Flexible sigmoidoscopy screening: is once enough?
Authors: Paul F Pinsky
Journal: The Lancet (2017)

Worldwide, colorectal cancer is the third most common incident cancer and the fourth leading cause of cancer death, with 1·4 million new cases and 700 000 deaths estimated in 2012—most of these from the developed world.1Ferlay J Soerjomataram I Ervik M et al.GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC Cancer Base No. 11. International Agency for Research on Cancer, Lyon, France2013Google Scholar Over the past three decades, several methods to screen for colorectal cancer, and to detect, remove, or both, colorectal cancer precursors—namely, adenomatous polyps—have been developed. Current guidelines in the European Union include recommendations for stool-based tests (fecal occult blood test [FOBT] and fecal immunochemical test [FIT]) and flexible sigmoidoscopy, whereas most US guidelines include those tests as well as colonoscopy.2von Karsa L Patnick J Segnan N et al.European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full Supplement publication.Endoscopy. 2013; 45: 51-59Crossref PubMed Scopus (8) Google Scholar, 3Bibbins-Domingo K Grossman DC et al.US Preventive Services Task ForceScreening for colorectal cancer: US Preventive Services Task Force Recommendation Statement.JAMA. 2016; 315: 2564-2575Crossref PubMed Scopus (1249) Google Scholar In The Lancet, Wendy Atkin and colleagues4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar report on the extended follow-up of the UK Flexible Sigmoidoscopy Screening Trial (UKFSST) through a median of 17 years of follow-up. This randomised controlled trial enrolled 170 432 eligible men and women to either an intervention group (offered one-time flexible sigmoidoscopy screening) or control group (not contacted), with primary outcomes of colorectal cancer incidence and mortality. The analysed cohort included 57 098 people in the intervention group, of whom 40 621 (71%) received screening, and 112 936 people in the control group. A previous report of 11 years of follow-up reported hazard ratios (HRs) in intention-to-treat (ITT) analyses of 0·77 (95% CI 0·70–0·84) for colorectal cancer incidence and 0·69 (0·59–0·82) for colorectal cancer mortality for the intervention versus control group.5Atkin WS Kralj-Hans I Wooldrage K et al.Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicenter randomised controlled trial.Lancet. 2010; 375: 1624-1633Summary Full Text Full Text PDF PubMed Scopus (1312) Google Scholar Rather remarkably, because the trial used only one flexible sigmoidoscopy screen at baseline, these HRs were maintained through an additional 6 years, with ITT HRs now of 0·74 (95% CI 0·70–0·80) for incidence and 0·70 (0·62–0·79) for mortality.4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar These new results are important for two reasons. First, and especially with regards to the reported reduction in incidence of distal colorectal cancer, the implications for our understanding of the natural history of adenomas and colorectal cancer are intriguing. Second, the reported reduction in incidence and mortality of overall colorectal cancer provides needed data from a public health perspective on the optimal design of a screening programme that incorporates flexible sigmoidoscopy. Because of ethical concerns in leaving colon polyps intact for appreciable time periods, the natural history of adenomas, especially with regards to quantitative transition rates to colorectal cancer, is largely unknown.6Vleugels JL Hazewinkel Y Fockens P Dekker E The natural history of diminutive and small colorectal polyps: a systematic literature review.Gastrointest Endosc. 2016; (published online Dec 23.)https://doi.org/10.1016/j.gie.2016.12.014Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar Estimates of transition rates and intervals largely derive from modelling studies, which generally rely on data covering only short periods of observation (5–10 years).7Kuntz KM Rutter CM et al.Lansdorp-VogelaarA systematic comparison of microsimulation models of colorectal cancer: the role of assumptions about adenoma progression.Med Decis Making. 2011; 31: 530-539Crossref PubMed Scopus (82) Google Scholar The findings of Atkin and colleagues' extended follow-up should inform future modelling efforts and lead to a better understanding of the natural history of adenoma. Based on the per-protocol analysis of Atkin and colleagues of the effectiveness in participants who received flexible sigmoidoscopy screening, the reduction in incidence for distal colorectal cancer was actually slightly greater at 17 years of follow-up (HR 0·44 [95% CI 0·38–0·50])4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar than at 11 years (0·50 [95% CI 0·42–0·59]).5Atkin WS Kralj-Hans I Wooldrage K et al.Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicenter randomised controlled trial.Lancet. 2010; 375: 1624-1633Summary Full Text Full Text PDF PubMed Scopus (1312) Google Scholar After exclusion of prevalent cases, and with the assumption that the rate of such cases was the same in the control group as in those actually screened (126 [0·31%] of 40 621), a per-protocol analysis would show a striking 66% reduction in the incidence of distal colorectal cancer over 17 years. With the exception of the small subset referred for surveillance colonoscopy, this prevention was all due to a single flexible sigmoidoscopy screen at baseline. These findings suggest that the rate at which de-novo adenomas formed and transitioned to symptomatic colorectal cancer within 17 years was quite low. Current models of the natural history of adenoma should be reassessed to see if they are consistent with these long-term results. The trial protocol called for surveillance colonoscopy for patients found to be at high risk on the baseline screen. Of the 40 621 people actually screened, 1745 (4%) were reported to have undergone surveillance.5Atkin WS Kralj-Hans I Wooldrage K et al.Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicenter randomised controlled trial.Lancet. 2010; 375: 1624-1633Summary Full Text Full Text PDF PubMed Scopus (1312) Google Scholar Additional information about this surveillance cohort in terms of yield of adenomas and colorectal cancer over time would be useful to understand the various components of the sustained incidence reduction. From a public health perspective, the updated findings of a reduction in the overall colorectal cancer incidence and mortality through to 17 years raises the issue of whether once-only flexible sigmoidoscopy might be a reasonable screening strategy. Outside of the USA, where colonoscopy is the primary method of colorectal cancer screening,8Smith RA Manassaram-Baptiste D Brooks D et al.Cancer screening in the United States, 2015: a review of current American Cancer Society guidelines and current issues in cancer screening.CA Cancer J Clin. 2015; 65: 30-54Crossref PubMed Scopus (289) Google Scholar colorectal cancer screening guidelines generally recommend either flexible sigmoidoscopy or stool-based testing, either alone or in combination.2von Karsa L Patnick J Segnan N et al.European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full Supplement publication.Endoscopy. 2013; 45: 51-59Crossref PubMed Scopus (8) Google Scholar However, within this general framework, uncertainty exists regarding several issues, including how (and whether) to combine flexible sigmoidoscopy with stool testing, starting and stopping ages, and testing intervals.2von Karsa L Patnick J Segnan N et al.European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview and introduction to the full Supplement publication.Endoscopy. 2013; 45: 51-59Crossref PubMed Scopus (8) Google Scholar The extended findings of the UKFSST contribute substantively to this conversation, although they do not provide a definitive answer. The current UK national screening programme includes biennial FOBT for people aged 60–74 years and, starting in 2013 and gradually being fully implemented, one-time flexible sigmoidoscopy at age 55 years.4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar Based on the UKFSST findings,4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar and the absence of a reduction in incidence of colorectal cancer with use of FOBT in most trials,9Armaroli P Villain P Suonio E et al.European Code against Cancer, 4th Edition: Cancer screening.Cancer Epidemiol. 2015; 39S: S139-S152Summary Full Text Full Text PDF Scopus (62) Google Scholar the addition of the FOBT will probably have relatively little effect on colorectal cancer incidence, especially distal colorectal cancer. However, the addition of FOBT might well have added benefit in terms of reducing colorectal cancer mortality, and especially of proximal colorectal cancer type. In the absence of a subsequent FOBT (or FIT) testing programme, screening programme planners need to assess the probable added benefit of a second flexible sigmoidoscopy screen, say 10–15 years after the first. The results of Atkin and colleagues' study suggest that such added benefit might well be restricted in terms of additional reductions in colorectal cancer incidence or mortality. However, data from continued follow-up of this cohort beyond 17 years, which the investigators state they plan on doing, will further inform this issue. Additionally, with or without stool testing, another important issue concerns the referral algorithm for colonoscopy. In view of the absence of a significant effect on proximal colorectal cancer in the UKFSST, which had a relatively low 5% colonoscopy referral rate,4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar the tradeoff between the additional resource utilisation (and patient harms) of higher referral rates against the greater protection from proximal colorectal cancer needs to be considered. Note that the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial10Schoen RE Pinsky PF Weissfeld JL et al.Colorectal cancer incidence and mortality with screening flexible sigmoidoscopy.N Engl J Med. 2012; 366: 2345-2357Crossref PubMed Scopus (748) Google Scholar of flexible sigmoidoscopy showed a significant reduction in incidence of proximal colorectal cancer (relative risk 0·86 [95% CI 0·76–0·97]), although it had a substantially higher colonoscopy referral rate of 21·9% cumulatively over two screening rounds than did the study by Atkin and colleagues.4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar These results from Atkin and colleagues4Atkin WS Wooldrage K Parkin DM et al.Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trial.Lancet. 2017; (published online Feb 21.)http://dx.doi.org/10.1016/S0140-6736(17)30396-3PubMed Google Scholar might also be relevant for colonoscopy screening. Although the protection provided by colonoscopy is believed to be less for proximal than for distal colorectal cancer, if these findings were to hold for colonoscopy in a relative sense—ie, if the reduction in incidence of proximal colorectal cancer through to 10 years was found to be maintained through to 17 years or more—it could prompt a re-evaluation of the standard 10 year interval for colonoscopy screening in the USA. Colorectal cancer is largely a preventable disease. As with cervical cancer, the ability to reduce incidence as well as mortality through minimally invasive removal of precursor lesions is a gift of nature that should be taken advantage of if at all possible. Flexible sigmoidoscopy screening, even once only, is a resource-conserving strategy that, as shown in the study by Atkin and colleagues, seems to achieve much of the potential of colorectal cancer prevention, but one which also misses a substantial fraction of potentially preventable or curable cancers. Assessment of screening strategies involving flexible sigmoidoscopy, colonoscopy, or stool-testing generally compare screening efficacy, in terms of colorectal cancer cases or deaths prevented, with the costs and resource utilisations of the screening programme.11Knudsen AB Zauber AG Rutter CM et al.Estimation of benefits, burden and harms of colorectal cancer screening strategies: modeling study of the US Preventive Services Task Force.JAMA. 2016; 315: 2595-2609Crossref PubMed Scopus (319) Google Scholar These latest long-term results from the UKFSST should provide additional data for researchers to re-assess these strategies. I declare no competing interests. Long term effects of once-only flexible sigmoidoscopy screening after 17 years of follow-up: the UK Flexible Sigmoidoscopy Screening randomised controlled trialA single flexible sigmoidoscopy continues to provide substantial protection from colorectal cancer diagnosis and death, with protection lasting at least 17 years. 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