either treatment modality. If non-inferiority is confirmed, ESORES could extend the organ-preserving approach to patients with adenocarcinoma and cCR after chemotherapy alone—a potentially major step toward individualized, less invasive therapy pathways.
Conclusion: The SANO trial marks a paradigm shift in curative management of esophageal cancer after nCRT, showing that radical surgery may be avoidable in selected patients. In comparison, the ESOPEC trial established FLOT as the preferred standard in adenocarcinoma, while TOPGEAR critically questioned the role of radiotherapy. The results of the ESORES trial will be pivotal in determining whether non-surgical strategies are also feasible and safe following chemotherapy alone. Together, these trials underscore that future treatment for esophageal and GEJ cancers should be increasingly personalized: guided by tumor biology, treatment response, and patient preference.
| Trial | Focus | Key finding | Clinical implication |
| SANO | AS after CROSS-based nCRT vs. surgery | Non-inferiority regarding survival; improved quality of life | AS as an option in cCR after CROSS, especially in squamous cell carcinomas |
| ESOPEC | FLOT vs. CROSS in adenocarcinoma | FLOT has better OS than CROSS | FLOT is the new standard for adenocarcinoma |
| TOPGEAR | FLOT vs. FLOT + radiotherapy (RT) | pCR higher with RT, but no OS benefit | RT not required with GEJ/gastric adenocarcinoma, FLOT remains the standard |
| ESORES | AS vs. surgery after nCT or nCRT (all types) | Pending – will test whether AS after FLOT is also possible and safe | Can extend the organ-preserving approach to broader groups |