Neoadjuvant chemoradiotherapy plus surgery versus active surveillance for oesophageal cancer: a stepped-wedge cluster randomised trial

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.

Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (preSINO trial): a prospective multicenter diagnostic cohort study

“…Active surveillance is currently being investigated in two European clinical trials, i.e. the Dutch SANO trial and the French ESOSTRATE trial, including patients with both AC and SCC [6,7]. Since the highest rate of pCR after nCRT is achieved in patients with SCC, an active surveillance strategy is highly relevant for Asian patients as well.…”

Neoadjuvant treatment strategy for locally advanced thoracic esophageal cancer

“…An esophagectomy is carried out only in patients with a proven or high suspicion of locoregional regrowth. The effectiveness of this active surveillance as compared to standard surgery has been assessed in the Surgery As Needed approach in Oesophageal cancer patients (SANO) trial . As reported from the JCOG0909 trial, in Japan, CRT followed by salvage surgery can provide a promising therapeutic strategy.…”

Klinische Umsetzung und Konsequenzen aus der S3-Leitlinie „Ösophaguskarzinom“

“…Für diese Patienten stellt sich die Frage, inwieweit eine transthorakale Ösophagektomie indiziert ist oder auch eine intensive Nachbeobachtung zu den gleichen onkologischen Langzeitergebnissen führt. Diese Frage versucht eine niederländische Studie zu beantworten (SANO-Trial), deren Studienprotokoll kürzlich publiziert wurde [17]. Zur gleichen Frage ist auch eine französische Studie in Vorbereitung (ESOSTRATE-Trial).…”