Leading article

Colorectal cancer screening R. J. C. Steele Medical Research Institute, Division of Cancer, Mailbox 4, Level 7, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK (e-mail: [email protected])

Published online 4 August 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9599

Population screening for colorectal cancer has now been rolled out across all the constituent countries of the UK. Although the algorithms differ slightly from one country to another, the first-line screening test is a guaiac-based faecal occult blood test (gFOBT) with the same analytical characteristics as those used in the randomized clinical trials (RCTs) that demonstrated convincing reductions in disease-specific mortality1 . A recent matched cohort study has indicated that the current programme is producing a mortality reduction of the expected magnitude2 , even though the guaiac-based test has significant weaknesses. The overall uptake of screening remains stubbornly below 60 per cent1 . Interval cancers (those arising within 2 years of a negative test result) are being increasingly recognized, with recent data suggesting that interval disease accounts for approximately 50 per cent of the cancers diagnosed in the screened population3 . A final disadvantage relates to the lack of efficacy of the current programme in the prevention of colorectal cancer; gFOBT at the analytical sensitivity used in the UK does not identify sufficient numbers of adenomas to have a measurable preventive effect4 . Although these UK screening programmes are undoubtedly preventing colorectal cancer deaths, future developments must address these deficiencies. One approach is to move to quantitative faecal immunochemical testing (QFIT) for blood. This has the advantages of being © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

specific for haemoglobin and providing a value for the concentration of haemoglobin in the stool. The best evidence supporting the use of QFIT comes from a randomized study5 in the Netherlands comparing QFIT at a cut-off of 100 ng haemoglobin per ml faeces in buffer with a guaiac-based test that has an analytical detection limit of around 400 ng haemoglobin per ml faeces. This study demonstrated better uptake with QFIT, and a higher sensitivity for both cancer and adenoma detection with a similar number needed to colonoscope. However, this came at the expense of a higher positivity rate and therefore the need for a larger overall number of colonoscopies. If QFIT is used at the same analytical sensitivity as the standard gFOBT, both tests perform in much the same way in terms of disease detection. For QFIT to reduce the interval cancer rate and increase the chances of adenoma detection it seems that it would be necessary to reduce the analytical threshold such that the positive predictive value would decrease and the number of colonoscopies required would increase. This is currently unpalatable given the pressures on endoscopy services in the UK, but there is increasing evidence that using QFIT to triage symptomatic patients could dramatically reduce the number of colonoscopies required in the symptomatic population and free up resources for screening6 . Furthermore, it should be possible to use the quantitative power of QFIT in a more intelligent way. For

example, it is known that interval cancers are more common in women than in men, and that the concentration of blood in stool is significantly lower in women than in men7 . It should therefore be possible to address the problem of interval cancers in women by using a differential cut-off to trigger colonoscopy. It is also feasible to decrease the analytical threshold and increase the interval between screens so that sensitivity of the test may be improved in a cost-neutral manner in terms of colonoscopy resource. With a little more imagination it may also be possible to vary the interval between screens based on the index faecal haemoglobin concentration, as it is known that this is directly proportional to the risk of having significant neoplastic disease8 . Thus an individual with a faecal haemoglobin concentration close to a predetermined cut-off may have a repeat test within 6 months, whereas someone with undetectable haemoglobin may have their next test deferred for a few years. Little is known about variations in faecal haemoglobin levels with time and this requires attention if we are to optimize screening based on faecal haemoglobin detection. Of course, there is good evidence from RCTs that using flexible sigmoidoscopy as the primary screening test can reduce both the mortality from, and incidence of, colorectal cancer9 . This test is being rolled out at around the age of 55 years across England, but not in Scotland where FOBT screening starts at age 50 years as opposed to 60 years in England. A pilot study of BJS 2014; 101: 1338–1340

Colorectal cancer screening

flexible sigmoidoscopy offered at the age of 60 years superimposed on the current FOBT screening programme in Scotland has been commissioned, and is about to commence. One of the problems with flexible sigmoidoscopy screening is that it does not appear to have a preventive effect on right-sided colonic cancer, even when colonoscopy is performed in those with high-risk index lesions found on initial examination9 . It follows that colonoscopy might be a better screening test, but observational studies suggest that, although colonoscopy can prevent left-sided cancer, it is not as effective at preventing rightsided cancer9 , presumably because the precursor lesions on the right side of the colon are more subtle than those on the left, and because bowel preparation on the right side is often suboptimal. Currently there are four RCTs of colonoscopy as the primary screening test in progress worldwide, but none has yet reported. FOBT screening, as employed in the UK, is effective in reducing colorectal cancer mortality, but can be enhanced by the use of more sophisticated and sensitive testing for blood and by supplementing FOBT with primary endoscopic screening. What, however, might the future hold? For many years there has been interest in testing stool for DNA mutations associated with colorectal cancer. Recent research suggests that, by using an appropriate panel of DNA abnormalities, this can outperform faecal immunochemical testing at a cut-off level of 100 ng haemoglobin per ml, at least in terms of sensitivity10 . This technology is not yet sufficiently developed, however, to be used in population screening, where ease of testing and cost are paramount. There has also been interest in using biomarkers in blood as screening tests, but to date no biomarker has been found with a sensitivity and specificity © 2014 BJS Society Ltd Published by John Wiley & Sons Ltd

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any better than those achieved in testing for blood in stool. For now, the most important development in the UK should be the replacement of gFOBT with QFIT, along with highquality prospective studies to establish the role of flexible sigmoidoscopy within national programmes. The UK is not the only country to engage in population screening. In Europe, Finland was early on the scene with gFOBT, and Denmark, the Netherlands and the Republic of Ireland have recently started screening with QFIT. France has a gFOBTbased programme, but is exploring the use of QFIT, Germany offers both gFOBT and colonoscopy, and Italy has regional programmes that use QFIT and flexible sigmoidoscopy. Other countries, such as Sweden and Spain, are exploring different options. Outside Europe, there are screening programmes based on faecal testing in Australia, New Zealand, Japan, Taiwan and Canada. In the USA, colorectal screening is delivered largely by opportunistic colonoscopy. The major issue that faces the international colorectal screening community is the plethora of different approaches, not all of them evidence-based, and not all operating as true population screening programmes. Firmly evidence-based guidelines are available11 , and for screening to have a truly global impact it is essential that this evidence is translated into public health action. Disclosure

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The author declares no conflict of interest. References 1 Logan RFA, Patnick J, Nickeson C, Coleman L, Rutter MD, von Wagner C; English Bowel Cancer Screening Evaluation Committee. Outcomes of the Bowel Cancer Screening Programme (BCSP) in England after

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the first 1 million tests. Gut 2012; 61: 1439–1446. Libby G, Brewster DH, McClements PL, Carey FA, Black RJ, Birrell J et al. The impact of population-based faecal occult blood test screening on colorectal cancer mortality: a matched cohort study. Br J Cancer 2012; 107: 255–259. Steele RJC, McClements P, Watling C, Libby G, Weller D, Brewster DH et al. Interval cancers in a FOBT-based colorectal cancer population screening programme: implications for stage, gender and tumour site. Gut 2012; 61: 576–581. Scholefield JH, Moss SM, Mangham CM, Whynes DK, Hardcastle JD. Nottingham trial of faecal occult blood testing for colorectal cancer: a 20-year follow-up. Gut 2012; 61: 1036–1040. Van Rossum LG, van Rijn AF, Laheij RJ, van Oijen MG, Fockens P, van Krieken HH et al. Random comparison of guaiac and immunochemical faecal occult blood test for colorectal cancer in a screening population. Gastroenterology 2008; 135: 82–90. McDonald PJ, Digby J, Innes C, Strachan JA, Carey FA, Steele RJC et al. Low faecal haemoglobin concentration potentially rules out significant colorectal disease. Colorectal Dis 2013; 15: e151–e159. McDonald PJ, Strachan JA, Digby J, Steele RJC, Fraser CG. Faecal haemoglobin concentrations by gender and age: implications for population-based screening for colorectal cancer. Clin Chem Lab Med 2011; 50: 935–940. Digby J, Fraser CG, Carey FA, McDonald PJ, Strachan JA, Diament R et al. Faecal haemoglobin concentration is related to severity of colorectal neoplasia. J Clin Pathol 2013; 66: 415–419. Brenner H, Stock C, Hoffmeister M. Effect of screening sigmoidoscopy and screening colonoscopy on incidence and mortality: systematic review and meta-analysis of randomised controlled trials and

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observational studies. BMJ 2014; 348: g2467 10 Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP et al. Multitarget stool

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DNA testing for colorectal-cancer screening. N Engl J Med 2014; 370: 1287–1297. 11 European Commission. European Guidelines for Quality Assurance in

Colorectal Cancer Screening and Diagnosis (1st edn). Publications Office of the European Union: Luxembourg, 2011.

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Colorectal cancer screening.

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