The STAR-TREC Trial SIV Presentation Introduction 26-JUN-2018 Funders: Cancer Research UK (CRUK) Sponsor: University of Birmingham Chief Investigator: Mr Simon Bach (UHB, Queen Elizabeth Hospital) Co-Chief Investigator: Prof David Sebag-Montefiore (St James's University Hospital, Leeds) Coordinating Centre: Birmingham Clinical Trials Unit (BCTU) Contact Details: Chief Investigator: Mr Simon Bach Co-Chief Investigator: Prof David Sebag-Montefiore E-mail: s.p.bach@bham.ac.uk E-mail: d.sebagmontefiore@leeds.ac.uk STAR-TREC Trial Office contact details: Trial Manager: Mrs Manjinder Kaur Address: STAR-TREC Trial Office, E-mail: m.kaur@bham.ac.uk Birmingham Clinical Trials Unit (BCTU), E-mail: STAR-TREC@trials.bham.ac.uk Institute of Applied Health Research, College of Medical and Dental Sciences Tel: 0121 415 9105 Public Health Building Fax: 0121 415 8871 University of Birmingham Edgbaston, Birmingham B15 2TT Version 4.0 01-JUN-2018 Slide 3 of 96 Version 4.0 01-JUN-2018

Scientific Background and Rationale: The STAR-TREC Trial SIV Presentation 26-JUN-2018 Scientific Background and Rationale: Increasing incidence of early rectal cancer poses new surgical dilemma Introduction of the bowel screening programme in 2006 changed how rectal cancer presents Current standard care for early stage rectal cancer = Total mesorectal excision (TME) surgery Low Anterior resection Abdominoperineal resection High rates of cure Only 2% and 12% of patients experience local or distant failure respectively Post-operative morbidity Permanent stoma in approximately 5-10% of cases Three prospective cohort studies have examined health related quality of life scores following rectal cancer. Each demonstrated persistently poor social, role, body image and defaecation scores. Concerns that radical surgery, may not be the optimal method of treatment for early screen-detected tumours. An organ preserving strategy may generate significantly less morbidity without substantially compromising oncological outcomes. Colorectal cancer is the third most common tumour in the UK, Netherlands and Denmark. with 41000, 14000 and 4000 new cases per year respectively. Approximately one-third of these are rectal cancers. In the UK, introduction of the NHS Bowel Screening Program (NBSP) from 2006 is changing how rectal cancer presents. The major benefit of screening is increased early detection; over 50% of screen-detected rectal cancers are early stage and limited within the bowel wall. By 2009 the proportion of early stage rectal cancer diagnosed in the UK had risen from 8 to 25%.1, 2 With the Netherlands and Denmark commencing screening in 2014, similar increases in early rectal cancer incidence are expected. Version 4.0 01-JUN-2018 Slide 6 of 96 Version 4.0 01-JUN-2018

The STAR-TREC Trial SIV Presentation 26-JUN-2018 Trial Design and Aims Trial Schema Design: Randomised feasibility study Primary Aim: Accelerate recruitment from 2 patients per month to 6 per month over a 2 year period Target Recruitment: 120 patients overall, 60 from the UK Duration: Two year recruitment Three year follow-up Version 4.0 01-JUN-2018 Slide 11 of 96 Version 4.0 01-JUN-2018

The STAR-TREC Trial SIV Presentation 26-JUN-2018 Inclusion criteria Biopsy proven adenocarcinoma MRI T1-3b N0 M0 MDT agrees patient suitable for: (a) TME surgery (b) CRT (c) SCPRT and (d) TEM Negative pregnancy test 16+ in UK 18+ in Netherlands and Denmark Able and willing to provide informed consent Version 4.0 01-JUN-2018 Slide 14 of 96 Version 4.0 01-JUN-2018

The STAR-TREC Trial SIV Presentation 26-JUN-2018 Exclusion Criteria On MRI: Node positive Extramural vascular invasion present Defined mucinous tumour Mesorectal fascia threatened (< 1 mm on MRI) Maximum tumour diameter > 40mm Anterior tumour location above the peritoneal reflection on MRI or ERUS No residual luminal tumour following endoscopic mucosal resection Prior pelvic radiotherapy Regional or distant metastases Patients with previous colon cancer or previous malignancy are not an exclusion. Version 4.0 01-JUN-2018 Slide 15 of 96 Version 4.0 01-JUN-2018

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