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

Abstract

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.

Keywords: Chemoradiotherapy; Complete response; Randomised control trial; Rectal cancer; Tumour cell density; Tumour regression; mrTRG.

Fig. 1

a Scheduled to receive 45 Gy–55 Gy long-course radiotherapy. b Treatment decision should be made prior to registration (planned choice is a randomisation stratification variable). Medical oncologist may choose to use CAPOX or FOLFOX, or single-agent capecitabine or 5-FU if concomitant use of oxaliplatin is contraindicated. c Patient defers surgery then the remaining 12 weeks of chemotherapy should be given as soon as possible following the repeat magnetic resonance imaging (MRI) scan and multidisciplinary team (MDT) meeting

Fig. 2

Flow chart for the management of tumour regrowth after initial deferral of surgery