Predictors of Advanced Colorectal Neoplasia for Colorectal Cancer Screening Martin C.S. Wong, MD, MPH, Thomas Y.T. Lam, MSc, Kelvin K.F. Tsoi, PhD, Victor C.W. Chan, BSc, Hoyee W. Hirai, MSc, Jessica Y.L. Ching, MPH, Joseph J.Y. Sung, MD, PhD Background: The Asia-Pacific Colorectal Screening (APCS) score based on age, gender, family history, and smoking is useful to predict advanced colorectal neoplasia (ACN) in asymptomatic Asian subjects. Purpose: To evaluate the factors in addition to those of APCS associated with ACN colonoscopic
findings.
Methods: Data from 5,220 asymptomatic subjects aged between 50 and 70 years who underwent screening colonoscopy in a community center between 2008 and 2012 were analyzed. One binary logistic regression analysis was conducted in 2013 with the presence of ACN or cancer as the outcome, controlling for APCS score, alcohol consumption, BMI, hypertension, and other chronic diseases as independent variables.
Results: The average participant age was 57.7 years (SD¼4.9) and 47.5% were men. Advanced neoplasms or cancers were identified at colonoscopy in 5.6% of all screening participants. From multivariate regression analysis, APCS scoreZ4 (adjusted OR [AOR]¼1.74, 95% CI¼1.34, 2.25, po0.001); overweight (BMI¼2324.9, AOR¼1.52, 95% CI¼1.12, 2.07, p¼0.007); obesity (BMIZ25, AOR¼1.56, 95% CI¼1.15, 2.10, p¼0.004); hypertension (AOR¼1.58, 95% CI¼1.21, 2.06, p¼0.001); and alcohol consumption (AOR¼1.47, 95% CI¼1.05, 2.06, p¼0.025) were associated with ACN. The c-statistic of APCS score alone was 0.560 (95% CI¼0.524, 0.595, p¼0.001) and that of APCS score plus BMI, hypertension, and alcohol consumption was 0.613 (95% CI¼0.578, 0.648, po0.001).
Conclusions: Alcohol consumption, hypertension, and BMI are independent predictors of ACN, which could be incorporated into the APCS for prioritizing Asian asymptomatic subjects for colorectal cancer screening. (Am J Prev Med 2014;46(5):433–439) & 2014 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine
Introduction
G
lobally, colorectal cancer (CRC) is the third most common malignancy in men, the second most common in women, and accounts for 10% of all cancers.1 In recent decades, many Asian countries,
From the Institute of Digestive Disease (Wong, Lam, Tsoi, Chan, Hirai, Ching, Sung) and School of Public Health and Primary Care (Wong), Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong Address correspondence to: Joseph J.Y. Sung, MD, PhD, Institute of Digestive Disease, Faculty of Medicine, Chinese University of Hong Kong, 7/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, 3032 Ngan Shing Street, Shatin NT, Hong Kong SAR. E-mail: jjysung@cuhk. edu.hk 0749-3797/$36.00 http://dx.doi.org/10.1016/j.amepre.2013.12.008
namely, China, South Korea, Japan, Singapore, and Hong Kong, have experienced a rapid rise in CRC incidence.2 In future years, it will continue to impose a major public health burden in terms of mortality, morbidity, and medical costs incurred.3 CRC screening using fecal tests4–6 and colonoscopy7 have been shown to reduce CRC mortality by up to 33% and 53%, respectively. Guidelines from authoritative societies in the U.S.8,9 and Europe,10 together with the Asia-Pacific Consensus statements,11 recommend CRC screening for average-risk individuals aged 50 years or older. However, the implementation of population-based CRC screening programs could be hindered by resource limitations in many countries.12–14 These include concerns over colonoscopy capacity and the requirement of establishing screening infrastructure.14
& 2014 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine
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In the light of these practical limitations, the AsiaPacific Colorectal Screening (APCS) score was constructed to prioritize asymptomatic Asian subjects for colorectal screening.15 The scoring system was based on age, gender, family history, and smoking status to stratify the risk of advanced colorectal neoplasia (ACN). The APCS is simple and can be used by general practitioners or nurse-educators. The tool is useful in clinical practice to calculate risk, thus offering an option of prioritizing high-risk subjects for colonoscopy screening and average-risk subjects for fecal blood tests.15 The scoring system has been shown to be robust, with good match between predicted and observed risk of ACN development. The APCS is currently used by physicians to predict ACN risk among asymptomatic Asian subjects, which helps to optimize the efficiency of screening resources. Nevertheless, this study was limited by the absence of BMI data. In addition, the sample size (n¼860) of the derivation cohort of this study is modest; thus, significant risk factors in the variable development phase of the scoring system might have been missed. This study recommends future research evaluating additional risk factors. A scoring system for predicting colorectal neoplasia was recently devised,16 but prediction of ACN, which bears greater malignant potential, is of greater interest. This study aimed to evaluate the variables associated with ACN in addition to the APCS scores from a larger cohort of asymptomatic subjects who received screening colonoscopy. The a priori hypothesis that these potential risk factors are independent predictors of ACN in addition to the variables contained in the APCS system was tested.
Methods Setting A detailed description of the study setting has been described elsewhere.17–19 Briefly, a bowel cancer screening center was established in Hong Kong in 2008, providing free CRC screening for all eligible Hong Kong residents aged 50–70 years who were asymptomatic for CRC. Data based on screening recruitment between 2008 and 2012 were collected. This study was approved by the Clinical Research Ethics Committee, the Chinese University of Hong Kong.
Study Design The center prospectively recruited self-referred screening participants for CRC screening who were able to register via telephone, fax, e-mail, or walk-in. The eligibility criteria for this study included (1) being aged between 50 and 70 years; (2) not having existing or previous symptoms suggestive of CRC such as hematochezia, melena, anorexia, or a change in bowel habits in the past 4 weeks, or weight loss of greater than 5 kg in the past
6 months; and (3) not having undergone any CRC screening tests in the past 5 years. Exclusion criteria were a personal history of CRC, colonic adenoma, diverticular disease, inflammatory bowel disease, a prosthetic heart valve, or vascular graft surgery. Participants with medical conditions that were contraindications to colonoscopy were also excluded.17–19 Registered participants were invited to complete a selfadministered questionnaire, which included information on their age, gender, family history of CRC, smoking status, drinking habits, previous medical history, and long-term medication use. Meanwhile, trained volunteers assisted survey completion for illiterate participants by reading the questions word by word. All participants were then offered an educational session using a standard video followed by health seminars led by trained educators. The video included information on the epidemiology and natural history of CRC risk factors, clinical features of this condition, importance of regular screening, and procedures of the fecal immunochemical test (FIT) and colonoscopy. Hemosure (Manufacturer, W.H.P.M., Inc, El Monte CA) was used as the FIT for all subjects who chose fecal tests, which obviated the need for dietary restriction before testing. The seminars were delivered in a standardized manner, with both FIT and colonoscopy being presented nonpreferentially. Participants were given a choice between yearly FIT for up to 5 years or a direct colonoscopy for CRC screening. Our subjects consisted of participants who chose colonoscopy, those who chose FIT initially but received a colonoscopy because of a positive FIT result, and those who received a colonoscopy after 3 consecutive years of negative FIT results. A total of 5,220 subjects were included in this study.
Outcome Variables and Covariates Outcome variables included the proportion of screening participants who were found to have ACN; this was defined as CRC or any colorectal adenoma Z10 mm in diameter, high-grade dysplasia, villous or tubulovillous histologic characteristics, or any combination thereof. The major covariate included the APCS score as a single variable, which was calculated for each subject on the basis of their age, gender, family history, and smoking status. Additional variables tested for association with the colonoscopic outcome of ACN included BMI (underweight, o18.5; normal, 18.5–22.3; overweight, 23–24.9; obese, Z 25); alcohol drinking (current drinkers with more than two drinks per week vs ex-drinkers or nondrinkers); self-reported history of diabetes mellitus, hypertension, cardiovascular diseases, liver cirrhosis, stroke, gastroesophageal reflux disease, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin; and self-reported current lifestyle habits as collected by validated survey items (“frequent intake of meat,” “physical inactivity,” “frequent intake of barbecued food,” and “frequent intake of fatty food”). The aforementioned BMI cut-off points were used according to the recognized definition of obesity among Asian subjects.20
Statistical Analyses In 2013, all data were entered into a predesigned database with logistic checking using Microsoft Access, and analyzed using SPSS software, version 18.0. The proportion of participants who had colonoscopic findings of ACN was computed. A univariate www.ajpmonline.org
Wong et al / Am J Prev Med 2014;46(5):433–439 analysis was conducted between ACN and each covariate consecutively. All covariates were included into a binary logistic regression model if the initial p-value was o0.05 in the univariate analysis. All variables selected in the multivariate regression analysis were detected for the presence of interactions.21 Each variable of interest was tested for interaction with other selected variables one by one. The variables with initial p-values o0.20 on univariate analysis were included in another similar multivariate regression model. The adjusted ORs (AORs) and 95% CIs of the potential independent predictors of ACN were estimated, and a p-value o0.05 in the multivariate regression analysis was considered statistically significant. Furthermore, we compared the cstatistics of APCS score alone versus APCS score plus all the independent predictors identified to evaluate whether the additional predictors enhanced the performance of APCS in predicting ACN risk factors. According to a generally accepted rule of thumb, a minimum of ten cases are required for each variable in the prediction rule.22 We assumed that the prevalence of ACN was 3% as evaluated in the validation cohort of the original APCS study.15 A total of 15 variables were tested in the prediction model; hence, a total of at least 5,000 subjects needed to be recruited.
Results Participant Characteristics Among 10,728 screening participants, 5,220 received a screening colonoscopy. The average participant age was 57.7 (SD¼4.9) years, and 47.5% were men. The average BMI was 23.5 (SD¼3.2); 8.3% were current smokers; and 10% were alcohol drinkers. More than 14% had a first-degree relative with CRC. The most frequently reported chronic diseases included hypertension (22.9%); diabetes mellitus (7.4%); and gastroesophageal reflux disease (5.3%). A few participants showed chronic use of NSAIDs (4.6%) or aspirin (2.5%). A significant number of participants reported frequent intake of meat (26.0%); physical inactivity (23.9%); frequent intake of barbecued food (21.4%); and frequent intake of fatty food (20.8%). The proportion of these screening participants found to have ACN or cancer was 5.6%, of which 265 subjects (5.1%) had ACN (Table 1).
Factors Associated with Advanced Colorectal Neoplasia On univariate analysis, APCS score (po0.001); BMI (p¼0.001); self-reported presence of diabetes (p¼0.047); hypertension (po0.001); and alcohol consumption (p¼0.001) were significantly associated with ACN. In the multivariate regression model, APCS score (AOR¼1.74, 95% CI¼1.34, 2.25, po0.001); overweight (BMI¼2324.9, AOR¼1.52, 95% CI¼1.12, 2.07, p¼0.007); obesity (BMIZ25, AOR¼1.56, 95% CI¼1.15, 2.10, p¼0.004); hypertension (AOR¼1.58, 95% CI¼1.21, 2.06, p¼0.001); and alcohol consumption (AOR¼1.47, May 2014
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95% CI¼1.05, 2.06, p¼0.025) were associated with the colonoscopic findings of ACN (Table 2). Diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, stroke, cirrhosis, gastroesophageal reflux disease, use of aspirin or other NSAIDs, and all self-reported lifestyle factors were not significantly associated with ACN. No interaction exists between covariates in the binary logistic regression model, thereby implying that the regression analysis is robust. Sensitivity analyses using po0.05 and o0.20 as the cut-off points for variable selection into the multivariate regression analyses, respectively, did not change the independent covariates identified. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve of APCS score alone was 0.560 (95% CI¼0.524, 0.595, p¼0.001) and that of APCS score plus BMI; hypertension; and alcohol consumption was 0.613 (95% CI¼0.578, 0.648, po0.001). For the comparison of these two ROC curves, the revised model with additional risk factors performed significantly better than the APCS score alone in terms of prediction of advanced neoplasia (z-statistic¼2.082, p¼0.037).
Discussion In this large cohort of CRC screening participants, the prevalence of ACN was 5.6%. Apart from the APCS scoring system, overweight or obesity, hypertension, and alcohol consumption were independently associated with the findings of ACN. Adding these three additional risk factors to the APCS increased its performance to predict ACN risk.
Relationship with Existing Literature The prevalence of ACN as reported in other Asian studies is between 3% and 12%.23–25 In the derivation and validation cohort of the APCS study,15 the prevalence of ACN was 4.5% and 3.0%, respectively. The prevalence of ACN in this study (5.1%) was therefore higher than the validation cohort (po0.001) but similar to the derivation cohort (p¼0.499) and the figures from other studies. One possible explanation for this difference is the younger mean age of the validation cohort as compared to our subjects (51.0 vs 57.7 years)—hence a higher proportion of subjects were found to have ACN in our study. Regarding the relationship between BMI and colorectal neoplasia, a recent pooled analysis of seven prospective studies involving 8,213 screening participants confirmed that BMI is associated with the risk of metachronous colorectal lesions, but is confined to men and lesions of the proximal colon.26 In a prospective
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Table 1. Participant characteristics (N¼5,220), n (%) unless otherwise noted Characteristics
M (SD), n (%)
Age (years, M [SD])
57.72 (4.89)
BMI (M [SD])
23.51 (3.17)
Gender, male
2,181 (47.5)
Current smoking
431 (8.3)
Alcohol consumption
522 (10.0)
Diabetes mellitus
386 (7.4)
Family history present for a first-degree relative
735 (14.1)
Hypertension
1,196 (22.9)
IHD/heart disease
91 (1.7)
COPD
39 (0.7)
Stroke
37 (0.7)
Cirrhosis
8 (0.2)
GERD
277 (5.3)
Use of NSAIDs
240 (4.6)
Use of aspirin
133 (2.5)
Frequent intake of red meat
1,358 (26.0)
Physical inactivity
1,245 (23.9)
High intake of barbecued food
1,115 (21.4)
Frequent intake of fatty food
1,087 (20.8)
Advanced neoplasia and colorectal cancer Colorectal cancer Advanced neoplasia
289 (5.6) 24 (0.5) 265 (5.1)
COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; IHD, ischemic heart disease; NSAIDs, nonsteroidal antiinflammatory drugs
cohort study of 33,403 African-American women aged Z30 years with no prior cancer or polyps, an increased risk of colon polyps was demonstrated among those with BMIZ35 compared to subjects with BMIo25.27 A cross-sectional study conducted in Korea demonstrated a weak association between BMI and the risk of adenoma among men at the highest BMI levels, but this association was abolished after adjustment for waist circumference.28 However, these studies were performed either on Western or African subjects, or suffered from a small sample size. The relatively large number of asymptomatic screening participants included in the present study reported the new finding that obese subjects had a 29% increased risk of ACN. In addition, this study also showed a dose-response
relationship between BMI and ACN, which implies that a potential cause–effect relationship might exist. The best established biochemical mediator between obesity and colorectal neoplasia is the pro-carcinogen insulin-like growth factor 1 and, to a lesser extent, leptin.29 From a clinical utilization perspective, these findings imply that Asian subjects who are overweight (BMI¼23–24.9) have statistically similar odds of developing ACN when compared with obese subjects (BMIZ25) (1.52-fold, 95% CI¼1.12, 2.07, vs 1.56-fold, 95% CI¼1.15, 2.10). Therefore, overweight patients should also be considered as having a higher risk of ACN and receive higher priority for screening than average-risk subjects. Turning to the association between alcohol consumption and ACN, a cross-sectional study conducted in the U.S. found that patients who consumed more than eight drinks of spirits or eight servings of beer per week were more likely to have significant colorectal neoplasia but that the consumption of one to eight glasses of wine per week was associated with a lower risk.30 A pooled analysis of primary data from more than 489,000 persons in eight cohort studies in North American and European countries has shown that alcohol drinkers of more than 2–2.5 drinks daily had a 1.16-fold increased risk of developing CRC.31 A large prospective cohort study conducted in Japan found a positive association between alcohol drinking and CRC,32 yet a smaller-scale case– control study in the same country reported only modestly increased risks of distal colon and rectal adenomas, but not large adenomas.33 However, subjects in both analyses were not CRC screening participants, and their inclusion criteria did not include the absence of CRC symptoms. From the existing literature, the relationship between alcohol drinking and colorectal neoplasia among asymptomatic subjects in Asia has been inconclusive. Ethanol has been shown to promote, rather than initiate, colorectal carcinogenesis.33 Thus, the present finding that alcohol drinkers had a 50% higher risk of ACN than nondrinkers implies that alcohol consumption should be included as one of the important predictive factors for the presence of ACN. The positive association between hypertension and ACN has not been reported in previous literature and thus could represent a novel finding. Moreover, it is interesting that diabetes was only found to be significantly associated with ACN in univariate analysis but not in multivariate regression models. There are a few explanations for the absence of this association. First, diabetes and ACN share some common risk factors, such as alcohol consumption and obesity. This may compromise the independent predictive ability of diabetes for ACN when these other factors are controlled for. Also, a weaker www.ajpmonline.org
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Table 2. Univariate and multivariate predictors of advanced colorectal neoplasia and colorectal cancer Unadjusted (univariate analysis)
Adjusted (multivariate regression analysis)
Risk factors
OR (95% CI)
p-value
APCS High risk versus low or moderate risk
1.858 (1.439, 2.398)
o0.001
Z18.5 to o23 (normal)
0.553
SE
OR (95% CI)
p-value
0.133
1.738 (1.339, 2.254)
o0.001
o0.001
BMI o18.5 (underweight)
B coefficient
0.812 (0.371, 1.776)
0.601
0.009 0.157
0.400
ref
0.854 (0.390, 1.873)
0.694
ref
Z23 to o25 (overweight)
1.610 (1.188, 2.184)
0.002
0.420
0.157
1.522 (1.119, 2.069)
0.007
Z25 (obesity)
1.830 (1.371, 2.445)
o0.001
0.442
0.153
1.556 (1.154, 2.099)
0.004
Diabetes
1.489 (1.005, 2.205)
0.047
0.160
0.209
1.173 (0.779, 1.767)
0.444
Hypertension
1.821 (1.415, 2.343)
o0.001
0.456
0.137
1.578 (1.206, 2.064)
0.001
IHD/heart disease
1.663 (0.797, 3.470)
0.175
—
—
Alcohol
1.772 (1.275, 2.462)
0.001
0.172
1.471 (1.050, 2.061)
COPD
1.963 (0.693, 5.562)
0.204
—
—
—
—
Stroke
0.472 (0.065, 3.456)
0.460
—
—
—
—
N/A
1.000
—
—
—
—
GERD
1.198 (0.732, 1.962)
0.473
—
—
—
—
Use of NSAIDs
0.581 (0.317, 1.064)
0.078
—
—
—
—
Use of aspirin
1.365 (0.717, 2.601)
0.344
—
—
—
—
Frequent intake of red meat, n (%)
0.907 (0.688, 1.197)
0.907
—
—
—
—
Physical inactivity, n (%)
0.777 (0.577, 1.045)
0.096
—
—
—
—
Low intake of fruit or vegetables, n (%)
1.010 (0.756, 1.348)
0.948
—
—
—
—
Frequent intake of fatty food, n (%)
1.210 (0.915, 1.601)
0.180
—
—
—
—
Cirrhosisa
— 0.386
— 0.025
Note: Boldface indicates po0.05. a None of the eight subjects with cirrhosis had advanced neoplasia. APCS, Asia Pacific Colorectal Scoring System; COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; IHD, ischemic heart disease; NSAIDs, nonsteroidal anti-inflammatory drugs
association exists between diabetes and ACN among Asian subjects compared to Western populations. For instance, a systematic review of 16 cohort studies and eight case-control studies involving more than 3.6 million individuals showed that the presence of diabetes was May 2014
associated with a 1.26-fold increased risk of CRC,34 which was lower among Asian populations (relative risk¼1.19, 95% CI¼1.11, 1.28) than European ones (relative risk¼1.39, 95% CI¼1.26, 1.53). Lastly, most previous studies have found an association between type 2 diabetes
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and ACN, but not type 1 diabetes.35,36 The association between ACN and type 1 diabetes remains to be explored.
Strengths and Limitations This is a large-scale study that evaluated asymptomatic subjects who were self-referred for CRC screening. It is unique because the analysis was based on the wellvalidated APCS scoring system, which allows the exploration of additional risk factors for ACN. However, some limitations should be acknowledged. First, consecutive sampling was adopted, which might have limited its generalizability to the whole population. However, given the screening infrastructure of the community, it was not feasible to conduct a study using population-based, simple random-sampling methodology owing to the absence of an accurate sampling frame and high refusal rates. Second, the characteristics of Chinese subjects aged between 50 and 70 years might be different from those in the original APCS study, which included asymptomatic subjects with a wider age range recruited from different centers in the Asia-Pacific region. In addition, although our recruitment excluded subjects with some well-known risk factors, such as a past history of CRC and inflammatory bowel disease, not all confounders could be controlled in this analysis. Lifestyle factors such as a high intake of red meat, fat, and barbecued food37,38 and physical inactivity39 were only measured in a simplified manner. Additionally, the survey did not collect information on the type of alcoholic beverages and their total consumption. Nevertheless, the variables pertaining to dietary habits require food frequency questionnaires or the accurate keeping of a 24hour food diary for assessment; this process is timeconsuming and therefore unlikely to be practical for inclusion as a component in the risk scoring system. Finally, the presence of chronic diseases was self-reported and may be subject to ascertainment bias, and their duration and treatment statuses have not been analyzed.
Implications for Clinical Practice and Future Research BMI, alcohol consumption, and self-reported hypertension should be considered as additional risk factors apart from the variables of the APCS scoring system.15 These additional factors could be easily obtained or measured in clinical or community settings. Patients with these risk factors should receive additional counseling efforts for CRC screening, as the colonoscopic yield of ACN is higher when compared with the average-risk general population. In resource-limited countries, physicians may use these risk factors to prioritize screening services, and
in low-prevalence countries, risk stratification could be adopted to selectively offer screening to high-risk individuals. Built on the APCS system, these additional variables could potentially inform policy makers and physicians when allocating CRC screening resources in the community. It is anticipated that these factors could risk-stratify CRC screening participants in a more costeffective manner. Because the additional variables found to be significant may have different associations with ACN in other patient groups, their generalizability to other populations such as Chinese immigrants living outside of China should be studied further. Future studies should also focus on developing and validating a modified system based on the present findings yet maintaining the simplicity of the predictive tool. We acknowledge the full funding support of the Hong Kong Jockey Club Charities Trust for this study. We are grateful to Dr. David Wilmshurst, the Chinese University of Hong Kong’s Academic Editor, for editing the first draft of this paper. No financial disclosures were reported by the authors of this paper.
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asymptomatic average-risk Chinese adults as determined by colonoscopic screening. Gastrointest Endosc 2005;61(4):547–53. Jacobs ET, Ahnen DJ, Ashbeck EL, et al. Association between body mass index and colorectal neoplasia at follow-up colonoscopy: a pooling study. Am J Epidemiol 2009;169(6):657–66. Wise LA, Rosenberg L, Palmer JR, et al. Anthropometric risk factors for colorectal polyps in African-American women. Obesity (Silver Spring) 2008;16(4):859–68. Kim Y, Kim Y, Lee S. An association between colonic adenoma and abdominal obesity: a cross-sectional study. BMC Gastroenterol 2009;9:4. Frezza EE, Wachtel MS, Chiriva-Internati M. Influence of obesity on the risk of developing colon cancer. Gut 2006;55(2):285–91. Anderson JC, Alpern Z, Sethi G, et al. Prevalence and risk of colorectal neoplasia in consumers of alcohol in a screening population. Am J Gastroenterol 2005;100(9):2049–55. Cho E, Smith-Warner SA, Ritz J, et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 2004;140 (8):603–13. Otani T, Iwasaki M, Yamamoto S. Alcohol consumption, smoking, and subsequent risk of colorectal cancer in middle-aged and elderly Japanese men and women: Japan Public Health Center-based prospective study. Cancer Epidemiol Biomarkers Prev 2003;12(12): 1492–500. Toyomura K, Yamaguchi K, Kawamoto H, et al. Relation of cigarette smoking and alcohol use to colorectal adenomas by subsite: the selfdefense forces health study. Cancer Sci 2004;95(1):72–6. Deng L, Gui Z, Zhao L, et al. Diabetes mellitus and the incidence of colorectal cancer: an updated systematic review and meta-analysis. Dig Dis Sci 2012;57(6):1576–85. McNeely MJ, Boyko EJ. Type 2 diabetes prevalence in Asian Americans: results of a national health survey. Diabetes Care 2004;27 (1):66–9. Khalili H, Chan AT. Is diabetes a risk factor for colorectal cancer? Dig Dis Sci 2012;57(6):1427–9. Giovannucci E, Ascherio A, Rimm EB, et al. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med 1995;122(5):327–34. Chan DS, Lau R, Aune D, et al. Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 2011;6:e20456. Fung T, Hu FB, Fuchs C, et al. Major dietary patterns and the risk of colorectal cancer in women. Arch Intern Med 2003;163(3):309–14.
findings.
Methods: Data from 5,220 asymptomatic subjects aged between 50 and 70 years who underwent screening colonoscopy in a community center between 2008 and 2012 were analyzed. One binary logistic regression analysis was conducted in 2013 with the presence of ACN or cancer as the outcome, controlling for APCS score, alcohol consumption, BMI, hypertension, and other chronic diseases as independent variables.
Results: The average participant age was 57.7 years (SD¼4.9) and 47.5% were men. Advanced neoplasms or cancers were identified at colonoscopy in 5.6% of all screening participants. From multivariate regression analysis, APCS scoreZ4 (adjusted OR [AOR]¼1.74, 95% CI¼1.34, 2.25, po0.001); overweight (BMI¼2324.9, AOR¼1.52, 95% CI¼1.12, 2.07, p¼0.007); obesity (BMIZ25, AOR¼1.56, 95% CI¼1.15, 2.10, p¼0.004); hypertension (AOR¼1.58, 95% CI¼1.21, 2.06, p¼0.001); and alcohol consumption (AOR¼1.47, 95% CI¼1.05, 2.06, p¼0.025) were associated with ACN. The c-statistic of APCS score alone was 0.560 (95% CI¼0.524, 0.595, p¼0.001) and that of APCS score plus BMI, hypertension, and alcohol consumption was 0.613 (95% CI¼0.578, 0.648, po0.001).
Conclusions: Alcohol consumption, hypertension, and BMI are independent predictors of ACN, which could be incorporated into the APCS for prioritizing Asian asymptomatic subjects for colorectal cancer screening. (Am J Prev Med 2014;46(5):433–439) & 2014 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine
Introduction
G
lobally, colorectal cancer (CRC) is the third most common malignancy in men, the second most common in women, and accounts for 10% of all cancers.1 In recent decades, many Asian countries,
From the Institute of Digestive Disease (Wong, Lam, Tsoi, Chan, Hirai, Ching, Sung) and School of Public Health and Primary Care (Wong), Faculty of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin NT, Hong Kong Address correspondence to: Joseph J.Y. Sung, MD, PhD, Institute of Digestive Disease, Faculty of Medicine, Chinese University of Hong Kong, 7/F, Lui Che Woo Clinical Sciences Building, Prince of Wales Hospital, 3032 Ngan Shing Street, Shatin NT, Hong Kong SAR. E-mail: jjysung@cuhk. edu.hk 0749-3797/$36.00 http://dx.doi.org/10.1016/j.amepre.2013.12.008
namely, China, South Korea, Japan, Singapore, and Hong Kong, have experienced a rapid rise in CRC incidence.2 In future years, it will continue to impose a major public health burden in terms of mortality, morbidity, and medical costs incurred.3 CRC screening using fecal tests4–6 and colonoscopy7 have been shown to reduce CRC mortality by up to 33% and 53%, respectively. Guidelines from authoritative societies in the U.S.8,9 and Europe,10 together with the Asia-Pacific Consensus statements,11 recommend CRC screening for average-risk individuals aged 50 years or older. However, the implementation of population-based CRC screening programs could be hindered by resource limitations in many countries.12–14 These include concerns over colonoscopy capacity and the requirement of establishing screening infrastructure.14
& 2014 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine
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In the light of these practical limitations, the AsiaPacific Colorectal Screening (APCS) score was constructed to prioritize asymptomatic Asian subjects for colorectal screening.15 The scoring system was based on age, gender, family history, and smoking status to stratify the risk of advanced colorectal neoplasia (ACN). The APCS is simple and can be used by general practitioners or nurse-educators. The tool is useful in clinical practice to calculate risk, thus offering an option of prioritizing high-risk subjects for colonoscopy screening and average-risk subjects for fecal blood tests.15 The scoring system has been shown to be robust, with good match between predicted and observed risk of ACN development. The APCS is currently used by physicians to predict ACN risk among asymptomatic Asian subjects, which helps to optimize the efficiency of screening resources. Nevertheless, this study was limited by the absence of BMI data. In addition, the sample size (n¼860) of the derivation cohort of this study is modest; thus, significant risk factors in the variable development phase of the scoring system might have been missed. This study recommends future research evaluating additional risk factors. A scoring system for predicting colorectal neoplasia was recently devised,16 but prediction of ACN, which bears greater malignant potential, is of greater interest. This study aimed to evaluate the variables associated with ACN in addition to the APCS scores from a larger cohort of asymptomatic subjects who received screening colonoscopy. The a priori hypothesis that these potential risk factors are independent predictors of ACN in addition to the variables contained in the APCS system was tested.
Methods Setting A detailed description of the study setting has been described elsewhere.17–19 Briefly, a bowel cancer screening center was established in Hong Kong in 2008, providing free CRC screening for all eligible Hong Kong residents aged 50–70 years who were asymptomatic for CRC. Data based on screening recruitment between 2008 and 2012 were collected. This study was approved by the Clinical Research Ethics Committee, the Chinese University of Hong Kong.
Study Design The center prospectively recruited self-referred screening participants for CRC screening who were able to register via telephone, fax, e-mail, or walk-in. The eligibility criteria for this study included (1) being aged between 50 and 70 years; (2) not having existing or previous symptoms suggestive of CRC such as hematochezia, melena, anorexia, or a change in bowel habits in the past 4 weeks, or weight loss of greater than 5 kg in the past
6 months; and (3) not having undergone any CRC screening tests in the past 5 years. Exclusion criteria were a personal history of CRC, colonic adenoma, diverticular disease, inflammatory bowel disease, a prosthetic heart valve, or vascular graft surgery. Participants with medical conditions that were contraindications to colonoscopy were also excluded.17–19 Registered participants were invited to complete a selfadministered questionnaire, which included information on their age, gender, family history of CRC, smoking status, drinking habits, previous medical history, and long-term medication use. Meanwhile, trained volunteers assisted survey completion for illiterate participants by reading the questions word by word. All participants were then offered an educational session using a standard video followed by health seminars led by trained educators. The video included information on the epidemiology and natural history of CRC risk factors, clinical features of this condition, importance of regular screening, and procedures of the fecal immunochemical test (FIT) and colonoscopy. Hemosure (Manufacturer, W.H.P.M., Inc, El Monte CA) was used as the FIT for all subjects who chose fecal tests, which obviated the need for dietary restriction before testing. The seminars were delivered in a standardized manner, with both FIT and colonoscopy being presented nonpreferentially. Participants were given a choice between yearly FIT for up to 5 years or a direct colonoscopy for CRC screening. Our subjects consisted of participants who chose colonoscopy, those who chose FIT initially but received a colonoscopy because of a positive FIT result, and those who received a colonoscopy after 3 consecutive years of negative FIT results. A total of 5,220 subjects were included in this study.
Outcome Variables and Covariates Outcome variables included the proportion of screening participants who were found to have ACN; this was defined as CRC or any colorectal adenoma Z10 mm in diameter, high-grade dysplasia, villous or tubulovillous histologic characteristics, or any combination thereof. The major covariate included the APCS score as a single variable, which was calculated for each subject on the basis of their age, gender, family history, and smoking status. Additional variables tested for association with the colonoscopic outcome of ACN included BMI (underweight, o18.5; normal, 18.5–22.3; overweight, 23–24.9; obese, Z 25); alcohol drinking (current drinkers with more than two drinks per week vs ex-drinkers or nondrinkers); self-reported history of diabetes mellitus, hypertension, cardiovascular diseases, liver cirrhosis, stroke, gastroesophageal reflux disease, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin; and self-reported current lifestyle habits as collected by validated survey items (“frequent intake of meat,” “physical inactivity,” “frequent intake of barbecued food,” and “frequent intake of fatty food”). The aforementioned BMI cut-off points were used according to the recognized definition of obesity among Asian subjects.20
Statistical Analyses In 2013, all data were entered into a predesigned database with logistic checking using Microsoft Access, and analyzed using SPSS software, version 18.0. The proportion of participants who had colonoscopic findings of ACN was computed. A univariate www.ajpmonline.org
Wong et al / Am J Prev Med 2014;46(5):433–439 analysis was conducted between ACN and each covariate consecutively. All covariates were included into a binary logistic regression model if the initial p-value was o0.05 in the univariate analysis. All variables selected in the multivariate regression analysis were detected for the presence of interactions.21 Each variable of interest was tested for interaction with other selected variables one by one. The variables with initial p-values o0.20 on univariate analysis were included in another similar multivariate regression model. The adjusted ORs (AORs) and 95% CIs of the potential independent predictors of ACN were estimated, and a p-value o0.05 in the multivariate regression analysis was considered statistically significant. Furthermore, we compared the cstatistics of APCS score alone versus APCS score plus all the independent predictors identified to evaluate whether the additional predictors enhanced the performance of APCS in predicting ACN risk factors. According to a generally accepted rule of thumb, a minimum of ten cases are required for each variable in the prediction rule.22 We assumed that the prevalence of ACN was 3% as evaluated in the validation cohort of the original APCS study.15 A total of 15 variables were tested in the prediction model; hence, a total of at least 5,000 subjects needed to be recruited.
Results Participant Characteristics Among 10,728 screening participants, 5,220 received a screening colonoscopy. The average participant age was 57.7 (SD¼4.9) years, and 47.5% were men. The average BMI was 23.5 (SD¼3.2); 8.3% were current smokers; and 10% were alcohol drinkers. More than 14% had a first-degree relative with CRC. The most frequently reported chronic diseases included hypertension (22.9%); diabetes mellitus (7.4%); and gastroesophageal reflux disease (5.3%). A few participants showed chronic use of NSAIDs (4.6%) or aspirin (2.5%). A significant number of participants reported frequent intake of meat (26.0%); physical inactivity (23.9%); frequent intake of barbecued food (21.4%); and frequent intake of fatty food (20.8%). The proportion of these screening participants found to have ACN or cancer was 5.6%, of which 265 subjects (5.1%) had ACN (Table 1).
Factors Associated with Advanced Colorectal Neoplasia On univariate analysis, APCS score (po0.001); BMI (p¼0.001); self-reported presence of diabetes (p¼0.047); hypertension (po0.001); and alcohol consumption (p¼0.001) were significantly associated with ACN. In the multivariate regression model, APCS score (AOR¼1.74, 95% CI¼1.34, 2.25, po0.001); overweight (BMI¼2324.9, AOR¼1.52, 95% CI¼1.12, 2.07, p¼0.007); obesity (BMIZ25, AOR¼1.56, 95% CI¼1.15, 2.10, p¼0.004); hypertension (AOR¼1.58, 95% CI¼1.21, 2.06, p¼0.001); and alcohol consumption (AOR¼1.47, May 2014
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95% CI¼1.05, 2.06, p¼0.025) were associated with the colonoscopic findings of ACN (Table 2). Diabetes, cardiovascular diseases, chronic obstructive pulmonary disease, stroke, cirrhosis, gastroesophageal reflux disease, use of aspirin or other NSAIDs, and all self-reported lifestyle factors were not significantly associated with ACN. No interaction exists between covariates in the binary logistic regression model, thereby implying that the regression analysis is robust. Sensitivity analyses using po0.05 and o0.20 as the cut-off points for variable selection into the multivariate regression analyses, respectively, did not change the independent covariates identified. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve of APCS score alone was 0.560 (95% CI¼0.524, 0.595, p¼0.001) and that of APCS score plus BMI; hypertension; and alcohol consumption was 0.613 (95% CI¼0.578, 0.648, po0.001). For the comparison of these two ROC curves, the revised model with additional risk factors performed significantly better than the APCS score alone in terms of prediction of advanced neoplasia (z-statistic¼2.082, p¼0.037).
Discussion In this large cohort of CRC screening participants, the prevalence of ACN was 5.6%. Apart from the APCS scoring system, overweight or obesity, hypertension, and alcohol consumption were independently associated with the findings of ACN. Adding these three additional risk factors to the APCS increased its performance to predict ACN risk.
Relationship with Existing Literature The prevalence of ACN as reported in other Asian studies is between 3% and 12%.23–25 In the derivation and validation cohort of the APCS study,15 the prevalence of ACN was 4.5% and 3.0%, respectively. The prevalence of ACN in this study (5.1%) was therefore higher than the validation cohort (po0.001) but similar to the derivation cohort (p¼0.499) and the figures from other studies. One possible explanation for this difference is the younger mean age of the validation cohort as compared to our subjects (51.0 vs 57.7 years)—hence a higher proportion of subjects were found to have ACN in our study. Regarding the relationship between BMI and colorectal neoplasia, a recent pooled analysis of seven prospective studies involving 8,213 screening participants confirmed that BMI is associated with the risk of metachronous colorectal lesions, but is confined to men and lesions of the proximal colon.26 In a prospective
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Table 1. Participant characteristics (N¼5,220), n (%) unless otherwise noted Characteristics
M (SD), n (%)
Age (years, M [SD])
57.72 (4.89)
BMI (M [SD])
23.51 (3.17)
Gender, male
2,181 (47.5)
Current smoking
431 (8.3)
Alcohol consumption
522 (10.0)
Diabetes mellitus
386 (7.4)
Family history present for a first-degree relative
735 (14.1)
Hypertension
1,196 (22.9)
IHD/heart disease
91 (1.7)
COPD
39 (0.7)
Stroke
37 (0.7)
Cirrhosis
8 (0.2)
GERD
277 (5.3)
Use of NSAIDs
240 (4.6)
Use of aspirin
133 (2.5)
Frequent intake of red meat
1,358 (26.0)
Physical inactivity
1,245 (23.9)
High intake of barbecued food
1,115 (21.4)
Frequent intake of fatty food
1,087 (20.8)
Advanced neoplasia and colorectal cancer Colorectal cancer Advanced neoplasia
289 (5.6) 24 (0.5) 265 (5.1)
COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; IHD, ischemic heart disease; NSAIDs, nonsteroidal antiinflammatory drugs
cohort study of 33,403 African-American women aged Z30 years with no prior cancer or polyps, an increased risk of colon polyps was demonstrated among those with BMIZ35 compared to subjects with BMIo25.27 A cross-sectional study conducted in Korea demonstrated a weak association between BMI and the risk of adenoma among men at the highest BMI levels, but this association was abolished after adjustment for waist circumference.28 However, these studies were performed either on Western or African subjects, or suffered from a small sample size. The relatively large number of asymptomatic screening participants included in the present study reported the new finding that obese subjects had a 29% increased risk of ACN. In addition, this study also showed a dose-response
relationship between BMI and ACN, which implies that a potential cause–effect relationship might exist. The best established biochemical mediator between obesity and colorectal neoplasia is the pro-carcinogen insulin-like growth factor 1 and, to a lesser extent, leptin.29 From a clinical utilization perspective, these findings imply that Asian subjects who are overweight (BMI¼23–24.9) have statistically similar odds of developing ACN when compared with obese subjects (BMIZ25) (1.52-fold, 95% CI¼1.12, 2.07, vs 1.56-fold, 95% CI¼1.15, 2.10). Therefore, overweight patients should also be considered as having a higher risk of ACN and receive higher priority for screening than average-risk subjects. Turning to the association between alcohol consumption and ACN, a cross-sectional study conducted in the U.S. found that patients who consumed more than eight drinks of spirits or eight servings of beer per week were more likely to have significant colorectal neoplasia but that the consumption of one to eight glasses of wine per week was associated with a lower risk.30 A pooled analysis of primary data from more than 489,000 persons in eight cohort studies in North American and European countries has shown that alcohol drinkers of more than 2–2.5 drinks daily had a 1.16-fold increased risk of developing CRC.31 A large prospective cohort study conducted in Japan found a positive association between alcohol drinking and CRC,32 yet a smaller-scale case– control study in the same country reported only modestly increased risks of distal colon and rectal adenomas, but not large adenomas.33 However, subjects in both analyses were not CRC screening participants, and their inclusion criteria did not include the absence of CRC symptoms. From the existing literature, the relationship between alcohol drinking and colorectal neoplasia among asymptomatic subjects in Asia has been inconclusive. Ethanol has been shown to promote, rather than initiate, colorectal carcinogenesis.33 Thus, the present finding that alcohol drinkers had a 50% higher risk of ACN than nondrinkers implies that alcohol consumption should be included as one of the important predictive factors for the presence of ACN. The positive association between hypertension and ACN has not been reported in previous literature and thus could represent a novel finding. Moreover, it is interesting that diabetes was only found to be significantly associated with ACN in univariate analysis but not in multivariate regression models. There are a few explanations for the absence of this association. First, diabetes and ACN share some common risk factors, such as alcohol consumption and obesity. This may compromise the independent predictive ability of diabetes for ACN when these other factors are controlled for. Also, a weaker www.ajpmonline.org
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Table 2. Univariate and multivariate predictors of advanced colorectal neoplasia and colorectal cancer Unadjusted (univariate analysis)
Adjusted (multivariate regression analysis)
Risk factors
OR (95% CI)
p-value
APCS High risk versus low or moderate risk
1.858 (1.439, 2.398)
o0.001
Z18.5 to o23 (normal)
0.553
SE
OR (95% CI)
p-value
0.133
1.738 (1.339, 2.254)
o0.001
o0.001
BMI o18.5 (underweight)
B coefficient
0.812 (0.371, 1.776)
0.601
0.009 0.157
0.400
ref
0.854 (0.390, 1.873)
0.694
ref
Z23 to o25 (overweight)
1.610 (1.188, 2.184)
0.002
0.420
0.157
1.522 (1.119, 2.069)
0.007
Z25 (obesity)
1.830 (1.371, 2.445)
o0.001
0.442
0.153
1.556 (1.154, 2.099)
0.004
Diabetes
1.489 (1.005, 2.205)
0.047
0.160
0.209
1.173 (0.779, 1.767)
0.444
Hypertension
1.821 (1.415, 2.343)
o0.001
0.456
0.137
1.578 (1.206, 2.064)
0.001
IHD/heart disease
1.663 (0.797, 3.470)
0.175
—
—
Alcohol
1.772 (1.275, 2.462)
0.001
0.172
1.471 (1.050, 2.061)
COPD
1.963 (0.693, 5.562)
0.204
—
—
—
—
Stroke
0.472 (0.065, 3.456)
0.460
—
—
—
—
N/A
1.000
—
—
—
—
GERD
1.198 (0.732, 1.962)
0.473
—
—
—
—
Use of NSAIDs
0.581 (0.317, 1.064)
0.078
—
—
—
—
Use of aspirin
1.365 (0.717, 2.601)
0.344
—
—
—
—
Frequent intake of red meat, n (%)
0.907 (0.688, 1.197)
0.907
—
—
—
—
Physical inactivity, n (%)
0.777 (0.577, 1.045)
0.096
—
—
—
—
Low intake of fruit or vegetables, n (%)
1.010 (0.756, 1.348)
0.948
—
—
—
—
Frequent intake of fatty food, n (%)
1.210 (0.915, 1.601)
0.180
—
—
—
—
Cirrhosisa
— 0.386
— 0.025
Note: Boldface indicates po0.05. a None of the eight subjects with cirrhosis had advanced neoplasia. APCS, Asia Pacific Colorectal Scoring System; COPD, chronic obstructive pulmonary disease; GERD, gastroesophageal reflux disease; IHD, ischemic heart disease; NSAIDs, nonsteroidal anti-inflammatory drugs
association exists between diabetes and ACN among Asian subjects compared to Western populations. For instance, a systematic review of 16 cohort studies and eight case-control studies involving more than 3.6 million individuals showed that the presence of diabetes was May 2014
associated with a 1.26-fold increased risk of CRC,34 which was lower among Asian populations (relative risk¼1.19, 95% CI¼1.11, 1.28) than European ones (relative risk¼1.39, 95% CI¼1.26, 1.53). Lastly, most previous studies have found an association between type 2 diabetes
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and ACN, but not type 1 diabetes.35,36 The association between ACN and type 1 diabetes remains to be explored.
Strengths and Limitations This is a large-scale study that evaluated asymptomatic subjects who were self-referred for CRC screening. It is unique because the analysis was based on the wellvalidated APCS scoring system, which allows the exploration of additional risk factors for ACN. However, some limitations should be acknowledged. First, consecutive sampling was adopted, which might have limited its generalizability to the whole population. However, given the screening infrastructure of the community, it was not feasible to conduct a study using population-based, simple random-sampling methodology owing to the absence of an accurate sampling frame and high refusal rates. Second, the characteristics of Chinese subjects aged between 50 and 70 years might be different from those in the original APCS study, which included asymptomatic subjects with a wider age range recruited from different centers in the Asia-Pacific region. In addition, although our recruitment excluded subjects with some well-known risk factors, such as a past history of CRC and inflammatory bowel disease, not all confounders could be controlled in this analysis. Lifestyle factors such as a high intake of red meat, fat, and barbecued food37,38 and physical inactivity39 were only measured in a simplified manner. Additionally, the survey did not collect information on the type of alcoholic beverages and their total consumption. Nevertheless, the variables pertaining to dietary habits require food frequency questionnaires or the accurate keeping of a 24hour food diary for assessment; this process is timeconsuming and therefore unlikely to be practical for inclusion as a component in the risk scoring system. Finally, the presence of chronic diseases was self-reported and may be subject to ascertainment bias, and their duration and treatment statuses have not been analyzed.
Implications for Clinical Practice and Future Research BMI, alcohol consumption, and self-reported hypertension should be considered as additional risk factors apart from the variables of the APCS scoring system.15 These additional factors could be easily obtained or measured in clinical or community settings. Patients with these risk factors should receive additional counseling efforts for CRC screening, as the colonoscopic yield of ACN is higher when compared with the average-risk general population. In resource-limited countries, physicians may use these risk factors to prioritize screening services, and
in low-prevalence countries, risk stratification could be adopted to selectively offer screening to high-risk individuals. Built on the APCS system, these additional variables could potentially inform policy makers and physicians when allocating CRC screening resources in the community. It is anticipated that these factors could risk-stratify CRC screening participants in a more costeffective manner. Because the additional variables found to be significant may have different associations with ACN in other patient groups, their generalizability to other populations such as Chinese immigrants living outside of China should be studied further. Future studies should also focus on developing and validating a modified system based on the present findings yet maintaining the simplicity of the predictive tool. We acknowledge the full funding support of the Hong Kong Jockey Club Charities Trust for this study. We are grateful to Dr. David Wilmshurst, the Chinese University of Hong Kong’s Academic Editor, for editing the first draft of this paper. No financial disclosures were reported by the authors of this paper.
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