Title: Non-invasive triage of symptomatic fast-track colorectal patients using volatile compounds: a feasibility study
Funder: Department of Health and Social Care

Abstract: Background and rationale There are 41,855 new cases (CRUK, 2012) and 16,000 deaths from colorectal cancer (CRC) every year in the UK. Diagnosing CRC is difficult as deciding which patients to reassure or investigate is challenging as colorectal symptoms are poor predictors of malignancy. The fast-track &ldquo;two week wait&rdquo; pathway was advocated for patients with suspected CRC with over 300,000 people now referred on this pathway annually in England. The majority of fast track patients undergo colonoscopic testing as the gold standard investigation. The procedure is invasive, requires bowel preparation and carries a risk of serious complications. Colonoscopy offers little benefit to fast-track patients except reassurance as only 3-10% have CRC. In addition, the cost of colonoscopy in the UK is over &pound;300 million annually. There is therefore a need for clinically applicable tests to guide which patients within the fast-track referral pathway require colonoscopy and which can be safely reassured. Recently, there has been an increasing interest in using volatile compounds (VC) for non-invasive detection of cancer including CRC. VCs are products of cellular metabolism, produced by human cells or microbiota. Canine scent detection of samples from CRC patients gave 97% and 99% sensitivity and specificity but its high costs prevent clinical use as screening tool. There are three main current methods for VC testing: gas chromatography-mass spectrometry (GC-MS) represents the gold standard. GC-MS testing is complex and not ideal for rapid throughput of samples limiting use in population screening or large sample of patients. Secondly, Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) is a quantitative mass spectrometry technique that allows real-time measurement of VC concentrations. A more recent development is Field Asymmetric Ion Mobility Spectrometer (FAIMS), which measures the movement of ionized molecules in electric fields. All VC reports are feasibility studies exploring testing in known CRC patients with no prospective investigations in symptomatic patients. It is also unclear which VC testing methodology is best for clinical practice. We aim to provide a comprehensive feasibility evaluation of VC profiling to establish the best clinical methodology of VC testing based on sensitivity and specificity, affordability and patient acceptability. This methodology would be further tested in a larger study to distinguish between cancer, adenomas and no pathology. Study design Prospective, multicentre feaability study involving 600 fast track patients from three centres over 24 months. A urine sample will be collected and sent to the University of West of England for VC testing. We choose urine samples as they are more acceptable to our patients, maintain their VC profile when frozen, whilst offering comparable sensitivity and specificity to other samples. Outcome measures include feasibility testing of the whole study within the clinical pathway including recruitment, urine storage, transfer and analysis to identify any challenges that will inform the main study. It will also estimate the sensitivity, specificity and test-retest reliability of each analysis method and patient acceptability within the context of the CRC fast-track pathway. Early economic evaluation will be tested to inform the main study. Impact of this study The overall goal of this research is to directly benefit patients through improving patient safety and experience by reducing unnecessary colonoscopy; optimising utilisation of healthcare resources by establishing better selection methods for patients requiring colonoscopy with associated cost savings. Although this feasibility study will not directly affect the current patient pathway, it will provide essential evidence on the feasibility of applying the novel test the clinical practice to triage patients. It will also provide the methodology of the main study, which will ultimately improve the efficiency of the current fast track referral system for CRC.

Lay abstract: Bowel cancer is diagnosed in approximately 41,000 people each year in the UK. Early detection and treatment of bowel cancer is important as it improves survival. This has led to a &ldquo;fast-track&rdquo; system to speed up waiting times and access to hospital tests. Deciding who to test is hard for GPs and hospital doctors because bowel symptoms are common and are not usually due to cancer and not all people with a bowel cancer develop symptoms. In the UK, 300,000 people a year are referred through the fast-track bowel system of which the vast majority of them undergo testing. An internal camera examination of the colon (colonoscopy) is the best way to look at the large bowel but this is invasive, can be uncomfortable and needs strong laxatives to prepare the bowel. The test also carries a risk of serious complications; is expensive and its demand keeps increasing in the NHS. Over 90% of fast track referrals have normal results meaning they have undergone unpleasant testing that did not help them. It is now possible to look at natural chemicals produced by human cells and normal bacteria that live in everybody s colon to help diagnose bowel conditions. Bowel cancer alters the chemical &ldquo;signature&rdquo; which can be detected in urine. We propose to test the urine of 600 people referred by their GP to the fast-track pathway to assess the feasibility and determine the methodology of a large study. The goal of the main study is to evaluate how good these chemical signature are at diagnosing bowel cancer. If the test works, this will safely reduce the number of patients undergoing unpleasant bowel tests without missing important diagnoses. The study will take place in three UK NHS Trusts between 2017 and 2019.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS