Colonoscopy Reduces Colorectal Cancer Incidence and Mortality in Patients With Non-Malignant Findings: A Meta-Analysis
Official journal of the American College of Gastroenterology
Colonoscopy Reduces Colorectal Cancer Incidence and Mortality in Patients With Non-Malignant Findings: A Meta-Analysis
Jun Pan 1
Lei Xin 1
Yi-Fei Ma 0
Liang-Hao Hu 1
Zhao-Shen Li 1
0 Department of Surgery , or Zhao-Shen Li, MD , Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Second Military Medical University , 168 Changhai Road, Shanghai 200433 , China
1 Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Second Military Medical University , Shanghai , China
Observational studies have shown that colonoscopy reduces colorectal cancer (CRC) incidence and mortality in the general population. We aimed to conduct a meta-analysis quantifying the magnitude of protection by colonoscopy, with screening and diagnostic indications, against CRC in patients with non-malignant findings and demonstrating the potentially more marked effect of screening over diagnostic colonoscopy. PubMed, EMBASE, and conference abstracts were searched through 30 April 2015. The primary outcomes were overall CRC incidence and mortality. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effect models. Eleven observational studies with a total of 1,499,521 individuals were included. Pooled analysis showed that colonoscopy was associated with a 61% RR reduction in CRC incidence (RR: 0.39; 95% CI: 0.26-0.60; I2=93.6%) and a 61% reduction in CRC mortality (RR: 0.39; 95% CI: 0.350.43; I2=12.0%) in patients with non-malignant findings, although there was high heterogeneity for the outcome of CRC incidence. After excluding one outlier study, there was low heterogeneity for the outcome of incidence (I2=44.7%). Subgroup analysis showed that the effect of screening colonoscopy was more prominent, corresponding to an 89% reduction in CRC incidence (RR: 0.11; 95% CI: 0.08-0.15), in comparison with settings involving diagnostic colonoscopy (RR: 0.51; 95% CI: 0.43-0.59; P<0.001).
Colorectal cancer (CRC) is the third most common cancer and
the fourth leading cause of cancer-related death throughout the
). By means of detection and subsequent resection of
precancerous lesions and early-stage CRCs, screening is effective in
reducing CRC incidence and mortality, which has already been
demonstrated in trials with fecal occult blood test (
flexible sigmoidoscopy (
). Evidence for the effectiveness of
colonoscopy screening in average-risk general population, however, is
still limited as related large-scale randomized trials are still
Since 2009, mounting evidence from observational studies has
shown that colonoscopy screening is associated with reductions
in both CRC incidence and mortality (
colonoscopy screening programs have not been implemented in many
European countries (
) and most of the Asia-Pacific region
); even the colonoscopy screening rates in the United States and
Germany, where screening programs were introduced early this
century, were only 54% by 2013 (
) and ~20–30% by 2012 (
respectively. A great number of studies from the real-world settings
in which indications for colonoscopy included both screening and
diagnostic also supported the protective effect of colonoscopy in
W the general population (
IE Two previous meta-analyses found significant reductions in
EV CRC mortality (and incidence) after (screening) colonoscopy
), but the generalizability of the findings in the general
population is less than ideal due to the heterogeneity of the baseline
population, as subjects with malignant findings were enrolled in
some included studies but not in others. Ranging from negative
findings, hyperplastic polyps, adenomas to serrated lesions,
nonmalignant findings at the index colonoscopy, which constitutes
over 90% of the yield of colonoscopy in clinical practice (
differ with malignant findings in the following aspects:
non-malignant nature, mostly non-surgical treatment, longer surveillance
interval, and better prognosis (
). We therefore aim to
evaluate the magnitude of protection against CRC by colonoscopy, with
screening and diagnostic indications, in patients with
non-malignant findings and further determine the potentially more marked
effect of screening over diagnostic colonoscopy in the magnitude
of reductions in CRC incidence and mortality.
Th e meta-analysis was performed according to MOOSE
statement (MOOSE Checklist is available in Supplementary
Appendix A online) (
). A comprehensive, computerized
literature search was conducted in PubMed and EMBASE from
the beginning of indexing for each database to 30 April 2015 by
two reviewers (J.P. and L.X.) independently, with no restrictions
in language. The search for relevant studies was performed using
the following text words and corresponding Medical Subject
Heading/Emtree terms: “colonoscopy or endoscopy” AND
“colorectal, colon, rectum, or large bowel” AND “cancer, carcinoma,
neoplasm, tumo(u)r, or adenocarcinoma” AND “relative risk(s),
odds ratio(s), rate ratio(s), risk ratio(s), or hazard ratio(s)” AND
“cohort, or case–control” (detailed search strategy is available in
Supplementary Appendix B). Abstracts from Digestive Disease
Week (DDW) and United European Gastroenterology Week
(UEGW) were searched manually. In addition, we searched for
additional studies in reference lists of identified articles.
Th ree reviewers (J.P., L.X., and Y.-F.M.) independently evaluated
all of the studies retrieved according to the eligibility criteria.
Disagreements were resolved by consensus. Studies were included if
they met all of the following criteria: (i) studies from which effect
estimates assessing the effect of colonoscopy on CRC incidence
and/or mortality in patients with non-malignant findings vs.
no colonoscopy were extractable (patients with non-malignant
findings were defined as a consecutive collection of both cases
detected with non-malignant polyps and those with negative
findings at the index colonoscopy; the index colonoscopy was defined
as the initial colonoscopy performed during the study period for
either screening or diagnostic purpose); (ii) all of the participants
with and without the exposure to colonoscopy are from the same
population source; (iii) all of the participants had no history of
CRC; (iv) all (or the vast majority) of the participants had no
history of inflammatory bowel disease and no family history of
hereditary non-polyposis colorectal cancer, familial adenomatous
polyposis, or sporadic CRC; (v) effect estimates and the
corresponding 95% confidence intervals (CIs) were adjusted for age at
least; and (vi) studies with an observational design (prospective
cohort, retrospective cohort, or case–control studies). For studies
with multiple publications from the same population source, only
data from the most recent publication was included.
Data extraction and quality assessment
Two reviewers (J.P. and L.X.) extracted the data independently,
and disagreements were resolved by consensus. The following
data were extracted from each study: first author, publication
year, indications for index colonoscopy, study design, setting,
study period, number of participants, age at baseline, sex,
duration of follow-up, effect estimates with 95% CIs, and
adjustments. For studies with several multivariable-adjusted estimates,
we extracted those reflecting the greatest degree of control for
potential confounders. The primary outcomes were overall CRC
incidence and mortality; the secondary outcomes were CRC
incidence and mortality according to indications for colonoscopy, site
of cancer, sex, and study design. The study quality was assessed
using the Newcastle–Ottawa Scale (
), and the studies awarded
seven or more stars were considered of high quality.
Th e measure of effect of interest was the relative risk (RR). Odds
ratio, rate ratio, risk ratio, or hazard ratio yielded similar
estimates of RR (
). Study-specific RR estimates were combined
using a random-effects model, which considers both within- and
between-study variation (
). Statistical heterogeneity among
studies was evaluated by I2 and Q statistics (
). Studies with an I2
of <25%, 25–50%, 50–75%, and >75% were considered to have no,
low, moderate, and high heterogeneity, respectively. An I2 of >50%
indicated significant heterogeneity (
). Sensitivity analysis was
performed to evaluate the robustness of results, in which pooled
estimates were computed omitting one study in each turn (
Subgroup analysis was performed by indications for colonoscopy,
site of cancer, sex, and study design. We compared the pooled
RR estimates from different subgroups with a test of interaction
). Publication bias was evaluated by Begg’s test and Egger’s test
). All statistical analyses were performed with Stata
software, version 12.0 (Stata Corp, College Station, TX). P<0.05 was
considered statistically significant.
PubMed and EMBASE were searched for relevant studies. As
shown in Figure 1, a total of 1,247 studies met our search strategy.
Potential articles identified through literature search
PubMed (n = 863)
EMBASE (n = 656)
Duplicates removed (n = 272)
Potential articles included in meta-analysis (n = 1247)
Potential articles and conference abstracts included for more detailed assessment (n = 28)
Excluded after title/abstract review (n = 1227)
Potential articles included from reference review (n = 3)
Potential abstracts included from DDW and UEGW (n = 5)
Articles excluded (n = 17)
Baseline population above average-risk (n = 1)
Not all polyps removed (n = 1)
Effect estimates of interest not reported (n = 5)
Effect estimates of interest not adjusted (n = 1)
Different definition of outcome (n = 1)
Same data source (n = 8)
Articles included (n = 11)
After title/abstract review, we excluded 1,227 studies; after
including 3 studies from reference review and 5 abstracts from DDW
and UEGW, 28 studies remained. Another 17 studies were further
excluded for reasons listed as follows: baseline population above
average risk (n=1) (
), not all polyps removed (n=1) (
estimates of interest not reported (n=5) (
), effect estimates
of interest not adjusted (n=1) (
), different definition of outcome
), and same data source (n=8) (
). Finally, 11
studies were included in the meta-analysis (
Study characteristics and quality assessment
Details of the 11 included studies are listed in Table 1. Of the
11 observational studies, 5 were cohort studies (
) and 2 retrospective (
)) and 6 were
case–control studies (
). A total of 1,499,521
individuals were included, in which 1 study enrolled over 1,000,000
), 7 studies enrolled 10,000–100,000 individuals
), and the other 3 enrolled <10,000
individuals each (
). Duration of follow-up for cohort
studies (or corresponding duration from exposure of colonoscopy
to CRC occurrence/death for case–control studies) varied, with
three studies of over 10 years (
), seven studies of 5–10
), and one study of <5 years (
). Six studies
reported CRC incidence only (
), four reported
CRC mortality only (
), and one reported both CRC
incidence and mortality (
). Indication(s) for index colonoscopy
varied among studies, with screening in three studies (
screening/diagnostic in five (
), and diagnostic in
). Eight studies were conducted in North America
), and three in Europe (
). In each of
the 11 studies, colonoscopy at baseline (combination of
polypectomy with removal of all detected lesions and negative
colonoscopy) was compared with no colonoscopy.
Ef ect estimate of the study by Brenner et al. (
) was extracted
from authors’ reply letter in which a widely accepted definition of
screening exposure was adopted (
). One study by Müller and
Sonnenberg (64) separately reported effect estimates for colon and
rectal cancer, and we included the combined RR by pooling the
two estimates using a random-effect model.
Strategies for excluding CRC cases to form the group of patients
with non-malignant findings at the index colonoscopy varied
among studies: two studies excluded CRC cases diagnosed at the
index colonoscopy (
), four studies excluded CRC cases
diagnosed at or within 6 months (exclusion window) of the index
), one study used a longer exclusion window
of 12 months (
), three studies used variable exclusion windows
ranging from 0 to 24 or 36 months (
), and one study used
a variable exclusion window ranging from 0 to 60 months (
Results for study quality assessment are also shown in Table 1
(for details see Supplementary Appendices C and D). Six out of
the 11 studies were awarded seven or more stars, indicating high
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Seven studies were included for outcome of overall CRC incidence.
Pooling by a random-effect model (Figure 2) yielded a pooled RR
of 0.39 (95% CI: 0.26–0.60), corresponding to a 61% RR reduction
in CRC incidence after colonoscopy in patients with
non-malignant findings. There was evidence of high heterogeneity among
studies (I2=93.6%, P<0.001). Sensitivity analysis revealed that the
study by Brenner et al. (
) substantially influenced pooled RR.
After excluding this study, there was evidence of low heterogeneity
(I2=44.7%, P=0.11), and pooled RR was 0.51 (95% CI: 0.43–0.59).
Funnel plot asymmetry test for publication bias was negative using
both Begg’s test (P=0.07) and Egger’s test (P=0.43).
Five studies were included for outcome of overall CRC mortality.
Pooling by a random-effect model (Figure 3) yielded a pooled RR
of 0.39 (95% CI: 0.35–0.43), corresponding to a 61% RR reduction
in CRC mortality after colonoscopy in patients with non-malignant
findings. There was no evidence of heterogeneity among studies
(I2=12.0%, P=0.34). Sensitivity analysis further confirmed the
robustness of our findings. Funnel plot asymmetry test for publication bias
was negative using both Begg’s test (P=0.22) and Egger’s test (P=0.35).
Subgroup analyses were conducted for the following secondary
outcomes of CRC incidence (Table 2). As for indications,
screening colonoscopy was associated with greater protection (RR: 0.11;
95% CI: 0.08–0.15) than screening/diagnostic and diagnostic
colonoscopies (RR: 0.51; 95% CI: 0.43–0.59; Pinteraction<0.001). As
for site of cancer, colonoscopy was associated with a 28%
nonstatistically significant reduction in proximal CRC incidence (RR:
0.72; 95% CI: 0.50–1.03), whereas protection against distal CRC
(RR: 0.32; 95% CI: 0.20–0.50) was much stronger (Pinteraction=0.01).
As for sex, results were similar for studies in men (RR: 0.55;
95% CI: 0.47–0.64) and women (RR: 0.56; 95% CI: 0.47–0.66;
Pinteraction=0.88). As for study design, results were also similar for
cohort (RR: 0.47; 95% CI: 0.34–0.65) and case–control studies
(RR: 0.35; 95% CI: 0.16–0.77; Pinteraction=0.50).
Subgroup analyses were conducted for the following outcomes
of CRC mortality (Table 3). As for indications, screening
colonoscopy was associated with somewhat greater protection (RR:
0.36; 95% CI: 0.29–0.46) than screening/diagnostic and
diagnostic colonoscopies (RR: 0.40; 95% CI: 0.32–0.49), but the difference
between subgroups was not statistically significant (Pinteraction=0.51).
As for the site of cancer, colonoscopy was associated with less
protection against proximal CRC mortality (RR: 0.57; 95% CI:
0.52–0.63) than distal CRC (RR: 0.18; 95% CI: 0.11–0.31;
Pinteraction<0.001). As for sex, colonoscopy provided a similar magnitude
of protection for men (RR: 0.36; 95% CI: 0.32–0.40) and women
(RR: 0.23; 95% CI: 0.10–0.54; Pinteraction=0.30). As for study design,
results were similar in the cohort (RR: 0.34; 95% CI: 0.26–0.45) and
case–control studies (RR: 0.40; 95% CI: 0.37–0.43; Pinteraction=0.26).
Th is meta-analysis shows that CRC incidence and mortality in
patients with non-malignant findings were both 61% lower after
colonoscopy. The protective effect was more prominent after screening
colonoscopy, corresponding to an 89% reduction in CRC incidence.
Interpretations of study findings
Our study is the first meta-analysis to quantify the magnitude of
protection against CRC that patients with non-malignant
findings benefit from colonoscopy. When interpreting the study
results, both the overall effect of colonoscopy and the individual
Eldridge et al. (2013)
Nishihara et al. (2013)
CI, confidence interval; CRC, colorectal cancer; NA, not available; RR, relative risk.
effect of screening colonoscopy derived from subgroup analysis
are informative. As regular colonoscopy screening has not been
implemented even in many developed countries (
primary outcome, which estimated the benefit derived from both
screening and diagnostic colonoscopies, reflected the effect of
regular colonoscopy in routine clinical practice. Subgroup analysis of
screening colonoscopy provides data on the maximum cases of
CRCs and CRC-related deaths that may be prevented in patients
with non-malignant findings by population-based screening
programs in standardized conditions, which is more important from
a public health perspective.
Th ere are several explanations for our findings. First, removal of
all detected polyps (i.e., clearing colonoscopy) is the main modality
responsible for the decreased CRC risk (
), while individuals with
negative findings are inherently associated with lower risks of
developing CRC even compared with postpolypectomy individuals (71).
Second, interval CRCs could hardly be avoided because of factors such
as missed lesions at the index colonoscopy, rapid growth of specific type
of neoplasms, and incomplete resection of polyps (
). Therefore, both
the aspects should be considered when interpreting the study findings.
In subgroup analysis, our study showed more prominent
protection against CRC incidence by screening colonoscopy than
colonoscopy with indications of screening/diagnostic and diagnostic
(Pinteraction<0.001), and, similar tendency was observed for CRC
mortality (RR: 0.36 (0.29–0.46) vs. 0.40 (0.32–0.49); Pinteraction=0.51),
as screening detects a different spectrum of findings (e.g., fewer
polyps) compared with that diagnosed in the symptomatic
). Our results showed that colonoscopy was less
effective in preventing proximal CRC incidence and mortality (both
Pinteraction<0.05) than distal CRC in patients with non-malignant
findings, which might be explained by several factors concerning
endoscopists, patients, and tumor biology: proximal serrated polyps
could be easily missed by endoscopists because of flat or sessile
appearance; patients’ poor bowel preparation usually results in
incomplete colonoscopy examination; differences in tumor biology
exist between proximal and distal lesions of the colorectum (
Novelty of the study
Two previous meta-analyses are important studies on the effect
of colonoscopy (
). Brenner et al. (30) found that
screening colonoscopy is associated with 69 and 68% reductions in
CRC incidence and mortality, respectively, and Elmunzer et al.
) concluded that colonoscopy reduces CRC mortality by 57%.
Novelty of our meta-analysis are threefold. First, in the two
metaanalyses, patients with malignant findings were enrolled in some
included studies but not in others. The significant
heterogeneity of baseline population may strongly affect generalizability of
their results in the general population. Therefore, we enrolled in
our meta-analysis patients with non-malignant findings, a more
homogeneous group constituting over 90% of the yield of
colonoscopy in clinical practice (
) and featured with
non-malignant nature, mostly non-surgical treatment, longer surveillance
interval, and better prognosis compared with malignant findings
). Second, the effect of screening colonoscopy and the effect
of colonoscopy regardless of indication were separately reported
in the two meta-analyses, without comparison, whereas our subgroup
analysis found a more prominent effect of screening colonoscopy
over screening/diagnostic and diagnostic colonoscopies on
reducing CRC incidence. Third, with expanded colonoscopy
indications (including both screening and diagnostic), study
outcomes (including both incidence and mortality), and an updated
inclusion of recent studies (
), our study (n=1,499,521) is
responsible for a more robust conclusion with a larger sample size.
Our study has several limitations. First, in addition to
excluding detected CRCs (CRCs diagnosed at or within 6 months of
the index colonoscopy) to arrive at non-malignant findings at
the index colonoscopy, five of the eleven included studies also
excluded interval CRCs (CRCs diagnosed within 6 to 36 (or even
60) months of the index colonoscopy) (
). As interval
CRCs certainly argue against the protective effect of colonoscopy
), results of our study might be biased, causing
overestimation of the magnitude of protection by colonoscopy. Therefore,
study results should be interpreted with caution. Second, it should
be noted that indications for colonoscopy according to original
publications of some studies may not reflect real circumstances,
e.g., studies by Nishihara et al. (18) and Eldridge et al. (
initiated earlier than the nationwide introduction of screening
colonoscopy. This may offer one of the explanations for the
nonsignificant difference between the effect of screening vs. screening/
diagnostic and diagnostic colonoscopy on CRC mortality. Third,
statistical heterogeneity was significant for outcome of incidence.
This might be explained by the differences in population enrolled,
intervention strategy, and study designs. After excluding the study
by Brenner et al. (
) (screening was the only indication for
colonoscopy), statistical heterogeneity became non-significant.
Fourth, results of our study might be biased due to several other
factors. Overestimation of the protective effect of colonoscopy
might be caused by selection bias introduced by observational
studies, e.g., participants in the colonoscopy (exposed) group tended
to be more health-conscious (
), whereas underestimation of the
results might be caused by contamination of the control
(unexposed) group, e.g., individuals with adenomas in this group may
present with symptoms and therefore receive colonoscopy
examination with polypectomy (
). Moreover, the initial age for
screening in one study (
) is earlier than the guideline-recommended
50 years of age. In this sense, our results should be interpreted with
caution, and randomized trials may better resolve this problem.
Fifth, our study did not quantify individual CRC risk after either
polypectomy or negative colonoscopy, as only one study by
Nishihara et al. (
) reported effect estimates in subgroups of patients
with polyps and those with negative findings.
In conclusion, findings from this meta-analysis of observational
studies indicate that CRC incidence and mortality in patients with
non-malignant findings are significantly reduced after colonoscopy,
especially after screening colonoscopy. This provides additional
evidence for the effectiveness of colonoscopy in the general population.
CONFLICT OF INTEREST
Guarantors of the article: Zhao-Shen Li, MD and Liang-Hao Hu, MD.
Specific author contributions: Jun Pan contributed to the study
concept and design, data acquisition and interpretation, and
drafting and final approval of the manuscript; Lei Xin and Yi-Fei Ma
contributed to the data acquisition, data analysis and interpretation,
and revision and final approval of the manuscript; and Zhao-Shen Li
and Liang-Hao Hu contributed to the study concept and design, data
analysis and interpretation, drafting and revision of the manuscript,
and final approval of the manuscript.
Financial support: None.
Potential competing interests: None.
WHAT IS CURRENT KNOWLEDGE
✓ Both screening and diagnostic colonoscopy have an
important role in colorectal cancer (CRC) prevention.
✓ Negative findings, hyperplastic polyps, adenomas, and
serrated lesions constitute over 90% of the yield of
colonoscopy in clinical practice, which are non-malignant
in nature and associated with better prognosis compared
with malignant findings.
✓ There is no meta-analysis quantifying the effect of
colonoscopy in patients with non-malignant findings and further
demonstrating the potentially more marked effect of
screening over diagnostic colonoscopy.
WHAT IS NEW HERE
✓ Colonoscopy, regardless of indication of screening or
diagnostic, significantly reduced CRC incidence and
mortality in patients with non-malignant findings.
✓ The protective effect was more prominent for screening
colonoscopy compared with diagnostic one.
✓ Greater protection was seen against distal CRC than
proximal CRC in patients with non-malignant findings.
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