Screening, Surveillance, and Primary Prevention for Colorectal Cancer: A Review of the Recent Literature

Abstract

Colorectal cancer (CRC) remains a major clinical and public health challenge, with 148,810 new cases and 49,960 deaths expected in the United States in 2008.1Jemal A. Siegel R. Ward E. et al.Cancer statistics, 2008.CA Cancer J Clin. 2008; 58: 71-96Google Scholar The field of CRC research is dynamic and expanding in several directions, encompassing areas of clinical and outcomes research, epidemiology, public health, and molecular sciences. In this review, we summarize important developments in CRC screening and surveillance over the past several years and discuss the present state of the art of this field.Risk Factors for Colorectal NeoplasiaMetabolic SyndromeAccording to the National Cholesterol Education Program's Adult Treatment panel III, metabolic syndrome is the presence of 3 or more of the following factors: hypertension (blood pressure of 130/85 mm Hg or greater), central adiposity (waist circumference greater than 102 cm in men or greater than 88 cm in women or a body mass index [BMI] greater than 27 [kg/m2]), low high-density lipoprotein (HDL) cholesterol (HDL <40 mg/dL in men or <50 mg/dL in women), hypertriglyceridemia (150 mg/dL or greater), and impaired glucose tolerance (fasting serum glucose of 110 mg/dL or greater).2Cheng A.Y. Leiter L.A. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.Curr Opin Cardiol. 2006; 21: 400-404Google Scholar Colorectal neoplasia has been associated with markers of glucose and insulin control; insulin resistance, which is the cornerstone of the metabolic syndrome, may be the mechanism by which several risk factors (obesity, diabetes mellitus, [lack of] fitness) affect colorectal carcinogenesis.3Kaaks R. Toniolo P. Akhmedkhanov A. et al.Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women.J Natl Cancer Inst. 2000; 92: 1592-1600Google Scholar, 4Saydah S.H. Platz E.A. Rifai N. et al.Association of markers of insulin and glucose control with subsequent colorectal cancer risk.Cancer Epidemiol Biomarkers Prev. 2003; 12: 412-418Google ScholarFour of the most recent studies of metabolic syndrome and CRC are summarized in Table 1.5Ahmed R.L. Schmitz K.H. Anderson K.E. et al.The metabolic syndrome and risk of incident colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2006; 107: 28-36Google Scholar, 6Chiu H.-M. Lin J.-T. Shun C.-T. et al.Association of metabolic syndrome with proximal and synchronous colorectal neoplasm.Clin Gastroenterol Hepatol. 2007; 5: 221-229Google Scholar, 7Kim J.H. Lim Y.J. Kim Y.-H. et al.Is metabolic syndrome a risk factor for colorectal adenoma?.Cancer Epidemiol Biomarkers Prev. 2007; 16: 1563-1566Google Scholar, 8Sturmer T. Buring J.E. Lee I.-M. et al.Metabolic abnormalities and risk for colorectal cancer in the Physicians' Health Study.Cancer Epidemiol Biomarkers Prev. 2006; 15: 2391-2397Google Scholar These studies comprise different study populations and different study designs but use the same or comparable definitions of metabolic syndrome, similar methods of analysis, and either adenoma or cancer as outcomes. The study findings are quite consistent: either the metabolic syndrome or its components increase the risk for colorectal neoplasia (both adenomas and cancer) by approximately 50%. The effect of metabolic syndrome on neoplasia risk appears to be greater in men than in women. The relationship between metabolic syndrome and large bowel location of neoplasia reported by Chiu et al6Chiu H.-M. Lin J.-T. Shun C.-T. et al.Association of metabolic syndrome with proximal and synchronous colorectal neoplasm.Clin Gastroenterol Hepatol. 2007; 5: 221-229Google Scholar is interesting and requires validation in analyses of other populations.Table 1Summary of Selected Studies on Metabolic Syndrome and Risk of Colorectal NeoplasiaFirst author, year (ref)Study populationStudy designCriteria for metabolic syndromeOutcomesType of risk modelMain findingsAhmed, 2006 (5Ahmed R.L. Schmitz K.H. Anderson K.E. et al.The metabolic syndrome and risk of incident colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2006; 107: 28-36Google Scholar)14,109 subjects from the Atherosclerosis Risk in Communities (ARIC) multicenter study)CohortATP IIIColorectal cancerMultiple logistic model, adjusted for age, gender, family history of CRC, physical activity, NSAID use, aspirin use, smoking, alcohol use, hormone replacement useMS associated with increased risk of CRC (age and gender adjusted RR, 1.49; 95% CI: 1.0–2.4), which attenuated after multivariate adjustment (RR, 1.39; 95% CI: 0.9–2.2). Adjusted risk was increased in men (RR, 1.78; 95% CI: 1.02–3.6) but not in women (RR, 1.16; 95% CI: 0.6–2.2)Sturmer, 2006 (8Sturmer T. Buring J.E. Lee I.-M. et al.Metabolic abnormalities and risk for colorectal cancer in the Physicians' Health Study.Cancer Epidemiol Biomarkers Prev. 2006; 15: 2391-2397Google Scholar)22,071 healthy male physicians initially ages 40–84 yearsCohortBMI of ≥27 kg/m2, total cholesterol of ≥240 mg/dL or use of lipid-lowering drugs, blood pressure of ≥130/85 mm Hg or use of antihypertensives, and a diagnosis of diabetes mellitusColorectal cancerMultiple logistic model, adjusted for age, smoking, exercise, alcohol use, multivitamin use, and consumption of fruits and vegetablesBMI >27 kg/m2 (RR, 1.4; 95% CI: 1.1–1.7) and diabetes (RR, 1.5; 95% CI: 1.1–2.0) were associated with CRC; hypertension and hypercholesterolemia were not.Kim, 2007 (7Kim J.H. Lim Y.J. Kim Y.-H. et al.Is metabolic syndrome a risk factor for colorectal adenoma?.Cancer Epidemiol Biomarkers Prev. 2007; 16: 1563-1566Google Scholar)3584 consecutive subjects undergoing screening colonoscopyCross-sectionalModified ATP III criteriaColorectal adenomaMultiple logistic model, adjusted for age, gender, smoking, alcohol use17% of subjects with adenomas and 11% of those without adenomas had MS. MS associated with increased risk of adenoma: OR, 1.51; 95% CI: 1.19–1.93. Waist circumference was an independent risk factor for adenoma: OR, 1.39; 95% CI: 1.15–1.68Chiu, 2007 (6Chiu H.-M. Lin J.-T. Shun C.-T. et al.Association of metabolic syndrome with proximal and synchronous colorectal neoplasm.Clin Gastroenterol Hepatol. 2007; 5: 221-229Google Scholar)4277 consecutive ethnic Chinese who had screening or surveillance colonoscopy as part of a medical health checkupCross-sectionalModified ATP III criteria, modified Asian criteria (HDL cholesterol of <40 mg/dL, waist circumference ≥90 cm for men, ≥80 cm for women)Colorectal neoplasia, anatomic locationMultiple logistic model, adjusted for age, gender, BMI, smoking, alcohol use, previous adenoma, family history of CRCMS associated with increased risk of any neoplasia (OR, 1.35; 95% CI: 1.05–1.73), proximal neoplasia (OR, 1.62; 95% CI: 1.14–2.30), synchronous lesions (OR, 2.15; 95% CI: 1.40–3.31), and synchronous lesions both proximal and distal (OR, 2.30; 95% CI: 1.42–3.72).MS, metabolic syndrome. Open table in a new tab Cigarette SmokingThe epidemiologic evidence that cigarette smoking increases the risk of CRC was elegantly reviewed by Giovannucci in 2001.9Giovannucci E. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2001; 10: 725-731Google Scholar An association between colorectal neoplasia and cigarette smoking is supported by several studies, with the association more consistently established for smoking and adenomas, including large adenomas, than for cancer.9Giovannucci E. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2001; 10: 725-731Google Scholar, 10Boutron M.C. Faivre J. Dop M.C. et al.Tobacco, alcohol, and colorectal tumors: a multistep process.Am J Epidemiol. 1995; 141: 1038-1046Google Scholar, 11Chao A. Thun M.J. Jacobs E.J. et al.Cigarette smoking and colorectal cancer mortality in the cancer prevention study II.J Natl Cancer Inst. 2000; 92: 1888-1896Google Scholar, 12Giovannucci E. Colditz G.A. Stampfer M.J. et al.A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in US women.J Natl Cancer Inst. 1994; 86: 192-199Google Scholar, 13Giovannucci E. Rimm E.B. Stampfer M.J. et al.A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in US men.J Natl Cancer Inst. 1994; 86: 183-191Google Scholar, 14Heineman E.F. Zahm S.H. McLaughlin J.K. et al.Increased risk of colorectal cancer among smokers: results of a 26-year follow-up of US veterans and a review.Int J Cancer. 1994; 59: 728-738Google Scholar, 15Honjo S. Kono S. Shinchi K. et al.Cigarette smoking, alcohol use and adenomatous polyps of the sigmoid colon.Jpn J Cancer Res. 1992; 83: 806-811Google Scholar, 16Jacobson J.S. Neugut A.I. Murray T. et al.Cigarette smoking and other behavioral risk factors for recurrence of colorectal adenomatous polyps (New York City, NY).Cancer Causes Control. 1994; 5: 215-220Google Scholar, 17Lee W.C. Neugut A.I. Garbowski G.C. et al.Cigarettes, alcohol, coffee, and caffeine as risk factors for colorectal adenomatous polyps.Ann Epidemiol. 1993; 3: 239-244Google Scholar, 18Longnecker M.P. Paganini-Hill A. Ross R.K. Lifetime alcohol consumption and breast cancer risk among postmenopausal women in Los Angeles.Cancer Epidemiol Biomarkers Prev. 1995; 4: 721-725Google Scholar, 19Nagata C. Shimizu H. Kametani M. et al.Cigarette smoking, alcohol use, and colorectal adenoma in Japanese men and women.Dis Colon Rectum. 1999; 42: 337-342Google Scholar, 20Newcomb P.A. Storer B.E. Marcus P.M. Cigarette smoking in relation to risk of large bowel cancer in women.Cancer Res. 1995; 55: 4906-4909Google Scholar, 21Potter J.D. Bigler J. Fosdick L. et al.Colorectal adenomatous and hyperplastic polyps: smoking and N-acetyltransferase 2 polymorphisms.Cancer Epidemiol Biomarkers Prev. 1999; 8: 69-75Google Scholar, 22Sturmer T. Glynn R.J. Lee I.M. et al.Lifetime cigarette smoking and colorectal cancer incidence in the Physicians' Health Study I.J Natl Cancer Inst. 2000; 92: 1178-1181Google Scholar, 23Terry M.B. Neugut A.I. Cigarette smoking and the colorectal adenoma-carcinoma sequence: a hypothesis to explain the paradox.Am J Epidemiol. 1998; 147: 903-910Google Scholar, 24Zahm S.H. Cocco P. Blair A. Tobacco smoking as a risk factor for colon polyps.Am J Public Health. 1991; 81: 846-849Google Scholar Recently, the bulk of the evidence supports an association with CRC as well. With men having begun smoking several decades earlier than women, the temporal pattern of the studies supports an induction period of 3–4 decades between exposure and the diagnosis of CRC.9Giovannucci E. An updated review of the epidemiological evidence that cigarette smoking increases risk of colorectal cancer.Cancer Epidemiol Biomarkers Prev. 2001; 10: 725-731Google Scholar Despite the volume of studies, several questions remain unanswered: What is the relationship between dose and duration and risk of neoplasia? Which persons are most susceptible to the effects of cigarette smoking? Is smoking associated to specific subgroups of cancer, perhaps having one or more prevalent mutations? By how much and how quickly does risk drop after quitting smoking?Table 2 summarizes recent selected endoscopic and population-based studies on smoking and risk for colorectal neoplasia.25Akhter M. Nishino Y. Nakaya N. et al.Cigarette smoking and the risk of colorectal cancer among men: a prospective study in Japan.Eur J Cancer Prev. 2007; 16: 102-107Google Scholar, 26Anderson J.C. Attam R. Alpern Z. et al.Prevalence of colorectal neoplasia in smokers.Am J Gastroenterol. 2003; 98: 2777-2783Google Scholar, 27Lieberman D.A. Prindiville S. Weiss D.G. et al.Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.JAMA. 2003; 290: 2959-2967Google Scholar, 28Paskett E.D. Reeves K.W. Rohan T.E. et al.Association between cigarette smoking and colorectal cancer in the Women's Health Initiative.J Natl Cancer Inst. 2007; 99: 1729-1735Google Scholar, 29Verla-Tebit E. Carmen L. Hoffmeister M. et al.Cigarette smoking and colorectal cancer risk in Germany: a population-based case-control study.Int J Cancer. 2006; 119: 630-635Google Scholar The 5 studies use different study designs: cohort, case-control, and cross-sectional, with sample sizes ranging from 1154 to 146,877 individuals. All 5 use multivariable analysis, which provides the independent effect of smoking after adjustment for covariates such as age, sex, BMI, and others.Table 2Summary of Selected Studies on Cigarette Smoking and Risk of Colorectal NeoplasiaFirst author, year (ref)Study populationStudy designOutcomesType of risk modelMain findingsLieberman, 2003 (27Lieberman D.A. Prindiville S. Weiss D.G. et al.Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.JAMA. 2003; 290: 2959-2967Google Scholar)3121 asymptomatic patients aged 50-75 years from 13 Veterans Affairs medical centersCross-sectionalAdvanced neoplasia (CRC or advanced polyps)Multiple logistic regression that adjusted for age, family history, BMI, physical activity, alcohol use, NSAID use, certain dietary featuresCurrent smoking was a risk factor for advanced neoplasia (OR, 1.85; 95% CI: 1.33-2.85) and was of comparable magnitude to having an FDR with CRC (OR, 1.66; 95% CI: 1.16–2.35).Anderson, 2003 (26Anderson J.C. Attam R. Alpern Z. et al.Prevalence of colorectal neoplasia in smokers.Am J Gastroenterol. 2003; 98: 2777-2783Google Scholar)1988 persons aged 40 and older undergoing screening colonoscopyCross-sectionalSignificant neoplasia (CRC, advanced polyps, or >2 adenomas of any size)Multiple logistic regression that adjusted for age, alcohol consumption, exercise, BMI, ethnicity, education, and consumption of fruits and vegetablesCurrent smokers were more likely to have any neoplasia (OR, 1.89; 95% CI, 1.42–2.51) and significant neoplasia (OR, 2.26; 95% CI: 1.56–3.27). Risk of significant neoplasia was greater for smokers than for those with a family history of CRC.Verla-Tebit, 2006 (29Verla-Tebit E. Carmen L. Hoffmeister M. et al.Cigarette smoking and colorectal cancer risk in Germany: a population-based case-control study.Int J Cancer. 2006; 119: 630-635Google Scholar)540 patients with incident CRC and 614 population-based, matched to cases by 5-year age group, sex, county of residenceCase-controlCRCMultiple logistic model that adjusted for age, sex, history of CRC in first-degree relatives, BMI, alcohol use, physical activity, fruit and vegetable intake, red meat consumption, NSAID use, previous endoscopy of the large bowel, education level, and use of hormone replacement therapyCompared with nonsmokers, smokers for ≥40 years had increased risk (OR, 1.92; 95% CI: 1.13–3.28). Among smokers ≥30 years, risk was greater among women (OR, 3.5; 95% CI: 1.29–9.52) than men (OR, 1.15; 95% CI: 0.69–1.91). Risk reduction observed after ≥20 years of quitting smoking and was significant for ≥40 years (OR, 0.46; 95% CI: 0.21–0.98).Akhter, 2007 (25Akhter M. Nishino Y. Nakaya N. et al.Cigarette smoking and the risk of colorectal cancer among men: a prospective study in Japan.Eur J Cancer Prev. 2007; 16: 102-107Google Scholar)25,279 Japanese men recruited when aged 40-64 yearsCohort (7 years of follow-up)CRCProportional hazards model that adjusted for age, family history of CRC, education, BMI, alcohol use, time spent walking per day, and consumption frequency of fruits, green-yellow vegetables, and red meatCompared with never smokers, the risk of CRC was increased for past smokers (RR, 1.73; 95% CI: 1.04–2.87) and current smokers (RR, 1.47; 95% CI: 0.93–2.34). Among current smokers, a greater number of cigarettes smoked per day and an earlier age of smoking onset were associated with a significant linear increase in CRC risk.Paskett, 2007 (28Paskett E.D. Reeves K.W. Rohan T.E. et al.Association between cigarette smoking and colorectal cancer in the Women's Health Initiative.J Natl Cancer Inst. 2007; 99: 1729-1735Google Scholar)146,877 women's Health Initiative participantsCohort (mean of 7.8 years of follow-up)CRCProportional hazards model that adjusted for age, ethnicity, study type (observational or clinical trial) study arm, family history of CRC, total physical activity metabolic equivalents, alcohol use, NSAID use, hormone therapy use, colonoscopy, diabetes, waist circumference, certain dietary featuresCurrent smokers had increased risk for rectal cancer (HR, 1.95; 95% CI: 1.10–3.47) but not colon cancer (HR, 1.03; 95% CI: 0.77–1.38). Open table in a new tab The study by Lieberman et al, a colonoscopy-based study, examined the effect of several candidate risk factors on the risk of advanced neoplasia in a cohort of 3121 asymptomatic patients aged 50–75 years from 13 Veterans Affairs medical centers.27Lieberman D.A. Prindiville S. Weiss D.G. et al.Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.JAMA. 2003; 290: 2959-2967Google Scholar Using a multivariate model that included family history of CRC, BMI, physical activity, smoking, alcohol use, and several dietary components, the investigators found that the effect of smoking on advanced neoplasia (odds ration [OR], 1.85; 95% confidence interval [CI]: 1.33–2.58) was comparable with having a first-degree relative (FDR) with CRC (OR, 1.66; 95% CI: 1.16–2.35). In a retrospective, cross-sectional analysis of 1988 persons undergoing screening colonoscopy, Anderson et al found that cigarette smoking increased the risk for any colorectal neoplasia (OR, 1.89; 95% CI: 1.42–2.51) and for significant neoplasia (OR, 2.26; 95% CI: 1.56–3.27) that was predominantly left-sided.26Anderson J.C. Attam R. Alpern Z. et al.Prevalence of colorectal neoplasia in smokers.Am J Gastroenterol. 2003; 98: 2777-2783Google ScholarResults of recent population-based studies have shown somewhat inconsistent results. The findings of the case-control study by Verla-Tebit et al are consistent with those of several earlier epidemiologic studies that support the 30–35 year induction period between exposure to cigarette smoking and CRC.29Verla-Tebit E. Carmen L. Hoffmeister M. et al.Cigarette smoking and colorectal cancer risk in Germany: a population-based case-control study.Int J Cancer. 2006; 119: 630-635Google Scholar The results also suggest that risk reduction requires at least 20 years and increases with increasing duration of smoking cessation. In addition to the findings described in Table 2, the study by Akhter et al, which studied only men, found that longer smoking duration, age of 18 or younger at onset of smoking, and consumption of 20 or more cigarettes per day significantly increased the risk of CRC, with risk ratios ranging from 1.46 to 1.86.25Akhter M. Nishino Y. Nakaya N. et al.Cigarette smoking and the risk of colorectal cancer among men: a prospective study in Japan.Eur J Cancer Prev. 2007; 16: 102-107Google ScholarIn the study from the Women's Health Initiative,28Paskett E.D. Reeves K.W. Rohan T.E. et al.Association between cigarette smoking and colorectal cancer in the Women's Health Initiative.J Natl Cancer Inst. 2007; 99: 1729-1735Google Scholar which is a pooled analysis of participants in the observational study and 3 clinical trials, the risk of rectal cancer was increased with longer smoking duration and its confounder, older age at smoking cessation; however, the risk of colon cancer was not increased. This study has limitations, including self-reported smoking exposure that did not allow for changes in smoking behavior after initial reporting and a rate of cigarette smoking that was lower than US women of similar ages.In summary, the majority of evidence indicates that CRC is a tobacco-associated malignancy. In the United States, it has been estimated that as many as 1 in 5 CRCs is attributable to cigarette smoking.11Chao A. Thun M.J. Jacobs E.J. et al.Cigarette smoking and colorectal cancer mortality in the cancer prevention study II.J Natl Cancer Inst. 2000; 92: 1888-1896Google Scholar, 13Giovannucci E. Rimm E.B. Stampfer M.J. et al.A prospective study of cigarette smoking and risk of colorectal adenoma and colorectal cancer in US men.J Natl Cancer Inst. 1994; 86: 183-191Google Scholar, 14Heineman E.F. Zahm S.H. McLaughlin J.K. et al.Increased risk of colorectal cancer among smokers: results of a 26-year follow-up of US veterans and a review.Int J Cancer. 1994; 59: 728-738Google Scholar, 20Newcomb P.A. Storer B.E. Marcus P.M. Cigarette smoking in relation to risk of large bowel cancer in women.Cancer Res. 1995; 55: 4906-4909Google Scholar The magnitude of the increase in risk for CRC and large adenoma appears to be the same as having an FDR with CRC. It would be useful to have a way to estimate the incremental effect of smoking on risk of advanced neoplasia that considers sex; age of smoking onset; degree and duration of cigarette consumption; and, for former smokers, time since smoking cessation. Greater consideration should be given to cigarette smoking when considering whether, when, and how best to screen patients.Coronary Artery DiseaseIn a study from Hong Kong, Chan et al compared the prevalence of colorectal neoplasia in 206 subjects with angiographically proven coronary artery disease (CAD), 208 subjects whose angiogram did not show CAD, and an age- and sex-matched control group of 207 subjects who were asymptomatic (other than having functional dyspepsia with a normal upper endoscopy) but who did not have angiography.30Chan A.O. Jim M.H. Lam K.F. et al.Prevalence of colorectal neoplasm among patients with newly diagnosed coronary artery disease.JAMA. 2007; 298: 1412-1419Google Scholar Colonoscopy was scheduled within 8 weeks after eligibility was determined or after revascularization. Endoscopists were blinded to CAD status.The prevalence of advanced neoplasia in the CAD-positive, CAD-negative, and control groups was 18.4%, 8.7%, and 5.8%, respectively (P < .001), whereas the prevalence of cancer was 4.4%, 0.5%, and 1.4%, respectively (P = .02). After adjustment for age and sex, CAD remained associated with advanced neoplasia (OR, 2.51; 95% CI: 1.43–4.35). Of interest, both metabolic syndrome and cigarette smoking were strong independent predictive factors for the positive association between CAD and advanced neoplasia, meaning that persons who were smokers and/or had the metabolic syndrome were much more likely to develop both conditions.Although it is not clear that the CAD-positive group was free of symptoms of signs of early CRC, this study links CAD with advanced neoplasia and is consistent with previously published studies.31Colangelo L.A. Gapstur S.M. Gann P.H. et al.Colorectal cancer mortality and factors related to the insulin resistance syndrome.Cancer Epidemiol Biomarkers Prev. 2002; 11: 385-391Google Scholar, 32Trevisan M. Liu J. Muti P. et al.Markers of insulin resistance and colorectal cancer mortality.Cancer Epidemiol Biomarkers Prev. 2001; 10: 937-941Google Scholar It is unclear whether and to what extent the association would remain after further adjustment for other confounding factors. Nevertheless, most likely because of a common set of risk factors that includes cigarette smoking, waist circumference, diabetes, and others, CAD appears to be a marker for colorectal neoplasia. Although the prevalence of advanced neoplasia in persons with CAD suggests the need for earlier or more aggressive CRC screening, the extent to which CAD as a comorbid condition may reduce the benefits of screening requires careful consideration.Diabetes MellitusPrevious studies have shown that the risk of CRC is higher among persons with diabetes, although this finding is not consistent among studies nor is the contribution of confounding factors to the increased risk well established. In a population-based cohort study, Limburg et al identified incident cases of CRC among 1975 type 2 diabetic individuals and compared them with what was expected from the general population.33Limburg P.J. Vierkant R.A. Fredericksen Z.S. et al.Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study.Am J Gastroenterol. 2006; 101: 1872-1879Google Scholar Overall risk of CRC was increased among diabetic individuals (standardized incidence ratio= 1.39; 95% CI: 1.03–1.82). However, the increased risk was present among men only, both overall (SIR, 1.67; 95% CI: 1.16–2.33) and proximally (SIR, 1.96; 95% CI: 1.16–3.10). Furthermore, current and former cigarette smokers were at higher risk for CRC than diabetic individuals who never smoked.In addition to increasing baseline risk for colorectal neoplasia, insulin resistance also increases the risk for recurrent neoplasia. In an analysis from the Polyp Prevention Trial, Flood et al compared fasting insulin and glucose levels in 375 subjects with and 375 subjects without recurrent adenoma.34Flood A. Mai V. Pfeiffer R. et al.Elevated serum concentrations of insulin and glucose increase risk of recurrent colorectal adenomas.Gastroenterology. 2007; 133: 1423-1429Abstract Full Text Full Text PDF Scopus (41) Google Scholar After adjustment for age, sex, BMI, and intervention group, risk for recurrent adenoma was higher for subjects in the highest quartile compared with the lowest quartile: OR, 1.56; 95% CI: 1.00–2.43 for insulin; OR, 1.49; 95% CI: 0.95–2.31 for glucose. The highest quartile of glucose was associated with advanced adenoma as well: OR, 2.43; 95% CI: 1.23–4.79. The strength of the associations between high fasting glucose and risk of recurrent adenoma increased when the analysis was restricted to subjects with no family history of CRC.These studies support other research in which diabetes has been associated with increased risk for CRC and are consistent with a larger body of literature that links insulin resistance, metabolic syndrome, and coronary artery disease with colorectal neoplasia. Understanding both the mechanisms leading to neoplasia and the independent contribution of each of these factors to advanced adenoma and CRC risks requires further study.Although the literature is replete with data on risk factors for CRC and adenoma, most established risk factors are not incorporated into current screening guidelines. Current guidelines stratify risk with age and family history alone. Age is used only as a threshold factor, although CRC incidence increases with age in an approximately linear fashion. The risk of CRC in average-risk persons doubles by 10 years—approximately the same increase in risk as having an FDR with CRC.35Fletcher R.H. Screening colonoscop: option or preference?.Gastrointest Endosc. 2000; 51: 624-627Google Scholar We need a way to integrate all risk factors (age, sex, family history, cigarette smoking, metabolic syndrome, and others) quantitatively to estimate absolute risk for CRC and advanced adenoma. One study has integrated age, sex, and BMI to estimate the risk of advanced neoplasia anywhere in the large intestine.36Betes M. Munoz-Navas M.A. Duque J.M. et al.Use of colonoscopy as a primary screening test for colorectal cancer in average risk people.Am J Gastroenterol. 2003; 98: 2648-2654Google Scholar Another study used age, sex, and most advanced distal finding to estimate the risk of advanced proximal neoplasia.37Imperiale T.F. Wagner D.R. Lin C.Y. et al.Using risk for advanced proximal colonic neoplasia to tailor endoscopic screening for colorectal cancer.Ann Intern Med. 2003; 139: 949-965Google Scholar Both systems require validation and further development before they can be applied to clinical practice. Furthermore, the effect of more extensive risk stratification on screening remains to be determined. On the one hand, providing risk-specific information to patients and providers has the potential to improve screening rates and screening efficiency. On the other hand, if risk stratification is perceived as making CRC screening too complicated, there is the potential to adversely affect further uptake of screening. Whether incorporating several factors with modest relative risks would add significantly to using age, sex, and family history alone is also important to determine.Screening ColonoscopySeveral recent studies have described the findings of screening colonoscopy in an asymptomatic average-risk population.38Lin O.S. Kozarek R.A. Schembre D.B. et al.Screening colonoscopy in very elderly patients: prevalence of neoplasia and estimated impact on life expectancy.J Am Med Assoc. 2006; 295: 2357-2365Google Scholar, 39Regula J. Rupinski M. Kraszewska E. et al.Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia.N Engl J Med. 2006; 355: 1863-1872Google Scholar, 40Schoenfeld P. Cash B. Flood A. et al.Colonoscopic screening of average-risk women for colorectal neoplasia.N Engl J Med. 2005; 352: 2061-2068Google Scholar, 41Strul H. Kariv R. Leshno M. et al.The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years.Am J Gastroenterol. 2006; 201: 255-262Google Scholar, 42Kim D.H. Lee S.Y. Choi K.S. et al.The usefulness of colonoscopy as a screening test for detecting colorectal polyps.Hepatogastroenterology. 2007; 54: 2240-2242Google Scholar, 43Morikawa T. Kato J. Yamaji Y. et al.A comparison of the immunochemical fecal occult blood test and total colonoscopy in the asymptomatic population.Gastroenterology. 2005; 129: 422-428Google ScholarTable 3 summarizes the study characteristics of this body of literature. Although the study objectives, settings, and designs vary, the variation does not necessarily preclude compari