association between constipation and colorectal cancer systematic review and meta-analysis of...

8/13/2019 Association Between Constipation and Colorectal Cancer Systematic Review and Meta-Analysis of Observational S

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CLINICAL AND SYSTEMATIC REVIEWS

INTRODUCTION

Symptoms attributable to the lower gastrointestinal (GI) tract

are common in the community (15). Most o these, such as

chronic idiopathic constipation and irritable bowel syndrome,are unctional in nature. It is ofen assumed, despite their relaps-

ing and remitting natural history and adverse impact on health-

related quality o lie (6,7), that these unctional disorders run a

benign course, and do not affect mortality. Data rom two large

longitudinal studies, with a considerable length o ollow-up,

suggest that this is the case or most o these conditions ( 8,9),

but in one o these studies the presence o chronic constipation

at baseline appeared to be associated with a reduced likelihood

o survival (8).

Te reasons or any reduction in survival in chronic constipation

are unclear. Te condition may be associated with the developmento some organic anorectal and colonic pathologies, including rectal

prolapse, hemorrhoids, anal ssure, and diverticular disease, per-

haps due to straining and an increase in colonic transit time (10).

Tis delay in colonic transit has also been proposed, by some, as a

potential etiological mechanism in the development o colorectal

cancer (CRC) (11), due to prolongation o contact between carcin-

ogens in the stool, such as bile acids (12), and the colonic mucosa.

Association Between Constipation and Colorectal

Cancer: Systematic Review and Meta-Analysis ofObservational Studies

Andrew M. Power, BChD, MBChB, MFDS1, Nicholas J. alley, MD, PhD2and Alexander C. Ford, MBChB, MD, FRCP1,3

OBJECTIVES: Constipation is common in the community, and may affect survival adversely. An association

between constipation and development of colorectal cancer (CRC) could be one possible explanation.

We performed a systematic review and meta-analysis examining this issue.

METHODS: We searched MEDLINE, EMBASE, and EMBASE Classic (through July 2012). Eligible studies

were cross-sectional surveys, cohort studies, or casecontrol studies reporting the association

between constipation and CRC. For cross-sectional surveys and cohort studies, we recorded numberof subjects with CRC according to the constipation status, and for casecontrol studies, number of

subjects with constipation according to CRC status were recorded. Study quality was assessed

according to published criteria. Data were pooled using a random effects model, and the association

between CRC and constipation was summarized using an odds ratio (OR) with a 95% confidence

interval (CI).

RESULTS: The search strategy identified 2,282 citations, of which 28 were eligible. In eight cross-sectional

surveys, presence of constipation as the primary indication for colonoscopy was associated with a

lower prevalence of CRC (OR = 0.56; 95% CI 0.360.89). There was a trend toward a reduction in

odds of CRC in constipation in three cohort studies (OR = 0.80; 95% CI 0.611.04). The prevalence

of constipation in CRC was significantly higher than in controls without CRC in 17 casecontrol

studies (OR = 1.68; 95% CI 1.292.18), but with significant heterogeneity, and possible

publication bias.

CONCLUSIONS: Prospective cross-sectional surveys and cohort studies demonstrate no increase in prevalence of

CRC in patients or individuals with constipation. The significant association observed in casecontrol

studies may relate to recall bias.

Am J Gastroenterol2013; 108:894903; doi:10.1038/ajg.2013.52; published online 12 March 2013

1Leeds Gastroenterology Institute, St. Jamess University Hospital, Leeds, UK; 2Faculty of Health, University of Newcastle, New South Wales, Newcastle, Australia;3Leeds Institute of Molecular Medicine, University of Leeds, Leeds, UK. Correspondence: Alexander C. Ford, MBchB, MD, FRCP, Leeds Gastroenterology

Institute, St. Jamess University Hospital, Room 125, 4th Floor, Bexley Wing, Beckett Street, Leeds LS9 7TF, UK. E-mail: [email protected] 18 September 2012; accepted 19 January 2013

CME


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8

Constipation and Colorectal Cancer

I this theory were correct, it may contribute to an excess in mor-

tality in individuals with constipation, compared with those with-

out such symptoms. A meta-analysis o nine casecontrol studies

(13), published in 1993, suggested that this was the case, with a

pooled odds ratio (OR) or CRC in subjects with constipation o

1.48. However, subsequent studies have not all replicated such an

association (1416), and there have been much data published in

the intervening 20 years. We have, thereore, conducted a system-

atic review and meta-analysis o all available observational studies

examining this issue. We hypothesized that CRC is not causally

linked to chronic constipation.

METHODS

Search strategy and study selection

We perormed a literature search using MEDLINE (1946 to July

2012), EMBASE, and EMBASE CLASSIC (1947 to July 2012) to

identiy cross-sectional surveys, cohort studies, or casecontrol

studies that examined the association between constipation andCRC in adults (aged 16 years and over). In order to be eligible,

studies had to recruit at least 50 participants, and dene constipa-

tion using a symptom questionnaire, Rome I, II, or III criteria,

or sel-report at interview. Te diagnosis o CRC could be made

using lower GI endoscopy, barium enema, or computed tomogra-

phy colonography in cross-sectional surveys, and cancer registry

data or medical records in cohort and casecontrol studies. Tese

eligibility criteria, which were dened prospectively, are provided

in Box 1.

Te medical literature was searched using the ollowing terms:

colon cancer, rectal cancer, colorectal cancer, bowel cancer, colon

adj5 cancer, rectal adj5 cancer, colorectal adj5 cancer, bowel adj5cancer, colon adj5 carcinoma, rectal adj5 carcinoma, colorectal adj5

carcinoma, bowel adj5 carcinoma, colon adj5 adenocarcinoma,

rectal adj5 adenocarcinoma, colorectal adj5 adenocarcinoma, or

bowel adj5 adenocarcinoma. Tese were combined using the set

operator AND with studies identied with the terms: constipation,

unctional constipation, idiopathic constipation, chronic constipa-

tion, or slow transit.

Tere were no language restrictions. All abstracts yielded by the

search were then screened or potential suitability, and those that

appeared relevant were retrieved and examined in more detail.

We perormed a recursive search using the bibliographies o all

obtained articles. We translated oreign language articles, where

required. Eligibility assessment was perormed independently bytwo investigators, using pre-designed eligibility orms, with all

disagreements resolved by consensus.

Data extraction

Data were extracted independently by two investigators on to a

Microsof Excel spreadsheet (XP proessional edition; Microsof,

Redmond, WA), again with any discrepancies resolved by con-

sensus. Te ollowing data were collected or all studies: year

conducted, country, number o centers (where applicable), study

setting, type o study design, method o symptom data collection,

method used to conrm the presence or absence o CRC, criteria

used to dene constipation, total number o subjects providing

complete data, the number o subjects with constipation, and the

number o subjects with CRC.For cross-sectional surveys, where all participants were patients

reporting lower GI symptoms, we recorded the number o sub-

jects with CRC among those with constipation as the primary

indication or colonoscopy, compared with the number o subjects

with CRC among those whose primary indication was or other

lower GI symptoms. Several o these studies included patients

who required endoscopic visualization o abnormalities detected

at barium enema, or who were asymptomatic but undergoing ol-

low-up or surveillance or previous colorectal carcinoma, polyps,

or inammatory bowel disease. Tese groups o patients were

always excluded rom our analyses, as they were not relevant to

the clinical question we were addressing. We assessed quality othe identied cross-sectional surveys according to the QUADAS-2

tool, as we were using them as diagnostic studies (17). Tis does

not give an overall quality score, but rather assesses the risk o bias

o individual studies according to various domains. We deemed

high quality studies to be ones that were at low risk o bias across

six or more o these seven domains.

For cohort studies we recorded the number o subjects with CRC

among those with or without constipation, and or casecontrol

studies the number o subjects with constipation among cases with

and controls without CRC. For cohort and casecontrol studies we

assessed study quality using the Newcastle-Ottawa scale (18), with

a total possible score o 9, higher scores indicating higher quality

studies.

Data synthesis and statistical analysis

Te degree o agreement between the two investigators, in terms

o judging study eligibility, was measured using the Kappa statistic.

For cross-sectional surveys the proportion o individuals with and

without constipation as the primary indication or colonoscopy

who were ound to have CRC in each study were compared using

an OR, with a 95% condence interval (CI). For cohort studies,

the proportion o individuals with and without constipation who

were ound to have CRC were compared using an OR, with a 95%

CI. For casecontrol studies the proportion o individuals with

Box 1. Eligibility Criteria

Cross-sectional surveys, cohort studies, or casecontrol studies

Adults (aged 16 years).

Presence of constipation recorded at study inclusion

(using a symptom questionnaire, Rome I, II, or III criteria,

or self-reported).Diagnosis of CRC recorded (after lower GI investigation

(using lower GI endoscopy, barium enema, or CT colonography)

in cross-sectional surveys, or cancer registry data or medical

records in cohort studies or casecontrol studies).

Prevalence of CRC reported according to constipation symptom

status in cross-sectional surveys and cohort studies.

Prevalence of constipation reported according to CRC status in

casecontrol studies.

Sample size of 50 participants.


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constipation status, and the odds o constipation according to

the presence or absence o CRC. StatsDirect version 2.7.2 (Stats-

Direct, Sale, Cheshire, England) was used to generate Forest plots

o pooled ORs with 95% CIs. Evidence o publication bias was

assessed or, by applying Eggers test to unnel plots (21), where a

suffi cient number o studies were available (22).

RESULTS

Te search strategy yielded 2,282 citations (Figure 1), o which

87 potentially relevant articles were retrieved and assessed in

more detail. O these, 28 met our eligibility criteria and were

included. Agreement between reviewers was excellent (Kappa

statistic = 0.77). Tere were eight cross-sectional surveys (2330),

three cohort studies (3133), and 17 casecontrol studies eligible

or inclusion. (14,16,3448) Detailed characteristics o cross-sec-

tional surveys, cohort studies, and casecontrol studies, including

study quality, are provided in Tables 1, 2, and 3respectively. Gen-

der data were reported by six o the casecontrol studies (16,3436,38,40), but only one o the cohort studies (32), and none o the

cross-sectional surveys.

Prevalence of CRC in patients presenting with constipation

in cross-sectional surveys

Te eight cross-sectional surveys contained a total o 8,866 patients

undergoing colonic investigation or lower GI symptoms (2330).

Symptoms were recorded beore investigation in all studies. Five

studies used a questionnaire (2529), with symptoms recorded

by the patient in three studies (2729), and by a physician in the

remaining two studies (25,26). In the other three studies constipa-

tion status was dened according to sel-report (23,24,30). Treeo the studies were higher quality according to the QUADAS-2

tool (Table 1) (26,27,30).

In total, 1,497 (16.9%) patients underwent colonoscopy or

constipation as the primary indication, and 585 (6.6%) patients

were ound to have CRC afer investigation. Tere were 78 (5.2%)

o 1,497 patients with constipation as the primary indication or

colonoscopy who were ound to have CRC, compared with 507

(6.9%) o 7,369 without constipation as the primary indication.

Te pooled OR or CRC in participants with constipation as the

primary indication, compared with those without, was 0.56 (95%

CI 0.36 to 0.89), with no signicant heterogeneity detected between

studies (I2= 34.1%, P= 0.16) (Figure 2). Tere were too ew studies

to assess or publication bias.When only the three higher quality studies, containing a total

o 3,931 patients, were included in the analysis, the OR or CRC

in patients with constipation as the primary indication or colon-

oscopy was 0.57 (95% CI 0.42 to 0.79), with no signicant hetero-

geneity detected between studies (I2= 0%, P= 0.56). When data

rom the ve lower quality studies were pooled, the OR in patients

with constipation as the primary indication or colonoscopy, vs.

those without, was no longer statistically signicant (0.57; 95% CI

0.25 to 1.31), but with signicant heterogeneity between studies

(I2= 58.0%, P= 0.05). Tis difference in ORs was not statistically

signicant (Cochran Q= 0, P= 0.99).

and without CRC who reported constipation were compared,

again using an OR and a 95% CI. I there were no individuals with

or without constipation who were ound to have CRC in a single

study, 0.5 was added to all our cells or the purposes o the analy-

sis, as ORs cannot be calculated rom zero values.

Heterogeneity between studies was assessed using the I2statistic

with a cutoff o 50% (19), and the 2-test with a P value

< 0.10, used to dene a statistically signicant degree o heteroge-

neity. We planned to conduct sensitivity analyses, where suffi cientstudies existed, according to study quality, geographical region,

criteria used to dene constipation, and whether casecontrol

studies tried to minimize recall bias by asking participants to only

report symptoms that had been present or several years beore the

diagnosis o CRC, and to ignore any recent change in bowel habit.

We also perormed a subgroup analysis o the association between

constipation and CRC according to gender, where individual stud-

ies reported these data. We compared the individual ORs between

these subgroups using the Cochran Q statistic.

Data were pooled using a random effects model (20), to give

a more conservative estimate o the odds o CRC according to

Studies identified in literaturesearch (n= 2282)

Excluded (title and abstract revealed notappropriate) (n= 2195)

Excluded (n= 59) because:

Case series = 13

Review article = 12

Prevalence of CRC according toconstipation status not reported = 8

Retrospective surveys = 7

Systematic review = 6

Diagnosis of CRC not reported = 5Prevalence of constipation notreported = 3

Prevalence of colonic adenomaonly = 2

Data not extractable = 2

Case report = 1

Studies retrieved for evaluation

(n= 87)

Studies reporting associationbetween constipation and

colorectal carcinoma(n= 28)

8 Cross-sectionalsurveys

3 Cohort studies

17 Casecontrol studies

Figure 1. Flow diagram of assessment of studies identified in the system-

atic review and meta-analysis.


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Only two studies reported the duration o constipation (24,28),

and in one this was > 3 months (24), and in the other within the

last 3 months (28). Excluding the latter study rom the meta-analy-

sis in a subgroup analysis, due to the relatively short-time rame

o constipation, altered the pooled OR slightly (0.53; 95% CI 0.40to 0.71), but this difference in ORs was not statistically signicant

(Cochran Q= 0.04, P= 0.84).

Prevalence of CRC in individuals with constipation at baseline

in cohort studies

Tere were a total o 189,038 participants in the three cohort

studies (3133), and constipation status was recorded at entry into

the cohort in all three studies. Presence o CRC was conrmed

using cancer registry data in two studies, (32,33) and medical

records o participants in the third (31). Constipation was dened

as less than one stool per day in all three studies. wo o the studies

scored 6 on the Newcastle-Ottawa scale (31,32), and the third

study scored 5 (Table 2) (33).

Tere were 46,068 (24.4%) individuals with constipation at study

entry, and 1,511 (0.8%) subjects developed CRC during ollow-up.

Among those with constipation at baseline, 302 (0.7%) developedCRC, compared with 1,209 (0.85%) o 142,970 without constipa-

tion. Te pooled OR or CRC in participants with constipation,

compared with those without, was lower at 0.80 but this difference

was not statistically signicant (95% CI 0.61 to 1.04), and there

was signicant heterogeneity detected between studies (I2= 74.8%,

P= 0.02). Tere were too ew studies to assess or evidence o pub-

lication bias, or to perorm detailed sensitivity analyses according

to the study characteristics.

However, as all three studies recorded stool requency in

some detail, we were able to conduct a sensitivity analysis using

a requency o one stool every 3 days to dene the presence o

Table 1. Characteristics of included cross-sectional surveys

Study Country

Setting and

number of

centers

Method of collection

of constipation

symptom data

Consecutive

patients Blinding

Number with

constipation

(% with CRC)

Number without

constipation

(% with CRC)

Risk of

bias

Tate and Royle (30) UK Tertiary (1) Self-report Not reported No 16 (0) 114 (12.3) Low

de Bossett et al.(26) Switzerland Secondary (5) Physician-completed

questionnaire

Yes No 73 (1.4) 734 (5.2) Low

Selvachandran et al.

(29)

UK Secondary (1) Patient-completed

questionnaire

Not reported No 290 (1.4) 1,978 (4.6) Unclear

Panzuto et al.(28) Italy Primary (159) Patient-completed

questionnaire

Yes No 134 (15.7) 146 (13.7) Unclear

Bersani et al.(25) Italy Secondary (1) Physician-completed

questionnaire

Yes Yes 201 (1.5) 1,101 (5.7) Unclear

Adler et al.(23) Germany Secondary (39) Self-report Yes No 55 (0) 550 (1.8) Unclear

Bafandeh et al.(24) Iran Tertiary (1) Self-report Yes No 48 (4.2) 432 (3.2) Unclear

Huang et al.(27) China Tertiary (1) Patient-completed

questionnaire

Not reported No 680 (6.9) 2,314 (11.1) Low

CRC, colorectal cancer.

Table 2. Characteristics of included cohort studies

Study Country

Sample

used

Method used

to ascertain

CRC status

Method of

collection of

constipation

symptom

data

Stool frequency

used to define

constipation

Duration of

follow-up

(years)

Number with

constipation

(% with CRC)

Number without

constipation

(% with CRC)

Quality

score

Dukas et al.(31) USA Nurses Review of

medical

records

Questionnaire < 1 Bowel

movement

per day

12 22,684 (0.65) 61,755 (0.75) 6

Kojima et al.(32) Japan Generalpopulation

Cancerregistry data

Questionnaire < 1 Bowelmovement

per day

69 14,115 (0.7) 48,814 (1.1) 6

Watanabe et al.

(33)

Japan General

population

Cancer

registry data

Questionnaire < 1 Bowel

movement

per day

7 9,269 (0.6) 32,401 (0.6) 5

CRC, colorectal cancer.


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Table 3. Characteristics of included case-control studies

Study Country

Setting and

number of

centers

Source of

controls

Method

used to

ascertain

CRC status

Method of

collection of

constipation

symptom data

Threshold

used to

define

constipation

Onset of

constipation

Number with

CRC (% with

constipation)

Number

without CRC

(% with

constipation)

Quality

score

Higginson(34)

USA Secondarycare (7)

Hospitalpatients

Medicalrecords

Interview Occurringmore than

weekly

> 2 Yearsbefore

diagnosis

340 (20.0) 1,020 (16.7) 3

Wynder and

Shigematsu

(35)

USA Secondary

care (4)

Hospital

patients

Medical

records

Interview Mild or more 110 Years

before

diagnosis

793 (34.7) 407 (25.3) 2

Wynder

et al.(36)

Japan Tertiary care (2) Hospital

patients

Medical

records

Interview Occurring

sometimes or

more often

25 Years

before

diagnosis

157 (24.2) 307 (16.6) 2

Haenszel

et al.(37)

Hawaii Secondary care

(3)

Hospital

patients

Medical

records

Interview Not reported Not reported 179 (6.1) 357 (2.5) 2

Jain

et al.(38)

Canada General

population and

secondary

care (19)

General

population

Cancer

registry

data and

medicalrecords

Interview Not reported Not reported 542 (54.8) 542 (45.8) 4

Nakamura

et al.(39)

USA Tertiary care (1) Hospital

patients

and

spouses

Cancer

registry

data

Interview Mild or more > 5 Years

before

diagnosis

100 (30.0) 151 (31.8) 3

Kune

et al.(40)

Australia General

population

(N/A)a

General

population

Medical

records

Interview Not reported Before

diagnosis

685 (31.4) 723 (26.4) 3

Kotake

et al.(41)

Japan Tertiary care

(10)

Hospital

patients

Medical

records

Questionnaire No bowel

movement

for 3 days or

more

Not reported 363 (29.5) 363 (19.6) 2

Yang

et al.(42)

China Secondary care

(Multiple)

General

population

Medical

records

Medical

records

Not reported > 3 Years

beforediagnosis

1,328 (14.9) 1,451 (9.1) 1

Jacobs and

White (16)

USA General

population

(N/A)a

General

population

Cancer

registry

data

Interview Occurring

more than

never

Over last

10 years

424 (44.1) 414 (33.8) 5

Nascimbeni

et al.(43)

Italy Tertiary care (1) Hospital

patients

Medical

records

Questionnaire Rome I

criteria

For at least

3 years

55 (30.9) 96 (18.8) 3

Roberts

et al.(44)

USA General

population

(N/A)a

General

population

Cancer

registry

data

Interview < 3 stools

per week

Not reported 643 (7.3) 1,048 (2.9) 3

Hamilton

et al.(45)

UK General

population (21)

General

population

Cancer

registry

data

Medical

records

Not reported Not reported 349 (26.1) 1,744 (14.8) 6

Hamilton

et al.(46)

UK Primary

care (317)

Primary

carepatients

Medical

records

Medical

records

Not reported Not reported 5,477 (27.0) 38,314

(10.6)

3

Promthet

et al.(47)

Thailand Secondary

care (2)

Hospital

patients

Medical

records

Interview Occurring

occasionally

or more

1 Year

before diag-

nosis

130 (59.2) 130 (28.5) 3

Simons

et al.(14)

Holland General

population

(N/A)a

General

population

Cancer

registry

data

Questionnaire Occurring

sometimes or

more often

Not reported 1,207 (9.9) 1,753 (12.1) 3

Tashiro

et al.(48)

Japan Secondary

care (8)

General

population

Medical

records

Interview Not reported 1 Year

before diag-

nosis

212 (21.7) 790 (16.5) 5

CRC, colorectal cancer.aNot applicable: population-based casecontrol study.


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constipation. Using this threshold, 10,035 (5.3%) subjects had

constipation at study entry, o whom 69 (0.7%) developed CRC,

compared with 1,442 (0.8%) o 179,003 without constipation. Te

pooled OR increased slightly (0.90; 95% CI 0.70 to 1.15), but the

heterogeneity previously observed disappeared altogether (I2= 0%,

P= 0.59). Tis difference in ORs was not statistically signicant

(Cochran Q= 0.40, P= 0.53).

Prevalence of constipation in patients with CRC in

casecontrol studies

Te 17 casecontrol studies included a total o 62,594 subjects

(14,16,3448) 12,984 (20.7%) o whom were cases with CRC and

49,610 controls without. Presence o CRC was conrmed using the

medical records o participants in 11 studies (3437,4043,4648),

cancer registry data in ve studies (14,16,39,44,45) and a combina-

tion o both in the remaining study (38). Only our studies scored

4 or more on the Newcastle-Ottawa scale (Table 3) (16,38,45,48).

Tere were a total o 9,199 (14.7%) participants who were classi-

ed as having constipation. In total, 3,300 (25.4%) o 12,984 cases

with CRC reported constipation, compared with 5,899 (11.9%) o

49,610 controls without CRC. Te pooled OR or constipation in

cases with CRC was 1.68 (95% CI 1.29 to 2.18), but with signicant

heterogeneity between studies (I2= 93.8%, P < 0.001) (Figure 3).Tere was evidence o unnel plot asymmetry (Egger test, P= 0.005),

or other small study effects, with a lack o smaller studies show-

ing no difference in odds o constipation in cases with CRC com-

pared with controls without. When data rom the six studies that

reported the association between CRC and constipation according

to gender were pooled, the OR or constipation in males with CRC

was 1.58 (95% CI 1.34 to 1.87), compared with 1.25 (95% CI 1.04

to 1.52) in emales with CRC. Tis difference in ORs approached

statistical signicance (Cochran Q= 3.31, P= 0.07).

When only the our studies that scored our or more on the

Newcastle-Ottawa scale were included in the analysis (16,38,45,48),

the signicant association between constipation and CRC persisted

(OR 1.60; 95% CI 1.35 to 1.89), with no heterogeneity between

studies (I2= 29.1%, P= 0.24). In the 13 lower quality studies, the

pooled OR was similar (1.71; 95% CI 1.23 to 2.39), but hetero-

geneity between studies remained (I2= 94.7%, P< 0.001). Tis di-

erence in ORs was not statistically signicant (Cochran Q= 0.12,

P= 0.73).

Tere were 11 studies conducted in Western populations

(14,16,34,35,3840,4346), and six studies that recruited cases

and controls rom Eastern populations (36,37,41,42,47,48).When only Western studies were included in the analysis the OR

was 1.56 (95% CI 1.09 to 2.22), and the heterogeneity observed

persisted (I2= 95.8%, P < 0.001). When data rom Eastern stud-

ies were pooled the OR was 1.80 (95% CI 1.55 to 2.10), but the

observed heterogeneity was only borderline statistically signicant

(I2= 48.6%, P= 0.08). Again, this difference in ORs was not statisti-

cally signicant (Cochran Q= 0.53, P= 0.47).

Nine studies stated specically that they asked participants to

only report symptoms that had been present or several years

beore the diagnosis o CRC, and to ignore any recent change in

bowel habit (16,3436,39,42,43,47,48). In these studies the pooled

OR or constipation in CRC was 1.59 (95% CI 1.32 to 1.90),

again with borderline signicant heterogeneity between studies(I2= 54.0%, P= 0.03). In the eight studies that did not report this

inormation (14,37,38,40,41,4446), the pooled OR was higher

(1.76; 95% CI 1.14 to 2.72), with signicant heterogeneity between

studies (I2= 96.4%, P< 0.001). Once again, this difference in ORs

was not statistically signicant (Cochran Q= 0.18, P= 0.67).

DISCUSSION

Tis systematic review and meta-analysis has assembled data

rom all identied published observational studies examining

the association between constipation and CRC in adults. In eight

Odds ratio meta-analysis plot (random effects)

0.001 0.01 0.1 0.2 0.5 1 2 5 10

Huang et al., 2010 0.594 (0.421, 0.825)

Bafandeh et al., 2008 1.298 (0.139, 5.930)

Adler et al., 2007 0.464 (0.000, 3.959)

Bersani et al., 2005 0.250 (0.050, 0.777)

Panzuto et al., 2003 1.171 (0.571, 2.406)

Selvachandran et al., 2002 0.290 (0.077, 0.778)

de bossett et al., 2002 0.254 (0.006, 1.556)

Tate and Royle, 1988 0.210 (0.000, 1.841)

Combined (random) 0.563 (0.358, 0.885)

Odds ratio (95% Confidence interval)

Figure 2. Odds ratio for colorectal cancer in patients with constipation vs. patients without in cross-sectional surveys.


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discrepancies resolved by consensus. Te quality o each study was

assessed according to published criteria (17,18). Data were pooled

using a random effects model, in order to give a more conserva-tive estimate o the odds o CRC according to constipation status

in cross-sectional surveys and cohort studies, and the odds o

constipation according to the presence or absence o CRC in case

control studies. Tere was no signicant heterogeneity observed

when the results o cross-sectional surveys were combined, but

heterogeneity was observed among cohort studies and case-con-

trol studies. However, the use o sensitivity analyses allowed us to

explore potential reasons or the observed heterogeneity, and in

some cases this disappeared. Where possible, we also assessed or

evidence o publication bias, or other small study effects, by testing

unnel plots or obvious asymmetry.

As with any systematic review and meta-analysis, limitations

include the quality o the eligible studies, as well as the reportingo data within them. Te majority o the cross-sectional surveys

identied, while large in several cases, were o lower quality when

assessed using the QUADAS-2 tool. However, when only low-risk

o bias studies were considered in the analysis the summary esti-

mate was identical to that or unclear risk o bias studies. While the

cohort studies were o higher quality, with all scoring 5 or more

o a possible 9 on the Newcastle-Ottawa scale, the casecontrol

studies we identied scored poorly, with only our o the seventeen

casecontrol studies scoring over 4. It should be remembered that

there is no recommended threshold in use to dene higher quality

studies, but the consistently low scores among casecontrol studies

cross-sectional surveys, the presence o constipation as the pri-

mary indication or colonoscopy was associated with a signi-

cantly lower prevalence o CRC, with a 44% reduction in oddso CRC among patients with constipation according to either

sel-report or a questionnaire, and no signicant heterogeneity

detected between studies. Te data rom the three cohort stud-

ies demonstrated a non-signicant trend towards a lower OR

or development o CRC in individuals reporting constipation at

baseline, dened as less than one stool per day, with signicant

heterogeneity detected between studies. Tis heterogeneity disap-

peared altogether when the denition o constipation was changed

to a requency o one stool every 3 days. In contrast, when data

were pooled rom the 17 casecontrol studies, the prevalence o

constipation in patients with CRC was signicantly higher than

in controls without CRC, but again with signicant heterogene-

ity detected between studies, and possible publication bias. Whensensitivity analyses were conducted, the OR or constipation in

CRC remained signicantly higher in all analyses, and heteroge-

neity was reduced when only high quality studies or those con-

ducted in the East were considered.

Tere are several strengths o this study. We carried out a com-

prehensive and contemporaneous literature search that identied

suffi cient studies to allow the pooling o data rom over 250,000

recruited subjects. Tis was augmented by hand-searching o the

bibliographies o retrieved articles, and one oreign language paper

was translated. Te judging o study eligibility and data extrac-

tion were carried out independently by two investigators, with

Odds ratio meta-analysis plot (random effects)

0.5 1 2 5 10

Tashiro et al., 2011 1.41 (0.94, 2.08)

Simons et al., 2010 0.80 (0.62, 1.01)Promthet

et al

., 2010 3.65 (2.11, 6.34)

Hamilton et al., 2009 3.12 (2.92, 3.34)

Hamilton et al., 2005 2.03 (1.53, 2.69)

Roberts et al., 2003 2.68 (1.64, 4.43)

Nascimbeni et al., 2002 1.94 (0.83, 4.48)

Jacobs and White, 1998 1.54 (1.16, 2.06)

Yang et al., 1995 1.75 (1.38, 2.23)

Kotake et al., 1995 1.72 (1.20, 2.46)

Kune et al., 1988 1.27 (1.00, 1.62)

Nakamura et al., 1984 0.92 (0.51, 1.64)

Jain et al., 1980 1.44 (1.12, 1.84)

Haenszel et al., 1973 2.53 (0.93, 7.04)

Wynder et al., 1967b 1.60 (0.97, 2.64)

Wynder and Shigemastu, 1967a 1.57 (1.19, 2.07)

Higginson, 1966 1.25 (0.90, 1.72)

Combined (random) 1.68 (1.29, 2.18)

Odds ratio (95% Confidence interval)

Figure 3. Odds ratio for constipation in cases with colorectal cancer vs. controls without in casecontrol studies.


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9


is o concern. Tere was also considerable heterogeneity between

casecontrol studies in many o the analyses conducted. Te rea-

sons or this remain speculative, but may relate to variations in the

denition o constipation used, methods o acquiring data, demo-

graphic characteristics o recruited individuals, which were not

reported in the majority o studies, or cultural differences.

Te distinction between chronic and acute/new-onset constipation

is very important, as this could be the maniestation o mechanical

bowel obstruction resulting rom CRC. We sought out this inor-

mation or each study and described it where reported. Nine o the

casecontrol studies specically stated that they asked participants to

ignore any recent change in bowel habit (16,3436,39,42,43,47,48),

allowing us to pool data in a subgroup analysis according to this study

characteristic, but none o the cohort studies reported this inorma-

tion. Tis is probably less relevant or the cohort studies, as they were

prospective, and ollowed up individuals who reported constipation

at baseline or a long duration (anywhere rom 6 to > 10 years), in

order to detect new cases o CRC. For the cross-sectional surveys

only two studies reported the duration o constipation (24,28), andin one this was > 3 months (24), and in the other constipation had

occurred within the last 3 months (28), precluding any meaningul

pooling o data according to symptom duration.

A nal limitation is that we calculated ORs using raw data

reported by the studies, rather than pooling adjusted ORs as

reported by the individual studies, which would have been adjusted

or some potential underlying differences between study partici-

pants. However, as the majority o studies were not conducted with

the primary aim o studying the relationship between constipation

and CRC, very ew reported adjusted summary statistics, and those

that did ailed to use ORs in all cases, meaning that pooling o these

data would not have been possible. As a result o this, there may beresidual conounding issues that explain our ndings. For instance

it may be that patients with constipation are more likely to undergo

colonoscopy, and this is the reason or the negative association

between constipation and CRC seen in cross-sectional surveys.

However, given that the comparator in these studies was patients

with other lower GI symptoms, rather than asymptomatic healthy

individuals we eel this explanation is unlikely. In act, the largest

o the cross-sectional surveys that showed a signicant negative

association between constipation and CRC, and which accounted

or 60% o the weight o the meta-analysis, specically stated that

patients were undergoing colonoscopy or the rst time (27).

Tere have been several previous systematic reviews examining

the association between lower GI symptoms and CRC (13,4953),although none o these have reported exclusively on constipation

alone as a possible risk actor or CRC, and one did not study this

issue at all (49). Te earliest o these, published by Sonnenberg and

Muller (13) in 1993, identied nine casecontrol studies reporting

on the prevalence o constipation in patients with CRC, and

demonstrated a signicant association between the two, with

an OR o similar magnitude to the one we observed. In 2003,

Chen et al.(53) also examined this issue , but restricted their analy-

sis to our casecontrol studies conducted in China. Te pooled

OR was 2.23 in this study, higher than that observed in either the

present study or that by Sonnenberg et al.(13).

More recently, Jellema et al.(52) summarized data rom 47 stud-

ies that reported the accuracy o lower GI symptoms, blood tests,

and ecal occult blood testing in predicting CRC in primary or sec-

ondary care . Tere were only our studies identied that reported

on the diagnostic accuracy o constipation, and sensitivity ranged

rom 0% to 51%, and specicity rom 53% to 90%. Te authors

concluded that the diagnostic perormance o constipation in pre-

dicting CRC was poor. In a meta-analysis o observational studies

that examined the diagnostic accuracy o lower GI symptoms only

(50), constipation was not associated with the presence o CRC,

with a positive likelihood ratio o 1.1, although the number o stud-

ies providing data or this analysis was not reported. Finally, Astin

et al.(51) perormed a systematic review o studies conducted in

primary care, identiying only three that reported on the associa-

tion between constipation and CRC , with positive and negative

likelihood ratios o 1.74 and 0.84 respectively.

In our systematic review and meta-analysis we were deliberately

inclusive, and analyzed data rom cross-sectional surveys, cohort

studies, or casecontrol studies conducted in the general popula-tion and primary, secondary, or tertiary care. When data rom the

cohort studies were pooled, the presence o constipation at base-

line was not associated with the development o CRC afer 6 to 12

years o ollow-up. Te nding that constipation was commoner

in cases with CRC, compared with controls without, is in keeping

with the two aorementioned meta-analyses o casecontrol stud-

ies (13,53). It has been postulated that this signicant association is

due to reverse causation, because CRC leads to the development o

constipation, precipitating presentation to a physician (10). How-

ever, data rom the cross-sectional surveys we identied indicate

that this is not the case, with the presence o constipation as the

primary indication or colonoscopy being negatively associatedwith an ultimate diagnosis o CRC ollowing complete lower GI

investigation.

We would, thereore, propose that the signicant association

observed in casecontrol studies relates to a combination o poor

study quality, publication bias, and recall bias among participants.

Only 9 o the 17 provided inormation about the duration o symp-

toms relative to when the diagnosis o CRC was made, and the OR

was slightly lower when data rom these studies were pooled. Our

results, thereore, suggest that constipation alone does not warrant

lower GI investigation unless other alarm symptoms or signs are

present, although these also perorm poorly in predicting a diagno-

sis o CRC (49). Despite the act that constipation is not recognized

as an alarm eature, according to current guidelines or the detec-tion o suspected cancer (54), physicians continue to reer con-

stipated patients or lower GI examination to rule out CRC as an

underlying cause. Hopeully the data rom this systematic review

and meta-analysis will lead to an alteration in such behavior.

In conclusion, data rom this systematic review and meta-analy-

sis demonstrate that in cohort studies constipation is not associ-

ated with the development o CRC. In addition, when patients

are colonoscoped with constipation as the primary indication,

a diagnosis o CRC is less likely than in patients being colono-

scoped or other lower GI symptoms as the primary indication.

Te association between constipation and CRC observed in


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REVIEW

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casecontrol studies is likely to be due to a combination o poor

study quality and recall bias among participants. Te use o inva-

sive lower GI investigations to exclude CRC in patients presenting

with constipation, in the absence o other alarm eatures, should be

discouraged.

CONFLICT OF INTEREST

Guarantor of the article: Alexander C. Ford, MBChB, MD, FRCP.

Specic author contributions:N.J.. and A.C.F.: conceived and

drafed the study. A.M.P. and A.C.F.: collected all data. A.C.F.: ana-

lyzed and interpreted the data. A.C.F. and A.M.P.: drafed the man-

uscript. All authors commented on drafs o the paper. All authors

have approved the nal draf o the manuscript.

Financial support:Dr Fords time was reimbursed by an investiga-

tor-initiated grant rom Almirall. Almirall had no input into the

study conduct or design.

Potential competing interests: None.

ACKNOWLEDGMENTSWe thank Dr Cathy Yuhong Yuan or assisting us with the transla-

tion o oreign language articles.

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