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

Abstract

Background: Neoadjuvant 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.

Methods: This 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.

Discussion: If 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.

Keywords: Active surveillance; Neoadjuvant chemoradiotherapy; Oesophageal cancer; Standard oesophagectomy.

Fig. 1

Study algorithm. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; cNCR: clinically non-complete response; cCR: clinically complete response. *At this point the patient will be allocated to one of the two treatment arms, dependent on the institution in which the actual treatment takes place. Randomisation will be performed at the institutional level (see §3.1 and §8.2). Patients will know their allocated treatment at the moment of inclusion

Fig. 2

Stepped-wedge cluster design with addition of preSANO cCR-patients and sequential cross-over of 6 clusters comprising 2 centres every 4.5 months

Fig. 3

Expected distribution of patients. nCRT: neoadjuvant chemoradiotherapy; CRE: clinical response evaluation; S1: first surveillance evaluation; S2: second surveillance evaluation etc. Treatment allocation*: randomisation will be performed at institutional level and will be known already at the moment of inclusion; immediate surgery arm of randomisation not shown