Screening for colorectal cancer

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    Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK (N. Pawa, J.D.Norton). ICENI Centre, Department of Surgery, Colchester Hospital University NHS Foundation Trust, Turner Road, Colchester CO4 5JL, UK (T.Arulampalam).

    Correspondence to: J. D. Norton

    Screening for colorectal cancer: established and emerging modalitiesNikhil Pawa, Tan Arulampalam and John D. Norton

    Abstract | It has been estimated that >95% of cases of colorectal cancer (CRC) would benefit from curative surgery if diagnosis was made at an early or premalignant polyp stage of disease. Over the past 10years, most developed nation states have implemented mass population screening programs, which are typically targeted at the older (at-risk) age group (>5060years old). Conventional screening largely relies on periodic patient-centric investigation, particularly involving colonoscopy and flexible sigmoidoscopy, or else on the fecal occult blood test. These methods are compromised by either low cost-effectiveness or limited diagnostic accuracy. Advances in the development of diagnostic molecular markers for CRC have yielded an expanding list of potential new screening modalities based on investigations of patient stool (for colonocyte DNA mutations, epigenetic changes or microRNA expression) or blood specimens (for plasma DNA mutations, epigenetic changes, heteroplasmic mitochondrial DNA mutations, leukocyte transcriptome profile, plasma microRNA expression or protein and autoantibody expression). In this Review, we present a critical evaluation of the performance data and relative merits of these various new potential methods. None of these molecular diagnostic methods have yet been evaluated beyond the proof-of-principle and pilot-scale study stage and it could be some years before they replace existing methods for population screening in CRC.

    Pawa, N. etal. Nat. Rev. Gastroenterol. Hepatol. advance online publication 1 November 2011; doi:10.1038/nrgastro.2011.205

    IntroductionColorectal cancer (CRC) is one of the most prevalent forms of malignancy worldwide with approximately 1million new cases diagnosed each year, accounting for 500,000 deaths.1 The pathogenesis of CRC involves the progressive accumulation of gene mutations over a time-scale of years as the disease advances.1 Most cases of early stage disease are clinically silent and, as a result, approximately 55% of patients in the UK present with lymph node or distant metastases.2 The stage of disease at diagnosis is the single most important predictor of prognosis and disease-free survival.3 The overall 5-year age-standardized survival rate for CRC in Europe ranges from only 52% to 62%.2,4

    It has been estimated that over 95% of cases of CRC would benefit from curative surgery if diagnosis was made at an early or premalignant polyp stage, and several large-scale studies have demonstrated a statisti-cally signifi cant reduction in mortality with implementa-tion of mass CRC screening programs.5,6 It is perhaps relevant that during their lifetime, an estimated 4050% of the population in developed nations will develop one or more polyps, although the majority of these polyps will remain benign.7

    Broadly speaking, screening strategies are of two types: those that involve direct investigation of the patient, often with an invasive procedure, and those based on laboratory analysis of patient specimens (typically feces

    or peripheral blood) to detect disease biomarkers. Both strategies target the higher-risk older-aged population (>5060years old). An ideal screening strategy needs to fulfill four important criteria: acceptable performance in terms of positive and negative predictive value for the target population; a reduction in mortality from the disease; acceptable levels of patient compliance; and low enough cost to be affordable within the context of the specific health-care system. No such ideal diag-nostic screening procedure for CRC currently exists, and the main screening modalities that have so far been adopted (invasive diagnosis of the patient and the fecal occult blood test [FOBT]) represent a trade-off between the above four criteria. Several authors have recently reviewed the current state of practice and investigation in this field.5,6,8,9 The purpose of this Review is to sum-marize the different diagnostic screening strategies that have been or are being investigated (Table1; Box1), and to explore the potential of emerging technologies in the application of molecular markers for population screening for CRC.

    Established screening modalities Direct investigation of the patientColonoscopyColonoscopy is regarded as the gold standard for the diagnosis of colorectal polyps and malignancy, and has gained increased popularity in the USA and Canada over the past 1020years; however, Poland is currently the only European country utilizing colonoscopy as the sole

    Competing interestsThe authors declare no competing interests.


    2011 Macmillan Publishers Limited. All rights reserved


    screening method for individuals aged 5566years.10 Although its use is clearly associated with a decrease in CRC-related deaths, no direct evidence from random-ized controlled trials has demonstrated the effectiveness of colonoscopy in reducing mortality from CRC, and therefore inferences are drawn from indirect evidence. In a prospective observational study of asymptom-atic average-risk individuals, Kahi etal.11 reported a 65% reduction in CRC mortality and 67% reduc-tion in disease incidence with colonoscopy screen-ing. Similarly, Rabenck and colleagues12 identified an

    Key points

    Approximately 1 million new cases of colorectal cancer are diagnosed each year

    Population screening for detection of disease at an early stage has demonstrated a significant reduction in mortality

    The fecal occult blood test is the most widely adopted screening method, but is compromised by poor reliability and patient compliance

    Although flexible sigmoidoscopy is cost-effective, more definitive direct investigative procedures (such as colonoscopy) are prohibitively expensive for most national screening programs

    An expanding list of potential new screening methods based on the detection of DNA, RNA or protein molecular markers in patient stool or blood specimens is currently being evaluated

    The introduction of screening based on molecular markers is likely to be an incremental process; established screening modalities are likely to remain in widespread use for some years

    inverse association between mortality and increased rate of complete colonoscopy. A large population-based, case controlled study demonstrated a marked mortality reduction for left-sided lesions, but with very little reduc-tion for right-sided tumors in patients who underwent colonoscopy.13 This observation concurs with similar findings from a cross-sectional study of the German population.14 Despite some confounding issues in these studies, such as variability in procedural performance at different centers, they do question the presumed supe-riority of colonoscopy as a screening tool, especially for tumors of the proximal colon. Under the auspices of the Northern-European Initiative on Colorectal Cancer (NordICC), a large multicenter randomized trial is currently underway that aims to establish the clinical impact of colonoscopy screening on CRC incidence and mortality, with the final results expected in 2026.15

    Another area of concern with colonoscopy is that it is a very operator-dependent procedure; a miss rate of between 6% and 12% has been identified for larger polyps and 5% for cancers.16 As an invasive procedure, it is also not without some attendant risk of complications, such as bowel perforation. The rate of major complications has been reported at 0.2%, a figure representing approxi-mately 10 times that of any other cancer screening test.17 However, the main disadvantage of colonoscopy is its high cost, making it unaffordable as a population screening method for most of the global health-care sector.18

    Table 1 | Current CRC screening guidelines

    Risk European Union Guidelines 2010125 American Cancer Society Guidelines 2011126

    Average risk Screening age: 5074yearsScreening options: fecal occult blood test (2yearly)

    Screening age: 50years (45years for African Americans)Screening options: fecal occult blood test (yearly)*CT colonography (5yearly)*Flexible sigmoidoscopy (5yearly)*Double contrast barium enema (5yearly)*Colonoscopy (10yearly)

    Increased risk (history of polyps or other risk factors)

    Low risk (12 adenomas [


    Barium enemaThe double-contrast barium enema examination has a reported sensitivity of between 85% and 97% for CRCs and 73% for adenomas >7 mm when used as a screening tool.16 However, the bowel preparation involved in this labor-intensive procedure, together with its high cost, has limited its popularity.16 Additionally, a lack of well-designed studies assessing its effectiveness as a screening tool has led to further skepticism, particularly with the introduction of CT colonography. Glick and colleagues19 generated a model of 16 different screening strategies to analyze the cost-effectiveness of the barium enema examination. The model illustrated the cost-effectiveness of the examination every 5years, but only assuming the reported high sensitivity of early studies.16 However, in a population-based study, Toma and colleagues20 reported the chance of missing a cancer at barium enema examina tion to be one in five.