Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study
Authors: Simon P Bach, Alexandra Gilbert, Kristian Brock, Stephan Korsgen, Ian Geh, James Hill, Talvinder Gill, Paul Hainsworth, Matthew G Tutton, Jim Khan, Jonathan Robinson, Mark Steward, Christopher Cunningham, Bruce Levy, Alan Beveridge, Kelly Handley, Manjinder Kaur, Natalie Marchevsky, Laura Magill, Ann Russell, Philip Quirke, Nicholas P West, David Sebag-Montefiore, Gina Brown, Peter Antonio, Alex Vince, Nick Hilken, Chakanaka Sidile, Adrian Wilcockson, Richard Peto, Tom Crosby, Brendan Moran, Julie Olliff, Katti Ashok, Simone Slawik, Andrew Smethurst, Rajaram Sripadam, Veena Tagore, Monica Terlizzo, Bearn Philip, Robert Davies, Susan Dodd, Sharadah Essapen, Pasha Nisar, Alexandra Stewart, Jonathan Trickett, Bansal Ashish, Peter Billings, Palanichamy Chandran, Conor Corr, Edward Favill, Simon Gollins, Peter Marsh, Andrew Maw, Rakha Neupane, Ramesh Rajagopal, Rachel Cooper, John Griffith, Paul Hatfield, Andy Lowe, Julian Ostrowski, Jonathan Robinson, Rhian Simpson, Richard Adams, Robert Bleehen, Michael Davies, Meleri Morgan, Darren Boone, Nicola Lacey, Ian Seddon, Bruce Sizer, Helen Stunell, Shaobin Wu, Maher Hadaki, Dominic Blunt, Susan Cleator, Ara Darzi, Robert Goldin, Paul Ziprin, Mike Dobson, Mark Pitt, Shabbir Susnerwala, Deborah Williamson, Georgina Howarth, Stephen Lee, Paul Wright, Tim Hoare, Alan Horgan, Fiona McDonald, Stephanie Needham, John Scott, Timothy Simmons, Debashis Biswas, James Hernon, Gaurav Kapur, Sandeep Kapur, James Sington, Christopher Speakman, William Stebbings, Stuart Williams, Madhavi Adusumalli, Anil Agarwal, David Borowski, Dharmendra Garg, Talvinder Gill, Mohammed Hegab, Catherine Hobday, Veena Rao, Jyotsna Shrimankar, Mohamed Tabaqchali, David Wilson, Oliver Jones, Neil Mortensen, Andrew Slater, Aron Szuts, Lai Wang, Bryan Warren, Andrew Weaver, Mukhtar Ahmad, Julian Alexander, Maxine Flubacher, David Tarver, Suhail Baluch, Richard Beable, David Cowlishaw, Antony Higginson, Prokopios Vogiatzis, Neil Cruickshank, Howard Joy, David Peake, Ulises Zanetto, Mark Saunders, Arthur Sun-Myint, Rajaram Sripadam, Rachel Cooper, Paul Hatfield, Mark Teo, Arthur Allan, Ian Geh, John Glaholm, Mark Goldstein, Rahul Hejmadi, Gerald Langman, Dion Morton, Cyril Nelson, Deborah Tattersall, Stephen Falk, Robert Longman, Huw Roach, Jamshed Shabbir, Golda Shelley-Fraser, Michael Thomas, Neil Cripps, Yasser Haba, Guy Harris, Max Hookway, Jay Simson, Angela Skull, Tijani Umar
Journal: The Lancet. Gastroenterology & hepatology (2020)

BackgroundRadical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision.MethodsTREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743.FindingsBetween Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months' follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients.InterpretationShort-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules.FundingCancer Research UK.