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Obesity and colon and rectal cancer risk: a meta-analysis ofprospective studies 13

Susanna C Larsson and Alicja Wolk

ABSTRACTBackground: Whereas obesity has been associated with an in-creased risk of colon cancer in men, a weak or no association hasbeen observed in women. Results for rectal cancer have also beeninconsistent.Objective: The objective was to perform a meta-analysis to sum-marize the available evidence from prospective studies on the asso-ciations of overall and abdominal obesity with the risk of colon and

rectal cancer.Design: We searched MEDLINE (1966April 2007) and the refer-ences of the retrieved articles. Study-specific relative risks (RRs)were pooled by using a random-effects model.Results: Thirty prospective studies were included in the meta-analysis of body mass index (BMI; in kg/m 2 ). Overall, a 5-unitincrease in BMI was related to an increased risk of colon cancer inboth men(RR:1.30;95% CI:1.25,1.35)and women (RR: 1.12;95%CI: 1.07, 1.18), but the association was stronger in men ( P 0.001).BMI was positively associated with rectal cancer in men (RR: 1.12;95%CI:1.09,1.16)butnotinwomen(RR:1.03;95%CI:0.99,1.08).The difference in RRs between cancer sites was statistically signif-icant ( P 0.001 in men and P 0.04 in women). Colon cancer risk increased with increasing waist circumference (per 10-cm increase)in both men (RR: 1.33; 95% CI: 1.19, 1.49) and women (RR: 1.16;95%CI:1.09, 1.23) and withincreasing waist-hip ratio (per 0.1-unitincrease) in both men (RR: 1.43; 95% CI: 1.19, 1.71) and women(RR: 1.20; 95% CI: 1.08, 1.33).Conclusions: The association between obesity and colon and rectalcancer risk varies by sex and cancer site. Am J Clin Nutr 2007;86:55665.

KEY WORDS Body mass index, colorectal cancer, meta-analysis, obesity, prospective studies

INTRODUCTION

Colorectal cancer is the third mostcommon cancer worldwide(1).Incidence rates varyby 25-foldbetweencountries,withthehighest rates observed in North America,Australia, and WesternEurope and the lowest rates in Africa and Asia (1). Nutritional-related factors are considered to play a major role in colorectalcancerdevelopment (2). A mounting body of evidence indicatesthat insulin resistance and resulting hyperinsulinemia may beresponsible for many of the associations of nutritional factorswith colorectal cancer risk and for the high incidence of thismalignancy in westernized countries (3, 4). Obesity, especiallyabdominal obesity, is related to insulin resistance and hyperin-sulinemia (5,6). Althoughbody mass index (BMI), as a measure

of overall obesity, is positively associated with the risk of coloncancer in men, a weaker or no association has been observed inwomen (6). Findings for rectal cancer have also been inconsis-tent. We therefore undertook a meta-analysis of prospectivestudiesto quantitatively assess therelationsbetweenBMI andtherisk ofcolonand rectal cancerin men andwomen. Inaddition,weconducted a meta-analysis to summarize the prospective datarelating waist circumference and waist-hip ratio, indicators of

abdominal adiposity, to colon and rectal cancer risk.

METHODS

Literature search

We searched MEDLINE (US National Library of Medicine,National Institutes of Health, Bethesda, MD) for studies pub-lished in any language from 1966 to April 2007 using the searchterms obesity , body mass index , or BMI combined with colorec-tal cancer, colon cancer , or rectal cancer . The search wasrestricted to studies of human participants. We also reviewed thereference lists of pertinent articles to search for more studies.

Inclusion criteria

To be included in this meta-analysis, studies had to have aprospective study design; contain data on colon or rectal cancerincidence or mortality or both; report relative risks (RRs) withcorresponding 95% CIs for 3 categories of exposure (BMI,waist circumference, or waist-hip ratio); or provide an RR perunit increase in exposure. We did not include studies that onlyreported estimates that combined colon and rectal canceror menand women. When there were multiple published reports fromthe same study population, we included the one that had thelongest follow-up.

Data extraction

We extracted the following information from each study: firstauthors last name, year of publication, country where the study

1 From the Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

2 Supported by research grants from the Swedish Cancer Society.3 Reprints not available. Address correspondenceto SC Larsson, Division

of Nutritional Epidemiology, The National Institute of Environmental Med-icine, Karolinska Institutet, PO Box 210, SE-171 77 Stockholm, Sweden.E-mail: [email protected].

Received January 5, 2007.Accepted for publication April 6, 2007.

556 Am J Clin Nutr 2007;86:556 65. Printed in USA. 2007 American Society for Nutrition

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was performed, sample size, age range of the participants atbaseline, assessment of anthropometric measures (self-reportedcompared with measured), duration of follow-up, covariates ad- justed for in the analysis, and RRs with corresponding 95% CIsfor every exposure category or per unit increase in exposure.From each study,we extractedthe RRestimates that reflectedthegreatest degree of adjustment for potential confounders.

Statistical analysisThe cutoffs for the lowest and highest exposure categories

varied betweenstudies includedin thismeta-analysis.Therefore,toplacestudieson a commonscale,we calculated,for each study,theRR perunit increase in the anthropometric measures: a 5-unitincrease forBMI, a 10-cm increase forwaist circumference, anda 0.1-unit increase forwaist-hip ratio). This wasdone by relatingthe natural log of RRs for different exposure categories to themidpoint of the corresponding category. We used the methoddescribedby Greenlandet al (7,8),whichtakes into account thatthe level-specific risk estimates are correlated. This method re-quires thatthe numberofcases andtotal subjects(or person-time)foreach category areknown. Forstudies that didnotprovide this

information, we estimated the dose-response slopes usingvariance-weighted least-squares regression analysis. For open-ended categories (eg, BMI 30), we estimated the midpointusing data from the Cohort of Swedish Men (9) and the SwedishMammography Cohort (10) or obtained the values from the au-thors (for studies conducted in Asia; 1113). Summary RR es-timateswereobtained fromrandom-effectsmodelsapplied to thestudy-specific dose-response slopes (14).

Statistical heterogeneity among studies was tested with the Qstatistic, and inconsistency was quantified with the I 2 statistic(15). Besides analyses of cancer site and sex, we conductedanalyses of BMI stratified by subsite in the colon (proximalversus distal colon) and geographic region. To assess for publi-

cation bias, funnel plots (ie, plots of study results against preci-sion) were constructed and the Eggers regression test was usedto test funnel plot asymmetry (16). The potential influence thatunpublished studies could have on the summary RR estimateswas examined by using trim and fill analysis, which is a methodbased on the addition of studies to the funnel plot so that itbecomessymmetrical (17). P 0.05was considered statisticallysignificant. All statistical analyses were performed by usingSTATA (version 9.0; StataCorp, College Station, TX).

RESULTS

Our search strategy and inclusion criteria resulted in a total of 31 articles(withdatafrom 30 prospectivestudies)being includedin our analyses of BMI (913, 1843) ( Figure 1 ). Two addi-tional studies (44, 45) were included in the analyses of waistcircumference or waist-hip ratio; these 2 studies were not in-cluded in the analyses of BMI because more recent data wereavailable (29) The characteristics of the included studies aresummarized in Table 1 . Most of the studies were conducted intheUnitedStates ( n 12) or Europe ( n 11). The outcome wascolon or rectal cancer mortality in 5 studies (25, 26, 31, 34, 35)and incidence of these cancers in all of the other studies.

Body mass index

The estimatedRRs of colon cancer per5-unit increase in BMIfor each study, separately for men and women, are shown in

Figure2 . Thestudiescombinedinvolved3 128 274men(22 546cases)from24 studies and2 419 875women(22 231cases)from21 studies. In a meta-analysis, a 5-unit increase in BMI wasassociated with a 30% increased risk of colon cancer in men andwith a 12% increased risk in women (Figure 2). This sex differ-ence for BMI was statistically significant ( P 0.001). BMI wasstatistically significantly positively related to risk of proximalcolon cancer in men and with distal colon cancer in both sexes(Table 2 ). Although the association between BMI and risk of colon cancer was observed between studies conducted in both

North America and Europe (Table 2), the summary estimateswere higher in NorthAmericanstudies ( P 0.01 for differencesamong men; P 0.004 for differences among women). In-creased BMI was also associatedwith coloncancerriskamong incarried out in Asia, but the association was statistically signifi-cant in men only (Table 2). The summary estimates were non-significantly lower for thestudies in which weightandheight hadbeen measured (men, RR: 1.27; 95%CI: 1.23, 1.32;women, RR:1.07; 95% CI: 1.01, 1.15) than for those that relied on self-reporting(men, RR: 1.36; 95%CI: 1.27, 1.46; women,RR: 1.17;95% CI: 1.08, 1.26).

Physical activity is potentially the most likely confounder of thepositiverelationbetweenBMIand riskof colon cancer.Whenwe restricted the meta-analysis to studies that controlled forphysical activity, the results were similar to those of the overallanalyses for10 studies inmen (RR:1.33;95%CI:1.24,1.43)andfor 8 studies in women (RR: 1.16; 95% CI: 1.07, 1.25).

The studies on BMI and rectal cancer risk involved2 616 503 men (13 830 cases) from 15 studies and 1 802 320women (8878 cases) from 13 studies. Overall, BMI was sta-tistically significantly positively related to rectal cancer risk in men(12% increase per5-unithigher BMI) butnot in women(Figure 3 ; P 0.002 for difference in association betweenmen and women). A formal test for differences in the associ-ation with BMI between cancer sites showed that the RR wasstatistically significantly higher for colon cancer than for rec-tal cancer ( P 0.001 in men and P 0.01 in women). Among

771 Publications identifiedfrom literature search

726 Articles excluded after titleand abstract review

45 Articles retrieved for moredetailed assessment

14 Articles excluded after fulltext review7 multiple publications1 no relative risk2 insufficient information

to estimate trend4 colon and rectal cancers

combined

31 Articles included in meta-analysis of BMI and colonand/or rectal cancer risk*

FIGURE 1. Flow diagram of study selection . * Two additional studieswereincludedin the analysesof waistcircumference,waist-hipratio,or both.(Thesestudies were excluded from theanalysesof BMIbecausemore recentdata were available.)

OBESITY AND COLON AND RECTAL CANCER 557

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TABLE 1Characteristics of prospective studies of obesity and colon cancer (CC) and rectal cancer (RC) risk 1

Reference Country, study name Study participantsNo. of case

subjectsYears of

follow-up 2

Assessmentof

anthropometricmeasures Adjustments

Lee andPaffenbarger,1992 (18)

United States, HarvardAlumni HealthStudy

17 595 men 290 CC 19621988(5.6)

Self-reported Age, family history of cancer, physicalactivity

Bostick et al,1994 (19)

United States, IowaWomens HealthStudy

35 215 womenaged 5569 y

212 CC 19861990(4.8)

Self-reported Age, height, parity, vitamin Asupplement use, intakes of energyand total vitamin E

Chyou et al,1994 (20)

United States,Japanese in Hawaii

7840 men 289 CC 19651992 Measured Age

Giovannucciet al, 1995(44)

United States, HealthProfessionalsFollow-Up Study

31 055 men aged4075 y

117 CC 19871992 Self-reported Age, history of endoscopy, familyhistory, smoking, physical activity,aspirin, intakes of red meat, alcohol,fiber, folate, methionine, and energy

Thune andLund, 1996(21)

Norway 53 242 men and28 274 womenaged 2069 y

230 CC(M)169 RC(M)99CC(F)55RC(F)

19721991(16)

Measured Age

Martinez et al,1997 (45)

United States, NursesHealth Study


161 CC 19861992 Self-reported Age, family history, smoking, physicalactivity, PMH use, intakes of redmeat and alcohol

Singh andFraser,1998 (23)

United States,Adventist HealthStudy

32 051 men andwomen aged

25 y

59 CC (M)83 CC (F)

19761982(5.6)

Self-reported Age, family history

Ford 1999 (22) United States, FirstNational Health andNutrition Survey

5506 men and7914 womenaged 2574 y

104 CC(M)118 CC(F)

19711992(16.2)

Measured Age, race, education, smoking, serumcholesterol, exercise, alcohol

Kaaks et al,2000 (24)

United States, NewYork WomensHealth Study

144 controls 3

aged 3565 y73 CC 19851998 Self-reported Age, menopausal status, smoking

Murphy et al,2000 (25)

United States, CancerPrevention Study II

379 167 men and496 239women aged

30 y

1792 CC(M)1616 CC(F)

19821994(8.8)

Self-reported Age, race, education, family history,smoking, exercise, PMH use(women), aspirin, intakes of fat,vegetables, and fiber

Terry et al,2001 (10)

Sweden, SwedishMammographyCohort


291 CC159 RC

19871998(9.6)

Self-reported Age, education, intakes of energy, redmeat, alcohol, fat, folate, vitamin D,vitamin C, and calcium

Colangelo etal, 2002(26)

United States, ChicagoHeart AssociationDetection Project inIndustry

20 433 men and15 149 women

160 CC(M)108 CC(F)

19671997(26.2)

Measured Age, race, education, height, postloadplasma glucose, insulin resistance

Terry et al,2002 (27)

Canada, CanadianNational BreastScreening Study


363 CC164 RC

19801993(10.6)

Self-reported Age, education, OC use, PMH use,parity, smoking, physical activity

Shimizu et al,2003 (28)

Japan 13 392 men and15 659 womenaged 35 y

104 CC(M)58RC (M)89CC(F)

41RC(F)

19932000(7.1)

Self-reported Age, education, height, smoking,physical activity, alcohol

Wei et al,2004 (29)

United States, HealthProfessionalsFollow-Up Study

46 030 men aged4075 y

467 CC135 RC

19862000 Self-reported Age, family history, height, smoking,physical activity, intakes of redmeat, alcohol, calcium, and folate

Wei et al,2004 (29)

United States, NursesHealth Study


672 CC204 RC

19802000 Self-reported Age, family history, height, smoking,physical activity, intakes of redmeat, alcohol, calcium, and folate

Moore et al,2004 (30)

United States,Framingham Studycohort

3345 men and4221 womenaged 3079 y

140 CC(M)166 CC(F)

19481999(23.1)

Measured Age, education, height, smoking,physical activity, alcohol

Tamakoshi etal, 2004(31)

Japan, JapanCollaborativeCohort

43 171 men and58 775 womenaged 4079 y

127 CC(M)122 CC(F)

19881999(10.0)

Self-reported Age, family history, smoking,exercise, intakes of meat,vegetables, and alcohol

(Continued )

558 LARSSON AND WOLK

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TABLE 1(Continued )

Reference Country, study name Study participantsNo. of case

subjectsYears of

follow-up 2

Assessmentof

anthropometricmeasures Adjustments

MacInnis etal, 2004(32)

Australia, MelbourneCollaborativeCohort Study

16 566 men aged2775 y

153 CC 19902002(8.8)

Measured Age, country of birth, education

Lin et al, 2004(33)

United States,Womens HealthStudy


158 CC40 CC

19932003(8.7)

Self-reported Age, family history, history of colonpolyps, aspirin, PMH use, smoking,physical activity, intakes of redmeat and alcohol

Kuriyama etal, 2005(12)

Japan 12 485 men and15 054 womenaged 40 y

88 CC (M)67 RC (M)72 CC (F)42 RC (F)

19841992(9)

Self-reported Age, smoking, intakes of meat, fish,fruits, vegetables, and alcohol

Eichholzer etal, 2005(34)

Switzerland, BaselCohort Study

2974 men aged2079 y

22 CC 19711990 Measured Age, smoking

Batty et al,2005 (35)

United Kingdom,Whitehall Cohort

Study

17 102 men aged4064 y

279 CC104 RC

19672002(28.1)

Measured Age, employment grade, height,smoking, diabetes, physical activity,

otherOh et al, 2005

(13)Korea, Korea National

Health InsuranceCorporation

781 283 men aged20 y

953 CC1563 RC

19922001(9.8)

Measured Age, residency area, family history,smoking, exercise, alcohol intake

Rapp et al,2005 (36)

Austria, VorarlbergHealth Monitoringand PromotionProgram Study


260 CC(M)138 RC(M)271 CC(F)133 RC(F)

19852001(9.9)

Measured Age, occupational group, smoking

Engeland etal, 2005(37)

Norway 962 901 men and1 037 077women aged2074 y

13805 CC(M)9182 RC(M)16638 CC(F)7492 RC(F)

19632002(23)

Measured Age, birth cohort

Otani et al,2005 (11)

Japan, Japan PublicHealth Center-basedProspective Study


424 CC (M)202 RC (M)229 CC (F)131 RC (F)

19902001(9.4)

Self-reported Age, smoking, Public Health Centerareas, refraining from salty foodsand animal fats, and intakes of misosoup and alcohol

Lukanova etal, 2006(38)

Sweden, NorthernSweden Health andDisease Cohort


73 CC (M)58 RC (M)76 CC (F)31 RC (F)

19852003(8.2)

Measured Age, calendar year, smoking




212 CC 19902003(10.4)

Measured Age, country of birth, education, PMHuse

Pischon et al,2006 (40)

Europe, EuropeanProspectiveInvestigation intoCancer andNutrition

129 731 men and238 546women aged2070 y

421 CC (M)295 RC (M)563 CC (F)291 RC (F)

19922004(6.1)

Measured Age, center, education, smoking,physical activity, and intakes of redmeat, processed meat, fish, fruit,vegetables, fiber, and alcohol

Bowers et al,

2006 (41)

Finland, Alpha-

Tocopherol, Beta-Carotene CancerPrevention Study

28 983 men aged

5069 y

227 CC

183 RC

19852002

(12.5)

Measured Age, smoking

Samanic et al,2006 (42)

Sweden, SwedishConstructionWorker Cohort

362 552 men aged1867 y

1795 CC1362 RC

19711999(19)

Measured Age, smoking

Larsson et al,2006 (9)

Sweden, Cohort of Swedish Men

45 906 men aged4579 y

309 CC190 RC

19982005(7.1)

Self-reported Age, family history, education, aspirin,smoking, diabetes, physical activity




134 RC (M)95 RC (F)

19902003(10.4)

Measured Age, country of birth

1 OC, oral contraceptives; PMH, postmenopausal hormones.2 Mean or median duration of follow-up in parenthesis.3 Nested case-control study within a prospective cohort.


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men, the association between BMI and rectal cancer was sim-ilar among studies conducted in Europe and Asia; only onestudy in men from North America precluded calculation of asummary RR. Among women, there was a statistically signif-icant positive association between BMI and rectal cancer risk among studies from North America, but not among studiesfrom Europe or Asia ( P 0.02 for difference in association

between geographic regions). Among men, the summary es-timate was similar for studies in which weight and height hadbeen measured (RR: 1.12; 95% CI: 1.09, 1.15) and for studiesthat relied on self-reporting (RR: 1.16; 95% CI: 1.01, 1.34),whereas among women, the summary estimate was lowerfrom studies based on measured weight and height (RR: 1.01;95% CI: 0.98, 1.03) than from those based on self-reporting

FIGURE 2. Relative risk of colon cancer per 5-unit increase in BMI (in kg/m 2 ).


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(RR: 1.16; 95% CI: 1.06, 1.24; 7 studies) ( P

0.003 fordifference). Because physical activity is not associated withrectal cancer risk (46), it is not a potential confounder of theassociation between BMI and rectal cancer.

There was no evidence of publication bias in the literature onBMI and colon cancerin men oron BMI and rectalcancer inmenor women (Eggers test: P 0.2 for all). For BMI and coloncancer in women, the funnelplot showed some asymmetry (datanot shown), which reflected the relative deficit of small studiesshowing no association or an inverse association (Eggers test: P

0.001). According to trim andfill analysis,4 such studies mayhave been missing. When those potentially missing studies wereadded to themeta-analysis, the summary RR of colon cancer per5-unit increase in BMI among women was 1.10 (95% CI: 1.05,1.16).

Waist circumference and waist-hip ratio

Overall, both waist circumference and waist-hip-ratio wasstatistically significantly positively associated with risk of coloncancer in both sexes ( Figure 4 ). A statistically significant sexdifference was found for waist circumference (stronger associ-ation in men than in women, P 0.04) and a nonsignificant sexdifference was found for waist-hip-ratio (stronger association inmen than in women, P 0.10). We did not detect evidence forpublication bias ( P 0.3).

Only 3 studies provided results on waist circumference andwaist-hip ratio in relation to rectal cancer risk in men (9, 40, 43)and women (40, 43). In a meta-analysis of these studies, thesummary RR estimates of rectal cancer per 10-cm increase inwaist circumference were 1.12 (95% CI: 1.03, 1.22; P for heter-ogeneity 0.93) in men and 1.09 (95% CI: 0.99, 1.20; P forheterogeneity 0.86) in women. The corresponding estimatesper 0.1-unit increase in waist-hip ratio were 1.22 (95% CI: 0.81,1.83; P for heterogeneity 0.001) in men and 1.15 (95% CI:0.95, 1.39; P for heterogeneity 0.22) in women.

DISCUSSION

This meta-analysis of prospective studies indicates that theassociation between obesity and risk of colorectal cancer varies

by sexand cancersite. Although colon cancerriskincreased withincreasing BMI, waist circumference, andwaist-hip-ratio in bothmen and women, the associations were stronger in men. Therelation between BMI andcolon cancerwas similar forproximaland distal colon cancer. With regard to rectal cancer, the risk increased with increasing BMI in men, whereas no overall asso-ciation was observed in women.

Available epidemiologic evidence suggests that abdominalobesity (as reflected by high waist circumference and waist-hipratio) may be more predictive of colon cancer risk than overallobesity (high BMI). Of the studies that provided results for bothabdominal and overall obesity in relation to risk of colon cancer(9, 19, 30, 32, 39, 40, 44, 45), most showed that abdominalobesity was more strongly related to increased colon cancer risk than was overall obesity (30, 32, 39, 40, 44). Furthermore, thesestudiesfound thatthe positiveassociationof waist circumferenceor waist-hip ratio with colon cancer remained after adjustmentfor BMI (30, 32, 40, 44, 45), whereas the relation betweenBMI and colon cancer was attenuated, and generally not statis-tically significant, after adjustment for waist or waist-hip ratio(30, 32, 40).

The exact biologic mechanisms underlying the associationbetween obesity and increased risk of colorectal cancer are notfully understood, but certainly involve alterations in the metab-olism of endogenous hormones, including insulin, insulin-likegrowth factors (IGFs), sex steroids, and possibly adipocyte-derived factors such as leptin and adiponectin. Obesity, particu-larly abdominal obesity, is linked to insulin resistance, to hyper-insulinemia, and to the development of type 2 diabetes (5, 6).Epidemiologic evidence indicates that high circulating concen-trations of insulin and C-peptide (a marker of pancreatic insulinsecretion) (24,4751)as wellas diabetes(52) areassociated witha greater risk of colorectal cancer. IGF binding protein-1(IGFBP-1) concentrations decrease with increasing adiposity(53), which may lead to elevated concentrations of free andbioavailable IGF-I (3). IGFBP-1 concentrations have beenshown to be inversely related to risk of colon cancer (48),whereas IGF-I concentrations, particularly relative to IGFBP-3,have been shown to be positively associated with risk of colon orcolorectal cancer in prospective studies (24,28, 5456). Obesity

TABLE 2Summary relative risks of colon cancer and rectal cancer per 5-unit increase in BMI (in kg/m 2 )

Men Women

No. of studies

Relative risk (95% CI)

Heterogeneity 1 No. of studies

Relative risk (95% CI)

Heterogeneity 1

P I 2 P I 2

% %

Colon cancerProximal colon 5 1.29 (1.17, 1.42) 0.41 0 6 1.13 (0.93, 1.36) 0.02 62.8Distal colon 5 1.35 (1.22, 1.48) 0.75 0 6 1.14 (1.01, 1.28) 0.70 0North America 8 1.39 (1.31, 1.48) 0.61 0 10 1.17 (1.08, 1.25) 0.04 50.1Europe 10 1.27 (1.22, 1.32) 0.29 17 6 1.04 (1.02, 1.07) 0.40 3Asia 5 1.27 (1.08, 1.49) 0.13 43.7 4 1.32 (0.96, 1.83) 0.03 67.4

Rectal cancerNorth America 1 2 2 3 1.17 (1.05, 1.31) 0.47 0Europe 9 1.12 (1.09, 1.15) 0.69 0 6 1.01 (0.98, 1.04) 0.64 0Asia 4 1.16 (1.05, 1.28) 0.46 0 3 1.09 (0.85, 1.40) 0.82 0

1 I 2 is interpreted as the proportion of total variation across studies that is due to heterogeneity rather than chance.2 Because there was only one study of rectal cancer in men in North America, a summary relative risk could not be calculated.


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is also positively associated with serum leptin but inversely as-sociated with adiponectin concentrations (57). In prospectivestudies, high leptin (47, 58, 59) and low adiponectin (60) con-centrationshavebeen related to an increase incolon or colorectalcancer risk.

The reasons for the apparent sexdifference in associations forBMI, waist circumference, and waist-hip ratio are unclear butmight be related to differences between men and women in theassociation between adiposity and testosterone concentrations.Adiposity is inversely related to testosterone concentrations inmen (6163) but positively related to testosterone concentra-tions in women (64, 65). Several clinical trials have shown thattestosterone therapy decreases adiposity and improves insulinsensitivity (66 69),whereas androgendeprivation increases ad-iposity and insulin resistance in men(70, 71). Moreover,a meta-analysis found that high testosterone concentrations were asso-ciatedwithalowerriskoftype2diabetesinmenbutwithahigherrisk inwomen(72). If insulin resistance isoneof themechanismslinking obesity to risk of colon and rectal cancer, an obesity-induced reduction in testosterone concentrations in men may beone reason for thestronger association of obesity with colon andrectal cancer risk in men than in women.

Other potential explanations for the sex difference in associ-ation withadipositymight be related toa counteracting beneficial

effect of obesity on colorectal cancer risk in women or to post-menopausal hormone use. BMI is positively associated withcirculating concentrations of estradiol in postmenopausalwomen and men (6365, 73). Exogenous estrogens (in the formof postmenopausal hormone therapy) have been associated witha decreased risk of colorectal cancer in observational and inter-vention studies (7476). Results of a recent large prospectivecohort study showed that abdominal adiposity was positivelyrelated to risk of colon cancer only in women who did not usepostmenopausal hormones (40). Likewise, a smaller prospectivecohort study found that BMI was significantly positively asso-ciated with the risk of colorectal cancer in never users of post-menopausal hormones but not in current users (33). Some (10,27) but not all (30) prospective studies have found that BMI ispositively related to risk of colorectal cancer in premenopausalwomen but not in postmenopausal women.

Results from this meta-analysis indicate that the associationbetweenBMI andcancerrisk is stronger forcolon cancerthanforrectal cancer. Similarly, another meta-analysis showed that in-creased leisure-time physical activity, which is related to im-proved insulin sensitivity (77,78),was associated witha reducedrisk of colon cancer but not of rectal cancer (46). This maysuggest that insulin resistance, hyperinsulinemia, and other fac-tors related to obesity are stronger risk factors for colon cancer

FIGURE 3. Relative risk of rectal cancer per 5-unit increase in BMI (in kg/m 2 ).


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than for rectal cancer. Indeed, several prospective studies re-ported that circulating C-peptide (24, 28, 47, 51) and leptin (47,58)concentrationsweremore stronglypositivelyassociatedwithrisk of colon cancer than with overall colorectal cancer or rectalcancer.

As with any meta-analysis of observational studies, our studyhas limitations. First, the possibility that the observed relationbetween obesity and colorectal cancer risk was due to unmea-sured or residual confounding should be considered. The mostlikely confounderof theobesity-coloncancer relationis physicalactivity, which is inversely associated with colon cancer risk (46). However, a positive association between BMI and risk of colon cancer in both men and women persisted when we re-stricted the meta-analysis to studies that controlled for physicalactivity. Second,halfof thestudies in thismeta-analysis reliedonself-reported anthropometric measures, which may have led tosomeunderestimation of the trueassociations. The summary RRestimate forthe studies that hadmeasuredweight andheight waslower thanthat forstudies thatreliedon self-reporting.Finally,ina meta-analysis of published studies, it is possible that an ob-served association is the result of publicationbias, because stud-ies with null results tend not to be published. There was anindication of publication bias in the literature relating BMI tocolon cancer risk in women. Nevertheless, the positive associa-tion remained when we controlled for potential unpublishedstudies.

In summary, the results of this meta-analysis showed thatobesity wassignificantly positively associated withcolon cancerrisk in both men and women and with rectal cancer risk in men.The association between obesity and risk of colon cancer wasstronger in men than in women. Moreover, increased BMI wasmore strongly related to risk of colon cancer than to risk of rectalcancer. The mechanisms accounting for the sex and cancer sitedifferences need further investigation. This meta-analysis pro-vides further support to public health efforts aiming to lower theprevalence of overweight and obesity to reduce the incidence of cancer and other chronic diseases (79).

The authors responsibilities were as followsSCL and AW: study con-cept and design, data collection, interpretation of results, critical revision of manuscript, and review of the finalmanuscript; SCL:statistical analyses andwriting of the manuscript. None of the authors had any personal or financialconflicts of interest.

REFERENCES1. ParkinDM, BrayF, FerlayJ, PisaniP. Globalcancerstatistics,2002.CA

Cancer J Clin 2005;55:74108.2. World Cancer Research Fund/American Institute for Cancer Research.

Food,nutrition andthe preventionof cancer:a global perspective.Wash-ington, DC: American Institute for Cancer Research, 1997.

3. Sandhu MS, Dunger DB, Giovannucci EL. Insulin, insulin-like growthfactor-I (IGF-I), IGF binding proteins, their biologic interactions, andcolorectal cancer. J Natl Cancer Inst 2002;94:97280.

FIGURE 4. Relativerisk ofcoloncancerper 10-cm increasein waistcircumference andper 0.1-unit increasein waist-hipratio. Relativerisks arenot adjustedfor BMI.


b y g u e s t o

nD e c em

b er 1 4

,2

0 1

3

a j c n.n


D ownl o a

d e d f r om


9/10

4. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: areview of the evidence. J Nutr 2001;131(suppl):3109S20S.

5. Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000;106:47381.

6. IARC. Weightcontrol andphysicalactivity. IARC handbooksof cancerprevention. In: Vainio H, Bianchini F, eds. Lyon, France: IARC Press,2002.

7. Greenland S, Longnecker MP. Methods for trend estimation from sum-marized dose-response data, with applications to meta-analysis. Am JEpidemiol 1992;135:13019.

8. Orsini N, Bellocco R, Greenland S. Generalized least squares for trendestimation of summarized dose-response data. Stata J 2006;6:4057.

9. Larsson SC,RutegrdJ, BergkvistL, WolkA. Physicalactivity, obesity,and risk of colon and rectal cancer in a cohort of Swedish men. Eur JCancer 2006;42:25907.

10. Terry P,GiovannucciE, BergkvistL, HolmbergL, WolkA. Bodyweightandcolorectal cancer risk in a cohort of Swedish women:relationvariesby age and cancer site. Br J Cancer 2001;85:3469.

11. Otani T, Iwasaki M, Inoue M. Body mass index, body height, andsubsequentrisk of colorectal cancer in middle-aged andelderlyJapanesemen and women: Japan public health center-based prospective study.Cancer Causes Control 2005;16:83950.

12. Kuriyama S, Tsubono Y, Hozawa A, et al. Obesity and risk of cancer inJapan. Int J Cancer 2005;113:148 57.

13. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer inci-dences depending on cancer sites and histologic findings among men:Korea National Health InsuranceCorporation Study. J ClinOncol 2005;23:474254.

14. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control ClinTrials 1986;7:17788.

15. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:153958.

16. EggerM, DaveySmith G,Schneider M,Minder C.Biasin meta-analysisdetected by a simple, graphical test. BMJ 1997;315:62934.

17. DuvalS, Tweedie R.Trimand fill: a simplefunnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics2000;56:45563.

18. Lee IM,Paffenbarger RSJr. Quetelets index andrisk of colon cancerincollege alumni. J Natl Cancer Inst 1992;84:132631.

19. Bostick RM,Potter JD,Kushi LH,et al.Sugar, meat, andfat intake, andnon-dietary risk factors for colon cancer incidence in Iowa women(United States). Cancer Causes Control 1994;5:3852.

20. Chyou PH, Nomura AM, Stemmermann GN. A prospective study of weight, body mass index and other anthropometric measurements inrelation to site-specific cancers. Int J Cancer 1994;57:3137.

21. Thune I, Lund E. Physical activity and risk of colorectal cancer in menand women. Br J Cancer 1996;73:1134 40.

22. Ford ES.Bodymassindexand colon cancer in a national sampleof adultUS men and women. Am J Epidemiol 1999;150:390 8.

23. Singh PN, Fraser GE. Dietary risk factors for colon cancer in a low-risk population. Am J Epidemiol 1998;148:76174.

24. Kaaks R, Toniolo P, Akhmedkhanov A, et al.SerumC-peptide,insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancerrisk in women. J Natl Cancer Inst 2000;92:1592600.

25. Murphy TK, Calle EE, Rodriguez C, Kahn HS, Thun MJ. Body massindex and colon cancer mortality in a large prospective study. Am JEpidemiol 2000;152:84754.

26. Colangelo LA, Gapstur SM, Gann PH, Dyer AR, Liu K. Colorectalcancer mortality and factors related to the insulin resistance syndrome.Cancer Epidemiol Biomarkers Prev 2002;11:38591.

27. Terry PD, Miller AB, Rohan TE. Obesity and colorectal cancer risk inwomen. Gut 2002;51:1914.

28. Shimizu N, Nagata C, Shimizu H, et al. Height, weight, and alcoholconsumption in relation to the risk of colorectal cancer in Japan: aprospective study. Br J Cancer 2003;88:103843.

29. Wei EK, Giovannucci E, Wu K, et al. Comparison of risk factors forcolon and rectal cancer. Int J Cancer 2004;108:43342.

30. Moore LL,BradleeML, SingerMR, et al.BMI andwaistcircumferenceas predictors of lifetime colon cancer risk in Framingham Study adults.Int J Obes Relat Metab Disord 2004;28:559 67.

31. Tamakoshi K, Wakai K, Kojima M, et al. A prospective study of bodysize and colon cancer mortality in Japan: The JACC Study. Int J ObesRelat Metab Disord 2004;28:5518.

32. MacInnis RJ, English DR, Hopper JL, Haydon AM, Gertig DM, Giles

GG. Body size and composition and colon cancer risk in men. CancerEpidemiol Biomarkers Prev 2004;13:5539.

33. LinJ, ZhangSM,CookNR,RexrodeKM,LeeIM,Buring JE.Body massindex and risk of colorectal cancer in women (United States). CancerCauses Control 2004;15:5819.

34. Eichholzer M, Bernasconi F, Jordan P, Stahelin HB. Body mass indexand the risk of male cancer mortality of various sites: 17-year follow-upof the Basel cohort study. Swiss Med Wkly 2005;135:2733.

35. Batty GD, Shipley MJ, Jarrett RJ, Breeze E, Marmot MG, Smith GD.Obesity and overweight in relation to organ-specific cancer mortality inLondon (UK): findings from the original Whitehall study. Int J Obes(Lond) 2005;29:126774.

36. Rapp K, Schroeder J, Klenk J, et al. Obesity and incidence of cancer: alarge cohort study of over 145,000 adults in Austria. Br J Cancer 2005;93:10627.

37. Engeland A, Tretli S, Austad G, Bjrge T. Height and body mass indexin relation to colorectaland gallbladder cancer in twomillion Norwegianmen and women. Cancer Causes Control 2005;16:98796.

38. LukanovaA, Bjor O,KaaksR, et al.Bodymassindexandcancer:resultsfrom the Northern Sweden Health and Disease Cohort. Int J Cancer2006;118:45866.

39. Macinnis RJ, English DR, Hopper JL, Gertig DM, Haydon AM, GilesGG. Body size and composition and colon cancer risk in women. Int JCancer 2006;118:1496500.

40. PischonT, LahmannPH, BoeingH, etal. Body size andriskof colonandrectal cancer in the European Prospective Investigation Into Cancer andNutrition (EPIC). J Natl Cancer Inst 2006;98:92031.

41. Bowers K, Albanes D, Limburg P, et al. A prospective study of anthro-pometric and clinical measurements associated with insulin resistancesyndrome andcolorectal cancer in malesmokers.Am J Epidemiol2006;164:65264.

42. Samanic C,ChowWH,GridleyG, JarvholmB, Fraumeni JF.Relationof body mass index to cancer risk in 362,552 Swedish men. Cancer CausesControl 2006;17:9019.

43. Macinnis RJ, English DR, Haydon AM, Hopper JL, Gertig DM, GilesGG. Body size and composition and risk of rectal cancer (Australia).Cancer Causes Control 2006;17:12917.

44. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Wil-lett WC. Physical activity, obesity, and risk for colon cancer and ade-noma in men. Ann Intern Med 1995;122:32734.

45. Martinez ME, Giovannucci E, Spiegelman D, Hunter DJ, Willett WC,Colditz GA. Leisure-time physical activity, body size, and colon cancerin women. Nurses Health Study Research Group. J Natl Cancer Inst1997;89:94855.

46. Samad AK, Taylor RS, Marshall T, Chapman MA. A meta-analysis of the association of physical activity with reduced risk of colorectal can-cer. Colorectal Dis 2005;7:20413.

47. Stattin P, Lukanova A, Biessy C, et al. Obesity and colon cancer: doesleptin provide a link? Int J Cancer 2004;109:14952.

48. Wei EK, Ma J, Pollak MN, et al. A prospective study of C-peptide,insulin-like growth factor-I, insulin-like growth factor bindingprotein-1, andthe risk of colorectal cancer in women.Cancer EpidemiolBiomarkers Prev 2005a\;14:850-5.

49. Schoen RE, Tangen CM, Kuller LH, et al. Increased blood glucose andinsulin, body size, and incident colorectal cancer. J Natl Cancer Inst1999;91:114754.

50. Ma J, Giovannucci E, Pollak M, et al. A prospective study of plasmaC-peptide and colorectal cancer risk in men. J Natl Cancer Inst 2004;96:54653.

51. Jenab M, Riboli E, Cleveland RJ, et al. Serum C-peptide, IGFBP-1 andIGFBP-2 and risk of colon and rectal cancers in the European Prospec-tiveInvestigationinto CancerandNutrition.Int J Cancer2007;121:36876.

52. Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectalcancer: a meta-analysis. J Natl Cancer Inst 2005;97:1679 87.

53. Wolk K, Larsson SC,Vessby B, Wolk A, Brismar K. Metabolic, anthro-pometric, and nutritional factors as predictors of circulating insulin-likegrowth factor binding protein-1 levels in middle-aged and elderly men.J Clin Endocrinol Metab 2004;89:1879 84.

54. Ma J, Pollak MN, Giovannucci E, et al. Prospective study of colorectalcancerrisk inmenand plasma levels of insulin-like growth factor (IGF)-Iand IGF-binding protein-3. J Natl Cancer Inst 1999a;91:6205.

55. Giovannucci E, Pollak MN, Platz EA, et al. A prospective study of plasma insulin-like growth factor-1 and binding protein-3 and risk of


b y g u e s t o

nD e c em

b er 1 4

,2

0 1

3

a j c n.n


D ownl o a

d e d f r om


10/10

colorectal neoplasia in women. Cancer Epidemiol Biomarkers Prev2000;9:3459.

56. Palmqvist R, Hallmans G, Rinaldi S, et al. Plasma insulin-like growthfactor 1, insulin-like growth factor binding protein 3, and risk of colo-rectal cancer: a prospective study in northern Sweden. Gut 2002;50:6426.

57. Laughlin GA, Barrett-Connor E, May S. Sex-specific association of theandrogen to oestrogenratio withadipocytokinelevels in olderadults:theRancho Bernardo Study. Clin Endocrinol (Oxf) 2006;65:50613.

58. Stattin P, Palmqvist R, Soderberg S, et al. Plasma leptin and colorectalcancer risk: a prospective study in Northern Sweden. Oncol Rep 2003;10:201521.

59. TamakoshiK, ToyoshimaH, WakaiK, et al.Leptin is associated with anincreased female colorectal cancer risk: a nested case-control study inJapan. Oncology 2005;68:45461.

60. Wei EK, Giovannucci E, Fuchs CS, Willett WC, Mantzoros CS. Lowplasma adiponectin levels and risk of colorectal cancer in men: a pro-spective study. J Natl Cancer Inst 2005b;97:168894.

61. Derby CA, Zilber S, Brambilla D, Morales KH, McKinlay JB. Bodymass index,waistcircumferenceand waist to hipratioand changein sexsteroid hormones: the Massachusetts Male Ageing Study. Clin Endocri-nol (Oxf) 2006;65:12531.

62. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sexhormones and the development of type 2 diabetes in older men andwomen: the Rancho Bernardo study. Diabetes Care 2002;25:5560.

63. Muller M, den Tonkelaar I, Thijssen JH, Grobbee DE, van der SchouwYT. Endogenous sex hormones in men aged 4080 years. Eur J Endo-crinol 2003;149:5839.

64. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sexhormones, and breast cancer risk in postmenopausal women. J NatlCancer Inst 2003;95:121826.

65. Bezemer ID, Rinaldi S, Dossus L, et al. C-peptide, IGF-I, sex-steroidhormones and adiposity: a cross-sectional study in healthy womenwithinthe EuropeanProspective Investigation intoCancerandNutrition(EPIC). Cancer Causes Control 2005;16:56172.

66. Marin P, Holmang S, Jonsson L, et al. The effects of testosterone treat-ment on body composition and metabolism in middle-aged obese men.Int J Obes Relat Metab Disord 1992;16:9917.

67. Malkin CJ,Jones TH,Channer KS.The effectof testosterone on insulinsensitivity in men with heart failure. Eur J Heart Fail 2007;9:4450.

68. Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replace-ment therapy improves insulin resistance, glycaemic control, visceral

adiposity and hypercholesterolaemia in hypogonadal men with type 2diabetes. Eur J Endocrinol 2006;154:899906.

69. Simon D, Charles MA, Lahlou N, et al. Androgen therapy improvesinsulin sensitivity and decreases leptin level in healthy adult men withlowplasma totaltestosterone:a 3-month randomized placebo-controlledtrial. Diabetes Care 2001;24:214951.

70. Smith MR, Lee H, Nathan DM. Insulin sensitivity during combinedandrogen blockade for prostate cancer. J Clin Endocrinol Metab 2006;91:13058.

71. Smith JC, Bennett S, Evans LM, et al. The effects of induced hypogo-nadism on arterial stiffness, body composition, and metabolic parame-ters in males with prostate cancer. J Clin Endocrinol Metab 2001;86:42617.

72. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sexhormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006;295:1288 99.

73. BjrneremA, Straume B, MidtbyM, et al.Endogenous sexhormones inrelation to age, sex, lifestyle factors, and chronic diseases in a generalpopulation: theTroms Study.J Clin Endocrinol Metab 2004;89:603947.

74. Chlebowski RT,Wactawski-WendeJ, Ritenbaugh C,et al.Estrogenplusprogestin and colorectal cancer in postmenopausal women. N EnglJ Med 2004;350:9911004.

75. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principalresults from the Womens Health Initiative randomized controlled trial.JAMA 2002;288:32133.

76. Nelson HD,Humphrey LL,NygrenP, TeutschSM,Allan JD.Postmeno-pausal hormone replacement therapy: scientific review. JAMA 2002;288:87281.

77. Houmard JA, Tanner CJ, Slentz CA, Duscha BD, McCartney JS, KrausWE. Effect of the volume and intensity of exercise training on insulinsensitivity. J Appl Physiol 2004;96:1016.

78. Ivy JL. Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus. SportsMed 1997;24:32136.

79. Kushi LH,Byers T, Doyle C,et al.American CancerSocietyGuidelineson Nutrition and Physical Activity for cancer prevention: reducing theriskof cancerwith healthy foodchoicesand physicalactivity.CA CancerJ Clin 2006;56:254 81.


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,2

0 1

3

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D ownl o a

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