Abstract
BackgroundNeoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer.MethodsThis is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4–6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6–8 weeks after CRE-I. CRE-II will include 18F–FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy.DiscussionIf active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.
Highlights
Neoadjuvant chemoradiotherapy plus surgery is a standard treatment for locally advanced oesophageal cancer
The randomised ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) showed an absolute 5-year overall survival benefit of 14% after neoadjuvant chemoradiotherapy plus surgery, compared to surgery alone [3, 4]
After Neoadjuvant chemoradiotherapy (nCRT) according to CROSS, 29% of all patients (49% for squamous cell carcinoma [Squamous Cell Carcinoma (SCC)] and 23% for adenocarcinoma [AC]) had a pathologically complete response in the resection specimen [3]
Summary
Study design The SANO-trial is a phase III multi-centre, stepped-wedge, cluster randomised controlled non-inferiority trial. Patients without (cyto)histological evidence of residual disease during CRE-II (cCR), in the absence of distant metastases, will be assigned to active surveillance (experimental arm) or standard surgery (control arm), according to the randomisation at the institutional level. During active surveillance we do allow a centralised multidisciplinary tumour board (MTB, Erasmus MC) to recommend surgical resection in selected patients who have a high clinical / diagnostic suspicion of tumour regrowth, despite repeatedly negative (cyto)histology This centralised MTB will monitor and decide on all such suspected patients from all participating centres. Statistical analysis Sample size calculation In the present phase-III study, we plan to randomise at institutional level 300 patients with cCR during CRE-II between active surveillance and standard surgical resection. Results will be communicated via international conferences, via publications and via the NTR
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