Journal Article

A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial

Moran, Brendan J., Rasheed, Shahnawaz, Quirke, Philip, Tekkis, Paris, Sadanandam, Anguraj, Thomas, Karen, Battersby, Nick J., Dattani, Mit, Khakoo, Shelize, Nagtegaal, Iris, Valeri, Nicola, Mirnezami, Alex, Tait, Diana, West, Nicholas P., Frost, Michelle, Brown, Gina, Rao, Sheela, Cunningham, David, Adams, Richard, Chong, Irene

2017

Overview

Background Pre-operative chemoradiotherapy (CRT) for MRI-defined, locally advanced rectal cancer is primarily intended to reduce local recurrence rates by downstaging tumours, enabling an improved likelihood of curative resection. However, in a subset of patients complete tumour regression occurs implying that no viable tumour is present within the surgical specimen. This raises the possibility that surgery may have been avoided. It is also recognised that response to CRT is a key determinant of prognosis. Recent radiological advances enable this response to be assessed pre-operatively using the MRI tumour regression grade (mrTRG). Potentially, this allows modification of the baseline MRI-derived treatment strategy. Hence, in a ‘good’ mrTRG responder, with little or no evidence of tumour, surgery may be deferred. Conversely, a ‘poor response’ identifies an adverse prognostic group which may benefit from additional pre-operative therapy. Methods/design TRIGGER is a multicentre, open, interventional, randomised control feasibility study with an embedded phase III design. Patients with MRI-defined, locally advanced rectal adenocarcinoma deemed to require CRT will be eligible for recruitment. During CRT, patients will be randomised (1:2) between conventional management, according to baseline MRI, versus mrTRG-directed management. The primary endpoint of the feasibility phase is to assess the rate of patient recruitment and randomisation. Secondary endpoints include the rate of unit recruitment, acute drug toxicity, reproducibility of mrTRG reporting, surgical morbidity, pathological circumferential resection margin involvement, pathology regression grade, residual tumour cell density and surgical/specimen quality rates. The phase III trial will focus on long-term safety, regrowth rates, oncological survival analysis, quality of life and health economics analysis. Discussion The TRIGGER trial aims to determine whether patients with locally advanced rectal cancer can be recruited and subsequently randomised into a control trial that offers MRI-directed patient management according to radiological response to CRT (mrTRG). The feasibility study will inform a phase III trial design investigating stratified treatment of good and poor responders according to 3-year disease-free survival, colostomy-free survival as well as an increase in cases managed without a major resection. Trial registration ClinicalTrials.gov, ID: NCT02704520 . Registered on 5 February 2016.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adenocarcinoma - diagnostic imaging / Adenocarcinoma - mortality / Adenocarcinoma - secondary / Adenocarcinoma - therapy / Biomarkers / Biomedicine / Cancer therapies / Chemoradiotherapy / Chemoradiotherapy, Adjuvant - adverse effects / Chemoradiotherapy, Adjuvant - economics / Chemoradiotherapy, Adjuvant - mortality / Chemotherapy / Clinical Protocols / Colorectal cancer / Colostomy / Complete response / Cost-Benefit Analysis / Disease Progression / Disease-Free Survival / Feasibility Studies / Health Care Costs / Health Sciences / Humans / Intention to Treat Analysis / Magnetic resonance imaging / Magnetic Resonance Imaging - economics / Medicine / Medicine & Public Health / Metastasis / Morbidity / Mortality / mrTRG / Multidisciplinary teams / Neoadjuvant Therapy - adverse effects / Neoadjuvant Therapy - economics / Neoadjuvant Therapy - mortality / Neoplasm Grading / Neoplasm Recurrence, Local / Patients / Predictive Value of Tests / Quality of Life / Radiation therapy / Randomised control trial / Recruitment / Rectal cancer / Rectal Neoplasms - diagnostic imaging / Rectal Neoplasms - mortality / Rectal Neoplasms - pathology / Rectal Neoplasms - therapy / Research Design / Statistics for Life Sciences / Study Protocol / Surgery / Time Factors / Treatment Outcome / Tumour regression