Prevalence, Risk Factors, and Outcomes of Interval Colorectal Cancers: A Systematic Review and Meta-Analysis Siddharth Singh, MD1, Preet Paul Singh, MD2, Mohammad Hassan Murad, MD, MPH3,4, Harminder Singh, MD, MPH5 and N. Jewel Samadder, MD, MSc, FRCPC6 OBJECTIVES:

We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs).

METHODS:

Systematic literature search through October 2013, identified population-based studies, reporting prevalence of interval CRCs (CRCs diagnosed within 6–36 months of colonoscopy). We estimated the pooled prevalence, patient, endoscopist, and tumor-related risk factors, as well as outcomes of interval CRCs, as compared with detected CRCs (CRCs diagnosed at or within 6 months of colonoscopy).

RESULTS:

Twelve studies reporting on 7,912 interval CRCs were included. Pooled prevalence of interval CRCs was 3.7% (95% confidence interval (CI) = 2.8–4.9%). These cancers were 2.4 times more likely to arise in the proximal colon (6.5%; 95% CI = 4.9–8.6%) as compared with distal colon (2.9%; 95% CI = 2.0–4.2%). Patients with interval CRCs were older (age > 65–70 years vs. < 65–70 years: odds ratio (OR) = 1.15; 95% CI = 1.02–1.30), have more comorbidities (high Charlson comorbidity index: OR = 2.00; 95% CI = 1.77–2.27), and have diverticular disease (OR = 4.25; 95% CI = 2.58–7.00). There was a nonsignificant time trend of declining prevalence of interval CRCs from 4.8% in 1990s to 4.2% between 2000 and 2005 and 3.7% beyond 2005. Patients with interval CRCs were less likely to present at an advanced stage (OR = 0.79; 95% CI = 0.67–0.94), although there was no survival benefit. Considerable heterogeneity was observed in most of the analyses.

CONCLUSIONS: Based on meta-analysis, approximately 1 in 27 CRCs are interval CRCs, although the confidence in

these estimates is low because of the heterogeneity among the studies. These are more likely to arise in the proximal colon and are diagnosed in older patients, patients with comorbidities or diverticular disease. SUPPLEMENTARY MATERIAL is linked to the online version of the paper at http://www.nature.com/ajg

Am J Gastroenterol 2014; 109:1375–1389; doi:10.1038/ajg.2014.171; published online 24 June 2014

INTRODUCTION Colorectal cancer (CRC) is the third most common malignancy worldwide, with a 6% lifetime risk of developing this cancer (1). Most cases of CRC are thought to arise from adenomatous polyps (2), with a mean observed sojourn time (i.e., duration of the preclinical screen-detectable period for CRCs) of 3–6 years (3). Removal of the premalignant adenomatous polyps leads to decrease in the risk of developing and dying from CRC (4,5).

Widespread uptake of colonoscopy as the preferred screening modality for CRC in the United States has been associated with a decrease in the incidence of and mortality from CRC (6,7). However, a small proportion of patients still develop “interval” CRCs after index colonoscopy before the next recommended surveillance examination (8–13). These have been variably referred to as missed, interval, or post-colonoscopy CRCs. Several recent studies have estimated the prevalence of interval CRCs. In a recent population-based study from Utah, Samadder et al.

1

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA; 2Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA; Division of Preventive Medicine, Mayo Clinic, Rochester, USA; 4Knowledge Synthesis Program, Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota, USA; 5Section of Gastroenterology, University of Manitoba and Cancer Care Manitoba, Winnipeg, Manitoba, Canada; 6Division of Gastroenterology, Huntsman Cancer Institute and University of Utah, Salt Lake City, Utah, USA. Correspondence: N. Jewel Samadder, MD, MSc, FRCPC, High Risk Gastrointestinal Cancers Program, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, Utah, 84112, USA. E-mail: [email protected] Received 16 March 2014; accepted 13 May 2014 3

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observed that 3.4% of all CRCs arose within 6–36 months of a colonoscopy (9); whereas Singh and colleagues reported that 7.9% of all CRCs in Manitoba, Canada, were interval CRCs (12). Various clinical (such as older age, female sex, presence of diverticular disease) and endoscopy-related (such as procedures performed by a nongastroenterologist, or at low-volume centers) risk factors have been identified in individual studies as being associated with risk of developing interval CRC, although results are inconsistent across studies (8,14). Besides clinical and endoscopy-related factors, differences in tumor biology may also contribute to development of interval CRCs (15–18). There is limited information on prognosis of interval CRCs. Some studies have suggested that interval CRCs have a better prognosis than detected CRCs (9), although this has not been replicated in other studies (12,19). To date, there has been no study that has systematically synthesized data from all available studies to estimate the prevalence, risk factors, and outcomes of interval CRCs, vis-à-vis detected CRCs. Hence, we performed a systematic review and meta-analysis to better characterize interval CRCs. For the quantitative synthesis, we focused on population-based studies from an unselected patient cohort to minimize risk of selection bias and misclassification bias.

METHODS We conducted and reported this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (20), and followed a priori established protocol. The quality of evidence was rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach (21). Selection criteria

In this systematic review, we included studies that met the following criteria: (i) population-based or multi-center studies; (ii) reported CRCs occurring within 3 years of a colonoscopy (for any indication); and (iii) reported the overall and/or site-specific prevalence of CRCs occurring within 3 years of a colonoscopy vis-à-vis the total number of CRC cases. Both retrospective and prospective studies were included, provided complete (or near-complete ( > 90%)), minimum 5-year follow-up was available, to allow accurate estimation of interval CRCs. We included case–control studies, in which the cases included all patients with CRC and a subset of patients with interval CRCs could be identified. Multicenter studies were only included if they were deemed to be representative of the majority of general population in a geographic area. We defined interval CRCs as those occurring after an index colonoscopy, regardless of whether an alternative screening strategy (flexible sigmoidoscopy, stool-based tests, etc.) had been used before or after index colonoscopy. We excluded the following studies from the meta-analysis: (i) single-center studies, as these may not be able to accurately identify all interval CRCs, (ii) referral-center studies, because of risk of selection bias, (iii) studies with inadequate information on total number of CRCs identified during the time period, as prevalence The American Journal of GASTROENTEROLOGY

of interval CRCs could not be determined, (iv) prospective studies with incomplete follow-up, and (v) randomized controlled trials given highly controlled environment in these with risk of Hawthorne effect. Although these studies were excluded from quantitative synthesis, key findings from these studies were included in the systematic review. In case of multiple studies from the same cohort, we included data from the most recent comprehensive report; if there was minimal overlap of time period, then both studies were included. Search strategy

We conducted a comprehensive search of multiple electronic databases from each databases’ inception to 8 October 2013, with no language restrictions. The databases included: Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. The search strategy was designed and conducted by an experienced medical librarian with input from the study investigators, using controlled vocabulary supplemented with keywords to search for studies of CRCs diagnosed after colonoscopy. The details of the search strategy are included in the Supplementary Appendix online. Two authors, independently, reviewed the title and abstract of studies identified in the search to exclude studies that did not address the research question of interest, based on pre-specified inclusion and exclusion criteria (see above). The full text of the remaining articles was examined to determine whether it contained relevant information; discrepancy in article selection was resolved by consensus, in conjunction with the senior investigator (N.J.S.). Next, a recursive search of reference lists of all relevant articles was also conducted to search for additional studies. Third, a manual search of conference proceedings of major gastroenterology and oncology conferences (Digestive Diseases Week, American College of Gastroenterology annual meeting, American Society of Clinical Oncology annual meeting as well as the Gastrointestinal Research Forum; European Society of Medical Oncology annual meeting, and World Congress on GI Cancer) between 2010 and 2013 was conducted to identify additional studies published only in the abstract form. Data extraction and quality assessment

Data on the following study- and patient-related characteristics were independently abstracted onto a standardized form by two investigators (and discrepancies were resolved by consensus): (i) study characteristics—primary author, time period of study/year of publication, geographic location of the population studied, study design; (ii) CRC characteristics—total number of patients with CRC (overall, proximal, and distal CRC), total number of patients with interval CRCs (overall, proximal, and distal CRC), definition and method of ascertainment of interval CRC (i.e., those patients with CRCs diagnosed within 6–36 months of an index colonoscopy) as well as detected CRCs (i.e., those patients with CRCs diagnosed during or within 6 months of index colonoscopy); (iii) risk factors (clinical and endoscopy-related) associated with interval CRCs, as compared with detected CRCs VOLUME 109 | SEPTEMBER 2014 www.amjgastro.com

in individual studies; (iv) outcomes—stage (I/II categorized as ‘early’ stage, III/IV categorized as ‘advanced’ stage), grade (welland moderately differentiated grouped into G1/G2, poorly differentiated and undifferentiated grouped into G3/G4), as well as differences in survival of interval and detected CRCs. In addition, where reported, the difference in the genetic profile of interval and detected CRCs was also abstracted. First or senior authors of studies were contacted to provide additional information where required. The methodological quality of observational studies was assessed using published, non-validated, criteria for prevalence studies, by two study investigators independently (22,23). This scale grades studies according to eight methodological criteria, with a total possible score from 0 to 8. Outcomes assessed

Primary outcome. The primary outcome of interest was the prevalence of interval CRCs, i.e., what proportion of CRCs are interval CRCs. These were separately assessed for any CRC site, proximal CRCs (cecum, ascending colon, transverse colon to the splenic flexure), and distal CRCs (descending colon, sigmoid colon, and rectum). A priori hypotheses to explain potential heterogeneity in the direction and magnitude of effect among different observational studies included location of study (North America vs. Europe) and study setting (population-based vs. multicenter studies). Sensitivity analysis based on modifying the definition of interval CRCs (diagnosed within 60 months of previous colonoscopy, as opposed to within 36 months of colonoscopy) was also performed.

on the proportion of patients identified as having interval CRCs based on time period of patient identification (1990s, 2000–2005, and beyond 2005); we did not perform an analysis based on the year of publication as these were not reflective of time period of patient recruitment. To give a more conservative estimate of the prevalence of interval CRCs, we pooled data using the random effects model described by DerSimonian and Laird (24). We assessed heterogeneity between study-specific estimates using inconsistency index (I2 statistic) (25). This estimates what proportion of total variances across studies was due to heterogeneity rather than chance; a value of > 50% was considered suggestive of substantial heterogeneity. Once heterogeneity was noted, we investigated between-study sources of heterogeneity using subgroup analyses by stratifying original estimates according to study characteristics as described above. We planned to ascertain publication bias, qualitatively, by visual inspection of Funnel plot, and quantitatively, by Egger’s regression test (26,27). For all tests (except for publication bias), a probability level < 0.05 was considered statistically significant. All analyses were performed using Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ).

RESULTS

Secondary outcomes. (i) Risk factors for interval CRCs: In order to identify risk factors associated with interval CRCs, we performed a meta-analysis of differences in the clinical, technical (or endoscopy-related), and tumor biology-related factors (genetic profile of tumors) by comparing patients who developed interval CRCs and those with detected CRCs; (ii) Outcomes of interval CRCs: We compared the stage, grade (at diagnosis), and differences in survival of patients with interval and detected CRCs.

From a total of 2,212 unique studies identified using the pre-specified systematic search strategy, 12 observational studies (10 population-based studies and 2 multicenter studies) were included in the quantitative synthesis (9–12,16,28–34). Six RCTs, including one pooled multi-cohort analysis of patients enrolled in eight randomized chemoprevention trials (13), thirteen studies with the absence of information on all CRCs (resulting in inability to estimate prevalence of interval CRCs vis-à-vis the total number of CRC cases), and one prospective study with lack of adequate follow-up were excluded (35). There were two studies performed in the same Surveillance, Epidemiology, and End Results (SEER)Medicare cohort with completely overlapping time periods (31,36) of which only one was included (31); sensitivity analysis was performed using the other study (36), which was also used for risk factor assessment in case data were not available from the primary study. Figure 1 shows the schematic diagram of study selection.

Statistical analysis

Characteristics and quality of included studies

We combined the proportions of patients with interval CRCs in individual studies to estimate a pooled prevalence of interval CRCs among all patients diagnosed with CRC, along with a 95% confidence interval (CI). We compared pooled prevalence of proximal interval CRCs, with the pooled prevalence of distal interval CRCs, using an odds ratio (OR) with 95% CI. We identified risk factors associated with development of interval CRCs relative to detected CRCs, by performing a meta-analysis of difference in distribution of clinical and endoscopy-related factors among the two groups by pooling maximally adjusted ORs reported in the respective studies as well as pooling unadjusted univariate analysis (using 2×2 tables, when the required data were available from the individual studies), and expressed the results as OR with 95% CI. We also performed a time-trend analysis by abstracting data

Table 1 describes the characteristics of the included studies. Overall, these 12 studies reported on 139,813 CRC cases, of which 7,912 were identified as interval CRCs diagnosed between 1988 and 2011 (9–12,16,28–34). Ten studies were categorized as population-based studies (9–12,28–32,34); one of these studies, performed using the SEER-Medicare database, was nationally representative but not indicative of all patients in the population (31). Two studies were conducted in Ontario with only slight temporal overlap (1997–2002 and 2000–2005) (10,30). Nishihara and colleagues performed a prospective cohort study following patients from two cohorts (Nurses’ Health Study and Health Professionals Follow-up study) from Massachusetts over 20 years (16). Haseman and colleagues identified all interval CRCs identified across 20 hospitals in Indiana between 1988 and 1993 (33). Nine of the

© 2014 by the American College of Gastroenterology

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Indentification

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Electronic database search: • Ovid (Embase, Medline) – 907 • Web of Science – 1,295 • Scopus - 341

12 additional records identified through other sources (manual abstract search)

2,212 abstracts reviewed

Eligibility

Screening

2,212 records after duplicates removed

85 full texts reviewed

Included

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12 studies included in quantitative synthesis (meta-analysis)

Excluded based on title and abstract review - 2,156 • Basic science articles, review articles, editorials • Cross-sectional studies • Did not study interval CRCs • Baseline exam not colonoscopy

Excluded - 73 • Single-center/referral-center studies (32) • Index exam not colonoscopy (8) • Inadequate information to compared interval CRCs to detected CRC (13) • Randomized controlled trials (6) • Overlapping population (11) • High-risk patients (2) • Inadequate prospective follow-up (1)

Figure 1. Flowchart summarizing study identification and selection. CRC, colorectal cancer.

included studies were retrospective in nature (9,10,12,28,30–34); three studies were prospective with adequate follow-up (11,16,28). Brenner and colleagues reported the results of their prospective population-based case–control study as two distinct cohorts— patients with negative index colonoscopy (i.e., no polyps identified at initial colonoscopy) and patients with polypectomy at index colonoscopy (11,29). Seven studies were performed in North America (three in Canada (10,12,30) and four in the United States (9,16,31,33)), four studies in the Europe (two in Germany (11,29), one in Denmark (32), and one in the Netherlands (34)), and one study in New Zealand (28). All studies were deemed to be of high quality. Individual quality items for each of the included studies are provided in the Supplementary Table S1. Prevalence of interval CRC

Overall. The prevalence of interval CRC ranged from 1.8 to 9.0% in the included studies. On pooled analysis, the prevalence of interval CRCs was 3.7% (95% CI = 2.8–4.9%; Figure 2). This corresponds to 1 in 27 (95% CI = 20–36) CRCs being interval CRCs.

Site specific. In nine studies, 53,847 proximal CRCs were identified, of which 4,615 were classified as interval CRCs (9,10,12,29–34). On pooled analysis, the prevalence of proximal interval CRCs was 6.5%. (95% CI = 4.9–8.6%; Figure 3). This corresponds to 1 in 15 (95% CI = 12–20) proximal CRCs being interval CRCs. In the same nine studies, 77,922 distal CRCs were identified, of which 2,726 were classified as interval CRCs. On pooled analysis, the prevalence of distal interval CRCs was 2.9% (95% CI = 2.0–4.2%; Figure 3). This corresponds to 1 in 34 (95% CI = 24–50) distal CRCs being interval CRCs. As compared with detected CRCs, interval CRCs were 2.4 times more likely to be proximal CRCs than distal CRCs (OR = 2.36; 95% CI = 2.11–2.65). The American Journal of GASTROENTEROLOGY

Subgroup analysis. Considerable heterogeneity was observed in the overall as well as site-specific analysis (I2 for prevalence of overall, proximal, and distal interval CRCs: 99%, 98%, and 98%, respectively). On subgroup analysis, the pooled prevalence of overall and proximal interval CRCs was significantly higher in population-based studies, as compared with multicenter studies, partially accounting for the observed heterogeneity (Pinteraction < 0.01; Table 2). Studies performed in the Europe observed a lower prevalence of proximal and distal interval CRCs as compared with North America (Pinteraction < 0.01).

Sensitivity analysis. When we used an alternative definition of interval CRCs as those diagnosed within 6–60 months of previous colonoscopy, the pooled prevalence of interval CRCs was 4.3% (95% CI = 2.6–6.9%; four studies) (9,16,32,34). Sensitivity analysis, replacing one study (31) performed using the SEERMedicare database with another (36), did not significantly change the prevalence estimate (prevalence of interval CRC, 4.1%; 95% CI = 3.2–4.3). On excluding the negative colonoscopy cohort study by Brenner et al. (no polyps identified in index colonoscopy), the pooled prevalence of interval CRCs in population-based studies was unchanged (prevalence = 4.4%; 95% CI = 3.9–5.2%); likewise, on excluding the study performed using the SEERMedicare database (older individuals), the pooled prevalence of interval CRCs in population-based studies was 4.4% (95% CI = 3.0–6.4%). To assess whether any one study had a dominant effect on the pooled prevalence of interval CRC, each study was excluded and its effect on the main summary estimate and I2 test for heterogeneity was evaluated; no study markedly affected the overall prevalence of interval CRC or degree of heterogeneity. As substantial heterogeneity was observed in the overall analysis, evaluation for publication bias using funnel plot asymmetry was not appropriate. VOLUME 109 | SEPTEMBER 2014 www.amjgastro.com

© 2014 by the American College of Gastroenterology

Ontario, Canada

Nationwide, United States

Bressler (30)

Cooper (31)

Indiana, United States

RhineNeckar, Germany

Brenner––Negative colonoscopy cohort (11)

Haseman (33)

RhineNeckar, Germany

Brenner–– Polypectomy cohort (29)

Nationwide, Denmark

Ontario, Canada

Baxter (10)

Erichsen (32)

Location

Study

1988–1993

2000–2009

Retrospective cohort; hospitalbased

Retrospective cohort; population-based with record linkage

Retrospective cohort; administrative database with record linkage

Retrospective cohort; administrative database with record linkage

1997–2002

1994–2005

Prospective case–control

Prospective case–control

Retrospective cohort; administrative database with record linkage

Design

2003–2007

2003–2010

2000–2005

Time period

Colonoscopy within 1–36 months before CRC diagnosis

Colonoscopy within 12–60 months before CRC diagnosis (sensitivity analysis, 3–36 months)

Colonoscopy within 6–36 months before CRC diagnosis

Colonoscopy within 6–36 months before CRC diagnosis

CRC diagnosed 1–36 months after negative colonoscopy

CRC diagnosed 1–36 months after colonoscopy with polypectomy

Colonoscopy within 6–36 months before CRC diagnosis

Definition of interval CRC

941 P: 415 D: 526

35,704 P: 9,782 D: 23,979

57,839 P: 28,721 D: 28,072

12,487 P: 4,065 D: 8,422

1945 NR

2,582 P: 750 D: 1,668

14,064 P: 5,472 D: 8,592

Total CRC (proximal; distal)

Table 1. Characteristics of included studies on the prevalence of interval colorectal cancers

27; P: 15 D: 12

982 P: 441 D: 433; using alternate definition (3–36 m), 1,201

4,192 P: 2,851 D: 1,253

430 P: 238 D: 192

35 P: 20 D: 13

60 P: 37 D: 21

1,260; P: 676 D: 584

Interval CRC (proximal; distal)

2.9% P: 3.6% D: 2.3%

2.8% P: 4.5% D: 1.8%; using alternate definition (3–36 m), 3.4%

7.2% P: 9.9% D: 4.5%

3.4% P: 5.9% D: 2.3%

1.8%

2.3% P: 4.9% D: 1.3%

9.0% P: 12.4% D: 6.8%

Proportion of all CRCs considered interval CRCs

NR

The American Journal of GASTROENTEROLOGY

Colonoscopy by nongastroenterologist

NR

Non-inpatient procedure; colonoscopy by non-gastroenterologist; low polypectomy rate ( < 24%), low colonoscopy volume ( < 48 procedures annually)

Office-based colonoscopy; colonoscopy by internist or family medicine

NR

Colonoscopy by non-gastroenterologist, colonoscopy in non-academic center; high incomplete colonoscopy completion rate ( < 85%); low polypectomy rate ( < 15%; only for proximal CRC)

Endoscopy related

REVIEW

Female sex; diverticular disease; high comorbidity score

Age < 85 years; high comorbidity score; diverticular disease

Older age; diverticular disease or history of abdominal/pelvic surgery

Female sex; colonoscopy performed for positive fecal occult blood test; incomplete index colonoscopy

NR

Higher comorbidity score; older age, female sex (only for distal interval CRC)

Clinical

Risk factors for interval CRC

Epidemiology of Interval Colorectal Cancers 1379

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South Limburg, the Netherlands

Massachusetts, United States

Utah, United States

Manitoba, Canada

New Zealand

le Clercq (34)

Nishihara (16)

Samadder (9)

Singh (12)

Atkinson [abstract] (28)

1996–2011

1992–2008

Retrospective cohort; population-based with medical record review

Retrospective cohort; population-based with record linkage

Retrospective cohort; population-based with record linkage

Prospective cohort; selfreport with medical record review

1988–2010

1995–2009

Retrospective cohort; population-based with record linkage

Design

2001–2010

Time period

Colonoscopy within 0–36 months before CRC diagnosis

Colonoscopy within 6–36 months before CRC diagnosis

Colonoscopy within 6–36 months before CRC diagnosis

CRC diagnosed 1–60 months after colonoscopy (sensitivity analysis, 1–36 months)

Colonoscopy within 12–60 months before CRC diagnosis

Definition of interval CRC

Proportion of all CRCs considered interval CRCs

49

388; P: 225 D: 147

4,883 P: 1,758 D: 2,633 1,299

3.4% P: 4.2% D: 3.0%

91 P: 45 D: 24

2,659 P: 1,063 D: 795

3.8%

7.9%; P: 12.8% D: 5.6%

7.1%; using alternate definition (1–36 months), 1.8%

2.9% P: 4.8% D: 1.8%

129; using alternate definition (1–36 months), 32

147 P: 87 D: 60

Additional 20 CRCs in patients with incomplete colonoscopy

Interval CRC (proximal; distal)

1,815

5,107 P: 1,821 D: 3,235

Total CRC (proximal; distal)

Previous colonoscopy with biopsy or polypectomy; low comorbidity score NR

Previous history of adenoma; family history of CRC (interval CRC defined as occurring 6–60 months after colonoscopy)

Colonoscopy by family practice

NR

NR

Colonoscopist specialty or setting did not affect risk of interval CRC

Endoscopy related

Risk factors for interval CRC

Molecular characteristics of interval CRC: CIMP positive, MSI high

NR

Clinical

CIMP, CpG island methylator phenotype; CRC, colorectal cancer; D-distal colorectal cancer; MSI, microsatellite instability; NR, not reported; P, proximal colorectal cancer.

Location

Study

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Pooled prevalence of interval CRCs Event rate and 95% Cl Event rate

Lower limit

Upper limit

Baxter

Total

0.090

0.085

0.094

Brenner - polypectomy cohort

Total

0.023

0.018

0.030

Brenner - negative colonoscopy cohort

Total

0.018

0.013

0.025

Bressler

Total

0.034

0.031

0.038

Cooper

Total

0.072

0.070

0.075

Erichsen

Total

0.034

0.032

0.036

Haseman

Total

0.029

0.020

0.042

Ie Clercq

Total

0.029

0.025

0.034

Nishihara

Total

0.018

0.012

0.025

Samadder

Total

0.034

0.028

0.042

Singh

Total

0.079

0.072

0.087

Atkinson

Total

0.038

0.029

0.050

0.037

0.028

0.049

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Subgroup within study

Study name

–0.15

–0.08

0.00

0.08

0.15

Figure 2. Pooled prevalence of interval colorectal cancers (CRCs), as compared with all CRCs. Numbers represented as proportion of interval CRCs per all CRCs. Overall, this transforms into a pooled prevalence of interval CRCs of 3.7% (95% confidence interval (CI) = 2.8–4.9%).

Pooled prevalence of interval CRCs by site - proximal v. distal Study name

Subgroup within study

Event rate and 95% Cl Event rate

Lower limit

Upper limit

Baxter

Distal

0.058

0.053

0.073

Brenner - polypectomy cohort

Distal

0.013

0.008

0.019

Bressler

Distal

0.023

0.020

0.025

Cooper

Distal

0.045

0.042

0.047

Erichsen

Distal

0.018

0.016

0.020

Haseman

Distal

0.023

0.013

0.040

Ie Clercq

Distal

0.019

0.014

0.024

Samadder

Distal

0.030

0.020

0.045

Singh

Distal

0.056

0.048

0.055

0.029

0.020

0.042

Baxter

Proximal

0.124

0.115

0.133

Brenner - polypectomy cohort

Proximal

0.049

0.035

0.057

Bressler

Proximal

0.059

0.052

0.055

Cooper

Proximal

0.099

0.095

0.103

Erichsen

Proximal

0.045

0.041

0.049

Haseman

Proximal

0.035

0.022

0.059

Ie Clercq

Proximal

0.048

0.039

0.059

Samadder

Proximal

0.042

0.032

0.056

Singh

Proximal

0.128 0.055

0.113 0.049

0.144 0.085 –0.15

–0.08

0.00

0.08

0.15

Figure 3. Site-specific pooled prevalence of interval colorectal cancers (CRCs; proximal vs. distal). Numbers represented as proportion of interval CRCs per all CRCs. Overall, this transforms into a pooled prevalence of proximal interval CRCs of 6.5% (95% confidence interval (CI) = 4.9–8.6%) and of distal interval CRCs of 2.9% (2.0–4.2%).

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Table 2. Subgroup analysis

Subgroups

Categories

Number of studies

Prevalence (95% CI)

I2 (heterogeneity within sub-groups), %

Pinteraction

0.23

All interval CRCs Locationa

Setting

Europe

4

3.6 (2.6–4.8)

92

North America

7

4.6 (3.5–6.1)

99

Population-based

10

4.6 (3.4–6.2)

99

multicenter

2

2.2 (1.4–3.6)

72

Europe

3

4.6 (4.2–5.0)

0

North America

6

7.8 (6.0–10.0)

97

Population-based

8

6.8 (5.1–9.2)

98

multicenter

1

3.6 (2.2–5.9)



Europe

4

1.8 (1.5–2.0)

27

North America

6

3.9 (2.8–5.4)

98

Population-based

8

3.0 (2.0–4.4)

99

multicenter

1

2.3 (1.3–4.0)



0.01

Only proximal interval CRCs Location

Setting

< 0.01

0.03

Only distal interval CRCs Location

Setting

< 0.01

0.46

CI, confidence interval; CRC, colorectal cancer. a One study was from New Zealand, and was not included in this subgroup analysis. Bold values represent significant P values (P < 0.05).

Time-trend analysis. Based on eight studies from which data allowed estimation of interval CRC risk at different time points, there was a declining trend in the prevalence of interval CRCs from 4.8% (95% CI = 2.9–7.8) in 1990s to 4.2% (95% CI = 2.3–7.4) between 2000 and 2005, and 3.7% (95% CI = 2.6–5.2) beyond 2005 (10,11,29–34); however, this trend was not statistically significant (P = 0.68). Quality of evidence. Using the GRADE approach for assessing the quality of evidence, our summary estimate on prevalence of interval CRC in this systematic review based on observational studies and with the high degree of heterogeneity among the studies, was classified as very low-quality evidence. Risk factors for interval CRCs

Clinical factors. Table 3 reports the baseline clinical characteristics comparing interval CRCs to detected CRCs. Seven studies (out of eleven studies for which data were available) observed that patients diagnosed with interval CRCs were slightly older than patients with detected CRCs (9–11,16,28–34). Using adjusted OR reported in individual studies, older patients ( > 65–70 years) had a higher risk of interval CRCs than younger individuals ( < 65–70 years; adjusted OR = 1.15, 95% CI = 1.02–1.30, I2 = 20%, four studies; unable to estimate unadjusted OR). Females were no more likely than males to develop interval CRCs (using males as reference: adjusted OR = 1.06, 95% CI = 0.93–1.20, I2 = 71%, six studies; unadjusted OR = 1.00, 95% CI = 0.87–1.15, I2 = 80%, nine studies) (9–11,16,29–32,34), although some studies individually reported The American Journal of GASTROENTEROLOGY

a higher prevalence of interval CRCs in females as compared with males (9,11,30,32). On pooled analysis, patients with interval CRCs were 1.6 times more likely to have a family history of CRC (variably defined as history of CRC in any first-degree relative or only those occurring at age < 50 years) as compared with detected CRCs (adjusted OR = 1.64, 95% CI = 1.40–1.90, I2 = 0%, two studies; unadjusted OR = 1.87, 95% CI = 1.41–2.47, I2 = 37%, four studies) (9,16,34,36). Patients with interval CRC were 4.3 times more likely to have been diagnosed with diverticular disease as compared with patients with detected CRCs (adjusted OR = 4.25, 95% CI = 2.58–7.00, I2 = 96%, four studies; unadjusted OR = 4.55, 95% CI = 3.04–6.82, I2 = 96%, five studies) (12,30–32,34); site-specific prevalence of interval CRCs in patients with diverticular disease was not available. Likewise, four studies (out of five studies which reported on comorbidities) reported a higher prevalence of comorbidities in patients who developed interval CRC, as compared with patients with detected CRC (10,12,31,32,34); on meta-analysis, the adjusted OR for risk of interval CRC in patients with multiple comorbidities using the Charlson comorbidity index was 2.00 (95% CI = 1.77–2.27, I2 = 26%, four studies; unable to estimate unadjusted OR). Smoking was not found to be a risk factor for interval CRCs, based on results from two studies (16,34). Three (out of four studies which reported this outcome) studies observed that patients who developed interval CRCs, as compared with detected CRCs, were more likely to have undergone a polypectomy on their index colonoscopy (9,12,30,36). On pooling these data, we observed that as compared with patients with detected CRCs, patients with VOLUME 109 | SEPTEMBER 2014 www.amjgastro.com

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66 (14); > 64 years: 55%

> 74 years: 37%

73±9 years

69 years

> 70 years: 65%

> 74 years: 74%

73±11 years

M: 55 F: 45

M: 52; F: 48

M: 39; F: 61

M: 54; F: 46

M: 52; F: 48

M: 44; F: 56

M: 56; F: 44

M: 66; F: 34

M: 59; F: 41

M: 57; F: 43

NR

NR

Detected CRC

51; 49

40; 60

55; 45

46; 54

43; 57

47; 53

46; 54

63; 37

53; 47

Interval CRC

Sex (M/F, as % total)

59%

23.5%

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Detected CRC

65%

23.1%

Interval CRC

Smoking

3.8%

16%

1.6%

NR

NR

NR

5.5%

21%

5.4%

Interval CRC

NR

Based on Wang et al., family history of CRC was associated with an increased risk of interval CRC family history (OR=1.64; 95 % CI=1.41–1.92)

NR

NR

NR

NR

Detected CRC

Family History of CRC

CI, confidence interval; CRC, colorectal cancer; F, female; H/O, history of; IQR, interquartile range; M, male; NR, not reported; OR, odds ratio. a Compared with screen-detected CRC.

> 69 years identified as risk factor for interval CRC

> 74 years: 20%

Nishihara (16)

Atkinson (abstract) (28)

Mean: 70±11 years

le Clercq (34)

Median (IQR): 69 (62–75)

Mean: 72 years

Haseman (33)

Singh (12)

> 70 years: 56%

Erichsen (32)

Mean: 66±14 years; > 64 years: 56%

> 74 years: 71%

Cooper (31)

Samadder (9)

Mean: 67±12 years

> 69 years: 43%

> 69 years: 45%

Brenner–Negative colonoscopy cohorta (11)

Bressler (30)

> 69 years: 52%

> 69 years: 47%

Brenner–Polypectomy cohort (29)

71 years (25–97)

Interval CRC

Median: 68 years (21–98)

Detected CRC

Age

Baxter (10)

Study

Table 3. Clinical characteristics of patients with interval and detected colorectal cancers

14.9%

25.4%

NR

NR

NR

NR

21.1%

47.6%

19.0%

69.3%

26.9%

3.3%

37.7%

Interval CRC

7.0%

NR

NR

NR

Detected CRC

Diverticular Disease

REVIEW

High comorbidity score: 22.1%; Abdominal surgery: 16.5%

NR

NR

Coronary artery disease: 23.7%

NR

High comorbidity score: 15%

High comorbidity score: 6%

NR; 17.0%

NR

NR

High comorbidity score: 1.9%

Detected CRC

14.2%; 19.3%

39.5%

28%

10%

NR; 24.4%

4.6%

Interval CRC

Comorbidities; H/O abdominal surgeries

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77%; 23% < 213: 74%; 213: 26%

NR

NR

72%; 28% < 141: 75%; 141: 25%

NR

384 (1.5–1819) Median: 391 (0.5–1965.5)

NR NR

NR

NR NR

NR

NR 81%; 19% G: 17%; S: 60%; O: 23% Singh (12)

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18%; 55%; 27%

No significant difference in risk of interval CRC between gastroenterologist and nongastroenterologists: adjusted OR=1.33 (95% CI=0.88–2.19) le Clercq (34)

Urban: 83%; Rural: 17%

NR 48%; 52% G: 80% O (including surgeons): 20% Haseman (33)

Inpatient: 33%; Outpatient: 51% 53%; 16%; 15% G: 60%; S: 13%; O: 21% Cooper (31)

No significant difference in risk of interval CRC between academic and non-academic hospital: adjusted OR=1.22 (95% CI=0.82–1.83)

52.9%; 47.1% < 0.34: 49.8%; 0.34: 50.2% 29%; 53%

NR 13%; 74% Academic: 19%; Non-academic: 73% 27%; 47%; 26% G: 31%; S: 49%; O: 20% Bressler (30)

Academic: 17%; Community: 77% G: 37%; S: 53%; O: 10% Baxter (10)

37%; 49%; 14%

17%; 73%

Median: 0.19 (0.0–1.00)

0.17 (0.0–0.78)

Median: 0.9 (0.0–1.0)

NR

0.89 (0.05–1.0)

Interval CRC Detected CRC Interval CRC Detected CRC Interval CRC Detected CRC Interval CRC Detected CRC Interval CRC Detected CRC

Procedure completion rate Polypectomy rate Setting of colonoscopy procedure Endoscopist’s specialty (gastroenterologist vs. surgeon vs. others)

Table 4. Endoscopy-related characteristics of patients with interval and detected colorectal cancers

Study

Volume of colonoscopies

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interval CRC were 1.6 times more likely to have had a polypectomy at their index colonoscopy, although this difference was not statistically significant (adjusted OR = 1.57, 95% CI = 0.97–2.56, I2 = 94%, four studies; unadjusted OR = 2.48, 95% CI = 0.95–6.45, I2 = 99%, four studies).

Endoscopy-related factors. Table 4 reports the endoscopy-related characteristics comparing interval CRCs to detected CRCs. In studies from Canada, surgeons were performing more colonoscopies than gastroenterologists (10,12,30); in contrast, in studies from the United States, gastroenterologists were the most common group of endoscopists (9,31,33). As compared with patients with detected CRCs, patients with interval CRCs were more likely to have had their index colonoscopy by a non-gastroenterologist (particularly by an internist or family practitioner) than by a gastroenterologist (index colonoscopy by internist or family practitioner: adjusted OR = 1.53, 95% CI = 1.32–1.77, I2 = 43%, four studies; index colonoscopy by surgeon: adjusted OR = 1.15, 95% CI = 1.03–1.28, I2 = 25%, four studies; unadjusted OR for index colonoscopy by non-gastroenterologist, 1.19, 95% CI = 0.96–1.49, I2 = 88%, six studies; unable to estimate unadjusted OR by specialty; Table 4) (9,10,30,31,33,34). One study reported that colonoscopies performed in academic centers had lower rates of interval CRC (10), although this was not apparent in two other studies (30,34); the pooled unadjusted OR for interval CRC in academic medical centers as compared with the non-academic setting was 1.09 (95% CI = 0.75–1.57, I2 = 82%; unable to estimate adjusted OR). Using polypectomy rate and procedure completion rates as surrogate measures of quality of endoscopists from claims-based studies, endoscopists with higher rates of interval CRCs had lower polypectomy rates (two studies) (10,31) and slightly lower procedure completion rate (one study) (10). On meta-analysis comparing endoscopists with the highest quartile of polypectomy rate with the endoscopists with lowest quartile of polypectomy rate, the risk of interval CRC was significantly lower in the former (adjusted OR = 0.70, 95% CI = 0.63–0.77, I2 = 0%, two studies; unable to estimate unadjusted OR). The studies evaluating effect of procedure volumes on risk of interval CRCs used different cutoffs to define high and low procedure volumes. There was no clear evidence whether high or low procedure volumes affected the prevalence of interval CRCs.

Biology-related factors. Nishihara and colleagues observed that interval CRCs were more likely to have CpG island methylator phenotype (CIMP; OR = 2.19, 95% CI = 1.14–4.21) and microsatellite instability (MSI; OR = 2.10, 95% CI = 1.10–4.02), as compared with non-interval CRCs; somatic BRAF, KRAS, and PIK3CA mutations were not significantly associated with interval CRCs (16). Other single-center studies, not included in the quantitative synthesis, also observed that interval CRCs were more likely to be CIMP positive and MSI high, as compared with detected CRCs (15), and less likely to be KRAS mutated (17).

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NR

L: 36%; R: 26%; M: 24%

Duke’s Class A/B: 63%; C/D: 37%

I: 21%; II: 29%; III: 24%; IV: 26%

L: 45%; R: 34%; M: 15%

I, II: 52%; III, IV: 48%

Erichsen (32)

Haseman (33)

le Clercq (34)

Samadder (9)

Singh (12)

51%; 49%

G1/G2: 86%; G3/G4: 14%

G1/G2: 75.6%; G3/G4: 24.4%

29%; 27%; 30%;14% 59%; 25%; 12%

NR

48%; 52%

38%; 20%; 23%

G1/G2: 72.7%; G3/G4: 27.3%

G1/G2: 79.2%; G3/G4: 20.8%

G1/G2: 75.3%; G3/G4: 24.7%

Detected CRC

NR

NR

NR

83%; 17%

69.0%; 31.0%

G1/G2: 84%; G3/G4: 16%

71.3%; 28.7%

61.8%; 38.2%

82.4%; 17.6%

Interval CRC

Grade of CRC (G1/G2: well or moderately differentiated; G3/G4: poorly differentiated or undifferentiated)

NR

27%

Interval CRC

4.5%

36%

NR

NR

NR

17.3%

58%

38.8%

Based on Wang et al., personal history of colon polyps was a strong risk factor for interval CRCs (OR=4.02; 95 % CI=3.57–4.53)

34%

100%

Detected CRC

Presence of polyps/qdenoma on index colonoscopy

CI, confidence interval; CRC, colorectal cancer; G1/2/3/4, grade of CRC; HR, hazard ratio; L/R/M, localized/regional/metastatic; NR, not reported; OR, odds ratio.

I: 24.9% II: 29.5%; III: 22.7%; IV: 12.3%

Cooper (31)

31.6%; 26.7%; 22.2%; 8.6%

14%; 37%; 29%; 20%

I: 41%; II: 24%; III: 30%; IV: 5%

Brenner – Negative colonoscopy cohort (11)

Bressler (30)

72%; 28%

Interval CRC

I/II: 54%; III/IV: 46%

Detected CRC

Brenner – Polypectomy cohort (29)

Study

Stage of CRC (L/R/M or stage I, II, III, IV)

Table 5. Outcomes of patients with interval and detected colorectal cancers

NR

NR

NR

NR

Interval CRC

REVIEW

No significant difference in survival of patients with interval and detected CRCs; adjusted HR=0.99 (95% CI=0.84–1.17)

Lower risk of mortality in patients with interval CRC: adjusted HR=0.63 (95% CI=0.49–0.81)

NR

NR

No difference in 1- or 5-year survival of patients with interval and detected CRCs; adjusted mortality rate ratio, 1.0 (95% CI=0.88–1.2)

Detected CRC

Survival

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Stage and grade of CRCs. Table 5 reports the outcomes of patients with interval and detected CRCs. As compared with detected CRCs, interval CRCs were less likely to be diagnosed at an advanced stage (stage III or IV; OR = 0.79, 95% CI = 0.67– 0.94, I2 = 70%, eight studies) (9,11,12,29,31–34). There was no significant difference in the grade distribution of interval and detected CRCs; interval CRCs were just as likely as detected CRCs to be well- to moderately differentiated (G1/G2: OR = 0.87, 95% CI = 0.71–1.06, I2 = 50%, five studies) (11,12,29,31,34).

Survival of interval CRCs. In a population-based cohort from Utah, Samadder et al. observed a better prognosis associated with interval CRCs as compared with detected CRCs, with a 37% lower risk of mortality (hazard ratio (HR) = 0.63, 95% CI = 0.49–0.81) (9). This survival benefit was seen both for early-stage cancer (stage 1: HR = 0.77, 95% CI = 0.52–1.15) as well as advanced stage cancer (stage 3: HR = 0.50, 95% CI = 0.29–0.88; stage 4: HR = 0.48, 95% CI = 0.29–0.80). However, Singh et al. did not find a survival benefit associated with diagnosis of interval CRCs (interval CRC vs. detected CRC: HR = 0.99, 95% CI = 0.84–1.17) in their population-based cohort in Manitoba, Canada (12). Likewise, in the Danish nationwide study, Erichsen et al. did not observe any difference in 1-year (mortality rate ratio = 0.92, 95% CI = 0.82–1.0) and 5-year survival (mortality rate ratio = 1.0, 95% CI = 0.88–1.20) of interval and detected CRCs (32). Single-center studies also did not find differences in 5-year survival of patients with interval or detected CRCs (19).

DISCUSSION In this systematic review of 12 observational studies (including 10 population-based studies) on 139,813 patients with CRC of whom 7,912 patients had interval CRCs, we made several key observations. First, approximately 3.7% (95% CI = 2.8–4.9%) or 1 in 27 (95% CI = 20–36) CRCs could be classified as interval CRCs, occurring within 3 years of a colonoscopy, with a nonsignificant decline in rate over the last two decades. As compared with detected cancers, interval CRCs were 2.4 times more likely to be located in the proximal colon than the distal colon and were less likely to present at an advanced stage. Second, several clinical- and endoscopy-related risk factors were associated with a higher risk of interval CRCs, albeit with moderate-considerable heterogeneity across studies. Patients with interval CRCs were older, had more comorbidities, were more likely to have a family history of CRC, and were 4.3 times more likely to have diverticular disease, as compared with patients with detected CRCs. Measures of quality of endoscopists were also related to risk of interval CRCs; patients whose index colonoscopy was performed by endoscopists with high polypectomy and procedure completion rates were less likely to develop interval CRCs as were those with index colonoscopy performed by a gastroenterologist. Third, from a tumor biology perspective, interval CRCs were more likely to have MSI and have positive CIMP status, which correlates with the proximal location, lower stage at presentation, and perhaps more rapid carcinogenThe American Journal of GASTROENTEROLOGY

esis, than observed with detected CRCs developing through the traditional pathway (37). Although one study suggested a survival benefit for interval CRCs after adjusting for stage, other studies do not suggest any significant difference in the mortality of patients with interval or detected CRCs; importantly, there is no suggestion that these tumors are overall more aggressive and carry a worse prognosis, than detected CRCs. It should be noted that, in accordance with the GRADE approach, given the high degree of heterogeneity observed among the studies in the analysis and the observational nature of the individual studies, the overall quality of evidence in this systematic review was rated as very low. Routine CRC screening with colonoscopy has been associated with a 50–80% lower risk of CRC, with greater reduction in the risk of distal CRC (6,7,38). Interval CRCs have limited the benefit accrued through colonoscopic screening as well as that of colonoscopy performed to follow-up the positive results of other CRC screening tests. The etiology of interval CRCs is multifactorial— broadly, interval CRCs have been categorized as (i) those arising because of missed lesions, either owing to inadequate examination (poor bowel preparation, incomplete colonoscopy) or because of incomplete visualization (or failure to recognize a polyp despite visualization of bowel segment), (ii) arising from incomplete resection of a recognized dysplastic polyp, (iii) arising de novo, as new, rapidly forming cancers, and (iv) arising as a result of failure of biopsy to identify a lesion as a CRC (13,19,39). In a pooled multicohort analysis of 9,167 participants in eight randomized chemoprevention trials, followed over a median 4 years, Robertson and colleagues identified 58 interval CRCs. Using this classification scheme for etiology of interval CRCs, they classified 30 cancers (52%) as probable missed lesions, 11 (19%) as possibly related to incomplete resection of an earlier, noninvasive lesion, 14 (24%) as probable new lesions, and 3 cases (5%) because of failed biopsy detection (13). Using a similar scheme, le Clercq and colleagues attributed 147 interval CRCs arising within 5 years of a colonoscopy to (i) missed lesions—85 CRCs (58%), (ii) inadequate examination—29 CRCs (20%), (iii) incomplete resection of an identified polyp—13 (9%), and (iv) newly developed CRCs—20 (13%) (34). In this systematic review, we were able to identify patient- and endoscopists-related factors that may contribute to increased risk of interval CRCs through these mechanisms. Older age, increasing comorbidities as well as diverticulosis have been associated with suboptimal bowel preparation interfering with mucosal visualization as well as higher risk of incomplete colonoscopy thereby increasing the risk of missed lesions. Technical or endoscopistrelated factors have also been implicated in modifying interval CRC risk. In a systematic review of six studies using tandem colonoscopy, the pooled polyp miss rate of any size was 22%; by polyp size, the miss rate was 2%, 13% and 26% for polyps ≥10, 5–10 and 1–5 mm, respectively (40). Even among experienced academic endoscopists, there is a high variability of adenoma detection rate, a robust measure of colonoscopic quality. Kahi and colleagues observed that as compared with the endoscopist with the highest adenoma detection rate, relative adenoma detection rates for individual endoscopists ranged from 36 to 98%; relative proximal serrated polyp detection rates ranged from 6 to 72% (41). Besides VOLUME 109 | SEPTEMBER 2014 www.amjgastro.com

higher risks of incomplete colonoscopy and missed lesions, even therapeutic interventions such as polypectomy are endoscopist dependent. In our review, we observed that patients with interval CRCs were 1.6 times more likely to have undergone a polypectomy during their index colonoscopy as compared with patients with detected CRCs; in these patients, incomplete polypectomy may have contributed to interval CRCs. In a prospective study of 1,497 patients in whom 346 neoplastic polyps were identified in 269 patients by 11 gastroenterologists, Pohl et al. observed that 10.1% of polyps were incompletely resected, with a higher risk of incomplete resection for large polyps (≥10 mm vs. 5–9 mm: RR = 2.1) and sessile serrated adenomas than for conventional adenomas (RR = 3.7) (42). In a randomized controlled trial, incomplete polyp resection rate was estimated to be 7.8% for cold snare polypectomy, compared with 24.1% for cold biopsy polypectomy (43). Accelerated tumorigenesis may also contribute to a small proportion of interval CRCs. Although the mean sojourn time of 3–6 years is applicable to tumors arising through the traditional adenoma-carcinoma sequence, some interval CRCs appear to have a different molecular phenotype. In this systematic review, we observed that a consistently higher proportion of interval CRCs are CIMP positive and have MSI, suggesting a biology similar to that observed in Lynch syndrome (8). This may also explain the better prognosis of interval CRCs, which are less likely to present at an advanced stage as compared with detected CRCs and a potential survival advantage (37). Strengths and limitations

The strengths of this systematic review include: (i) comprehensive and systematic literature search with well-defined inclusion criteria; (ii) limiting quantitative analysis to population-based and multicenter studies, which are more representative of community practice to allow estimation of burden of problem; (iii) exclusion of single-center and referral-center studies, which are at high risk of selection and misclassification bias, from the quantitative synthesis; (iv) quantitatively and qualitatively studying all aspects of interval CRCs, including prevalence, risk factors, and outcomes; and (v) sub-group and sensitivity analyses to evaluate the stability of findings and identify potential factors responsible for inconsistencies. Our study has several limitations, both at the meta-analysis level and individual study level. At the meta-analysis level, significant heterogeneity was observed in the pooled estimate of prevalence of interval CRCs. Heterogeneity is not uncommon in prevalence metaanalysis, partly due to large sample size of individual studies with precise estimates resulting in statistical heterogeneity (23,44,45). At a conceptual level, heterogeneity could be due to various factors, both implicit (patient characteristics such as age, comorbidities including presence or absence of inflammatory bowel disease) and explicit (study setting, differences in study design, definition of interval CRCs). We tried to minimize conceptual heterogeneity, by using strict inclusion and exclusion criteria in study design. We also performed pre-planned subgroup analyses to assess stability of association and explore sources of heterogeneity, and observed that multicenter studies generally report a lower prevalence of interval © 2014 by the American College of Gastroenterology

CRCs potentially due to misclassification of cases, as compared with population-based studies. Further, on post-hoc interpretation of the data, three studies in particular reported higher rates of prevalence of interval CRC (10,12,31). Although it is difficult to attribute the higher observed prevalence of interval CRCs in these studies to any clear factor, these studies had subtle differences as compared with some of the other included studies. In these studies, a significant proportion of colonoscopies were performed by non-gastroenterologists—62.9% in study by Baxter et al., 82.6% in the study by Singh et al. and 40.8% in the study by Cooper et al. In our analysis, we have observed that rates of interval CRC are higher if the index colonoscopy was performed by a non-gastroenterologist. Hence, it is possible that higher observed rates of interval CRC in these studies, is partly attributed to differences in specialty of performing endoscopist. Regardless, the presence of considerable heterogeneity for most of the analyses does decrease the confidence in a single summary estimate for prevalence of interval CRC and decreases the rating of the overall quality of evidence. Second, in our attempt to quantify risk factors associated with interval CRCs, we used available adjusted and unadjusted data from individual studies for pooling. Unfortunately, multivariate analysis was inconsistently reported with adjustment for different confounding variables across studies, and this somewhat limits the inference that can be drawn from these observations. We acknowledge that pooling unadjusted estimates is not able to account for confounding factors, and the implicated risk factors observed through this analysis, may not necessarily be due to the single studied factor, but rather a conglomeration of factors that go together in these patients (e.g., old age, comorbidities, diverticular disease, etc.). It should be noted, however, that results of adjusted and unadjusted analysis were fairly similar suggesting that any impact of confounding factors is limited. Finally, we defined interval CRC as those occurring within 6–36 months of an index colonoscopy (also referred to as postcolonoscopy CRCs), regardless of whether an alternative screening strategy (flexible sigmoidoscopy, stool-based tests, etc.) had been used before or after index colonoscopy. Moreover, this colonoscopy was not necessarily a screening examination, but had been performed for any indication. Hence, this analysis included a relatively heterogeneous cohort with some patients having had a “negative colonoscopy” (i.e., no adenomas identified) and others with an index colonoscopy showing adenomas. The surveillance follow-up interval ranges from 3 to 10 years, depending on findings on index colonoscopy. We chose 36 months as the upper limit for the definition, as that is the minimum recommended interval after removal of an advanced adenoma, for performance of a surveillance colonoscopy. Hence, our estimate of interval CRCs is conservative. At an individual study level, most of the included studies were population based, which are more representative of community practice and hence, generalizable. However, these vast studies were reliant on medical diagnostic codes and record linkage, which may result in misclassification of some patients. Data on patient level clinical and endoscopy characteristics, including indication for colonoscopy, quality of bowel preparation, completeness of colonoscopy etc., were not adequately captured. There was limited data The American Journal of GASTROENTEROLOGY

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on molecular phenotyping of interval CRCs, especially at a population-level to allow pooling; most of the data for qualitative review were available from two cohorts (15–18). Implications for clinical practice

Interval CRCs account for 2.8–4.9% of all CRCs, and are 2.4 times more likely to be proximal CRCs than are the detected CRCs. This risk should be discussed with patients at time of colonoscopy for shared discussion making. It has been estimated that missed lesions and incomplete polypectomy appear to be the underlying cause in ~50–70% of interval CRCs. Measures targeting these two problems, especially among patients at highest risk for interval CRCs, are likely to be most effective in decreasing the burden on interval CRCs. With greater use of more effective split-dose bowel preparations and increasing emphasis and adoption of quality metrics in colonoscopy, such as standardized reporting systems, adequate description of bowel preparation, endoscopists’ cecal intubation rate > 90%, withdrawal time > 6 min, and adenoma detection rate > 15–25%, as well as better recognition of serrated polyps, the likelihood of missed lesions is expected to decrease. Adoption of potentially better endoscopic techniques for complete polypectomy, such as routine use of hot snare polypectomy and submucosal injection to define polyp borders better, especially for larger polyps as well as shorter interval colonoscopy in case of suspected incomplete polyp resection, may decrease the risk and consequences of incomplete polyp resection. New and emerging technologies, such as high-definition colonoscopes, retroflexion, or wide-angle viewers, may allow a more thorough examination of the proximal colon and behind folds. In fact, on time-trend analysis, we observed that a trend toward a decrease in the proportion of interval CRCs from 1990s to 2010, potentially as a result of combination of these factors. CONCLUSION

Interval CRCs account for 2.8–4.9% of all sporadic CRCs, with a significantly higher proportion being proximal in origin. Several clinical-related (advanced age, family history of CRC, higher comorbidities, presence of diverticular disease, and history of polypectomy), endoscopy-related (low polypectomy rate, low procedural completion rate, procedural performance by a non-gastroenterologist) and biology-related (MSI, CIMP positivity) risk factors are associated with interval CRCs. With improvements in quality of colonoscopy to decrease miss rates and increase complete polypectomy rates as well as better understanding of tumor biology, the risk of interval CRCs should decrease. ACKNOWLEDGMENTS

We thank Mr Larry Prokop, M.L.S., Senior Medical Librarian at the Mayo Clinic Library for helping in the literature search for this systematic review and meta-analysis. CONFLICT OF INTEREST

Guarantor of the article: N. Jewel Samadder, MD, MSc, FRCPC. Specific author contributions: Study concept and design: S.S., N.J.S.; Acquisition of data: S.S., P.P.S., N.J.S.; Statistical analysis: The American Journal of GASTROENTEROLOGY

S.S., M.H.M.; Interpretation of results: S.S., H.S., N.J.S.; Drafting of the manuscript: S.S.; Critical revision of the manuscript for important intellectual content: P.P.S., M.H.M., H.S., N.J.S.; Approval of the final manuscript: S.S., P.P.S., M.H.M., H.S., N.J.S.; Study supervision: N.J.S. Financial support: None. Potential competing interests: None.

Study Highlights WHAT IS CURRENT KNOWLEDGE

3Colonoscopy is associated with decreased incidence of and mortality from colorectal cancer (CRC). 3A small proportion of patients may develop ‘interval’ CRC after index colonoscopy before the next recommended surveillance examination.

WHAT IS NEW HERE

3About 1 in 27 (95% CI = 20–36) CRCs are interval cancers, developing within 6–36 months of a colonoscopy, and are 2.4 times more likely to arise in the proximal colon. However, because of considerable heterogeneity among the studies, the overall confidence in these estimates is low.

3Patient (older age, diverticulosis, presence of comorbidi-

ties), endoscopy (low polypectomy rate, low procedure completion rate, procedural performance by a non-gastroenterologist), and tumor biology-related factors (microsatellite instability and CpG island methylator phenotype positive) are associated with interval CRC.

3Interval CRCs are more likely to be diagnosed at an early stage, and their outcomes are comparable to those for detected CRCs. REFERENCES

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Epidemiology of Interval Colorectal Cancers

Prevalence, risk factors, and outcomes of interval colorectal cancers: a systematic review and meta-analysis.

We performed meta-analysis to estimate pooled prevalence, risk factors, and outcomes of interval colorectal cancers (CRCs)...
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