Title: IntAct: Intraoperative Fluorescence Angiography to Prevent Colorectal Anastomotic Leak
Funder: Department of Health and Social Care

Abstract: Scientific abstract: Colorectal cancer is the third most common cancer in the UK, with 30% of cases involving the rectum. Surgery offers the only hope of cure, but comes at a cost in terms of morbidity and mortality. The most feared complication of rectal cancer surgery is anastomotic leak, which is reported in 10% to 15% of patients. Approximately 30,000 – 40,000 colorectal anastomoses are constructed each year in the NHS, most usually for colorectal cancer. Anastomotic leak is therefore a significant healthcare burden. It has a negative impact on patient recovery and consumes NHS resources for remedial interventions. It increases morbidity from ~20% to ~60%, mortality from <5% to ~20%, and extends in-patient stay from an average of 7 to 19 days. The mean cost of care for patients undergoing uncomplicated colorectal surgery is ~£17,000, increasing to ~£45,000 in those who suffer complications. Patients who survive anastomotic leak suffer long-term consequences with reduced quality of life, high rates of wound complications and permanent stoma, and increased risk of cancer recurrence. Intraoperative fluorescence angiography (IFA) has recently been introduced into clinical practice and promises to bring about a step change in the way that anastomoses are constructed and so reduce the anastomotic leak rate. A proof of concept study (PILLAR II), using surgery with IFA in 147 patients with rectal cancer, has documented an anastomotic leak rate of 1.4%; a massive 8-9 fold reduction as compared to standard care. If proof of efficacy can be confirmed in a large, multi-centre study, the implications for patients, in terms of safer recovery from surgery and improved quality of life, and healthcare providers, in terms of cost-savings, will be substantial. It is hypothesized that the use of IFA in rectal cancer surgery will reduce the anastomotic leak rate from 12.0% to 6.0%, based on the best available literature. To confirm this, it is proposed to undertake a multi-centre, UK and European, randomized controlled trial comparing surgery with IFA against standard care (surgery with no IFA). 880 patients will be recruited from 25 centres over a period of 36 months, allowing for a 10% drop-out rate. An interim analysis will be performed when primary endpoint data is available for 554 patients; if there is significant evidence of efficacy for the primary endpoint then the trial will conclude. To facilitate recruitment, we will build on the recent success of a multicentre international randomized trial in rectal cancer surgery, involving collaborators from high volume centres recruiting 12 patients per year. The primary outcome will be clinical anastomotic leak rate. Secondary outcomes will include change in planned anastomosis, rate of defunctioning stoma, postoperative complications, rate of interventions, quality of life, and health resource utilisation. Patients will be followed for 90-days postoperative, at which point they will exit the study. Two sub-studies studies will be undertaken to better understand the mechanism of anastomotic leak. One sub-study will assess rectal vascular anatomy and perfusion, as determined by preoperative CT angiography and perfusion CT, the relationship to intraoperative IFA, and the influence of radiotherapy. A second sub-study will analyse the rectal microbiome to determine the changes that occur with surgery and its potential role in anastomotic leak.

Lay abstract: Background: Colorectal cancer is one of the biggest cancer killers in the world, causing 16,000 deaths every year in the UK. Surgery offers the only hope of a cure, but is associated with complications and even death. One of the most serious complications is anastomotic leak. This happens when a join in the bowel does not heal properly, causing faecal contents to spill into the abdomen. Anastomotic leaks cause patients to become very unwell and 1 in 5 do not survive. Those who do survive can go on to experience difficulties with wound healing, longer stays in hospital, the need for a stoma (a bag to collect faeces), and increased risk of cancer coming back. One way to reduce the risk of anastomotic leak is to ensure that the bowel being joined has a good blood supply. Intraoperative fluorescent angiography (IFA) has recently been introduced to help with this. During IFA a drug is injected into the blood which fluoresces (glows) when viewed with a special camera. The blood supply to the bowel can then be seen and helps the surgeon to decide which part of the bowel to use for the anastomosis. In a previous study, 147 patients underwent IFA as part of bowel surgery and only 2 patients (1.4%) suffered an anastomotic leak(25). This is a massive drop when compared to previous rates of 10% - 15%. Aim: To undertake an evaluation of IFA in patients undergoing elective rectal cancer surgery. Design: The study will involve 25 surgical centres in the UK and Europe and will recruit 880 patients. Patients will be randomly allocated to either surgery with IFA or standard care (surgery without IFA). Pre and post-operative care will be similar in both groups. The rates of anastomotic leak will be compared between the groups to see if IFA decreases leak rate. We will also look at complications, bowel function, patients’ quality of life, and value for money. Patients will be followed up for 90-days after surgery. Two sub-studies will be undertaken to better understand why some anastomoses leak whilst others do not. 75 UK patients will undergo an additional preoperative CT scan to look at variations in blood supply to the bowel, how radiotherapy affects blood supply, and how this alters IFA assessment and surgical decision-making. 200 UK patients will also undergo evaluation of bacteria within the rectum (microbiome analysis) to see if the bacterial population changes with surgery and if there is a link with anastomotic leak. Patient and public involvement: Patient and public representatives have been involved in the design and drafting of this proposal. PPI will be included on the management team and steering committee. The research team has worked closely with PPI representatives from the NIHR Healthcare Technologies Cooperative (HTC) in Colorectal Therapies, a patient who has suffered an anastomotic leak, and Bowel Cancer UK, to ensure the study addresses the patient perspective and can be safely delivered without undue inconvenience. Dissemination: the results will be disseminated widely to healthcare professionals through presentations, publications, the NIHR Clinical Research Network (CRN) and professional organisations (e.g. ACPGB&I). We will work closely with NIHR HTC and Bowel Cancer UK to ensure that results reach patients, members of the public, academics, healthcare providers and funders, and industry partners.

Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS;ORAL AND GASTROINTESTINAL