Updated protocol of the SANO trial: a stepped-wedge cluster randomised trial comparing surgery with active surveillance after neoadjuvant chemoradiotherapy for oesophageal cancer

Abstract

Background The Surgery As Needed for Oesophageal cancer (SANO) trial compares active surveillance with standard oesophagectomy for patients with a clinically complete response (cCR) to neoadjuvant chemoradiotherapy. The last patient with a clinically complete response is expected to be included in May 2021. The purpose of this update is to present all amendments to the SANO trial protocol as approved by the Institutional Research Board (IRB) before accrual is completed. Design The SANO trial protocol has been published (10.1186/s12885-018-4034-1). In this ongoing, phase-III, non-inferiority, stepped-wedge, cluster randomised controlled trial, patients with cCR (i.e. after neoadjuvant chemoradiotherapy no evidence of residual disease in two consecutive clinical response evaluations [CREs]) undergo either active surveillance or standard oesophagectomy. In the active surveillance arm, CREs are repeated every 3 months in the first year, every 4 months in the second year, every 6 months in the third year, and yearly in the fourth and fifth year. In this arm, oesophagectomy is offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant metastases. The primary endpoint is overall survival. Update Amendments to the study design involve the first cluster in the stepped-wedge design being partially randomised as well and continued accrual of patients at baseline until the predetermined number of patients with cCR is reached. Eligibility criteria have been amended, stating that patients who underwent endoscopic treatment prior to neoadjuvant chemoradiotherapy cannot be included and that patients who have highly suspected residual tumour without histological proof can be included. Amendments to the study procedures include that patients proceed to the second CRE if at the first CRE the outcome of the pathological assessment is uncertain and that patients with a non-passable stenosis at endoscopy are not considered cCR. The sample size was recalculated following new insights on response rates (34% instead of 50%) and survival (expected 2-year overall survival of 75% calculated from the moment of reaching cCR instead of 3-year overall survival of 67% calculated from diagnosis). This reduced the number of required patients with cCR from 264 to 224, but increased the required inclusions from 480 to approximately 740 patients at baseline. Conclusion Substantial amendments were made prior to closure of enrolment of the SANO trial. These amendments do not affect the outcomes of the trial compared to the original protocol. The first results are expected late 2023. If active surveillance plus surgery as needed after neoadjuvant chemoradiotherapy for oesophageal cancer leads to non-inferior overall survival compared to standard oesophagectomy, active surveillance can be implemented as a standard of care.

Shrinkage versus fragmentation response in neoadjuvantly treated oesophageal adenocarcinoma: significant prognostic relevance

“…The increasing use of neoadjuvant chemoradiotherapy (nCRT) as standard of care for oesophageal cancer has initiated discussions regarding organpreserving treatment strategies using active surveillance if complete clinical, endoscopic and radiological response is achieved. 1,2 Currently, pathological assessment according to ypTNM remains the gold standard for prognostic response evaluation and staging. 3,4 Pathologically complete response after nCRT is achieved in 23% of potentially curable oesophageal adenocarcinomas 5 and is associated with a favourable disease-free survival.…”

Towards Personalized Treatment Strategies for Esophageal Adenocarcinoma; A Review on the Molecular Characterization of Esophageal Adenocarcinoma and Current Research Efforts on Individualized Curative Treatment Regimens

“…Firstly, the SANO (Surgery As Needed for Oesophageal cancer) trial (Netherlands Trial Register NTR6803), a non-inferiority phase III stepped-wedge cluster randomized controlled trial by the SANO-study group, compares overall survival rates in 224 patients with EAC and ESCC and clinically complete response to nCRT according to the CROSS regimen at 4–6 weeks, defined by bite-on-bite biopsies, and at 10–14 weeks, as defined by the CRE-II regimen [ 52 ]. Patients will undergo either active surveillance like the CRE-II regimen at 3–12 months intervals up to 60 months after neoadjuvant CRT, with surgery when needed, or neoadjuvant CRT and standard esophagectomy [ 53 ].…”

The effectivity of targeted therapy and immunotherapy in patients with advanced metastatic and non-metastatic cancer of the esophagus and esophago-gastric junction

“…To better select patients who will benefit from esophageal resection, efforts are ongoing to optimize and test "surgery as needed" strategies. In the Surgery As Needed for Oesophageal cancer (SANO) -1 trial, patients with a clinically complete response as assessed at 12 weeks after neoadjuvant chemoradiation were randomized to undergo resection or active surveillance [35]. While the results of this study are awaited, active surveillance as an alternative treatment strategy is offered to an increasing number of patients.…”