There is substantial indirect evidence for the effectiveness of colonoscopy in reducing colorectal cancer incidence and mortality. However, several recent studies have raised questions on the magnitude of effect for right-sided colorectal cancers. Well-documented variation in outcomes when colonoscopy is performed by different groups of endoscopists suggests that the recent emphasis on the quality of the procedures should lead to improved outcomes after colonoscopy including reduction in incidence and mortality due to right-sided colorectal cancers.
Key points
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Although the 3 large randomized controlled trials assessing efficacy of colonoscopy were initiated only recently, there is already substantial indirect evidence for the effectiveness of colonoscopy in reducing colorectal cancer incidence and mortality.
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However, several recently published observational studies suggest that colonoscopy has had a lower magnitude of benefit in reducing right-sided colorectal cancer incidence and mortality than that of left-sided colorectal cancers. This finding has raised questions on the magnitude of incremental benefit of colonoscopy compared with flexible sigmoidoscopy.
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The reports of variation in performance and outcomes after colonoscopy by different groups of endoscopy physicians, especially for the right-sided colorectal cancers, suggests that the recent quality assurance and enhancement efforts and technical advances in colonoscopy should lead to improvements in outcomes after colonoscopy.
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Because colonoscopy is an essential initial, intermediate, or final test for colon cancer screening and detection, improvements in outcomes after colonoscopy will benefit all undergoing colorectal cancer screening or detection, irrespective of the initial choice of the screening test.
Introduction
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. It is estimated that up to 52,000 deaths will be attributed to CRC in the United States in 2012. There has been a steady decline in age-adjusted incidence rates of CRC in the US over the last 3 decades. A substantial recent decline in CRC incidence has been attributed to the removal of premalignant polyps detected on screening. In addition, the removal of the adenomatous colon polyps and early-stage detection of CRC by screening have been shown to lead to reduction in CRC mortality.
CRC screening with fecal occult blood testing (FOBT) or flexible sigmoidoscopy (FS) has been shown in randomized controlled trials (RCTs) to lead to reduction in CRC mortality. However, the benefits of primary screening colonoscopy for CRC have not yet been established in an RCT of colonoscopy, and there is indirect evidence for the role of colonoscopy in CRC screening. Three RCTs of primary screening colonoscopy have recently been launched to address the unresolved issues.
In the United States, colonoscopy has become the most commonly used modality for CRC screening. A recent survey found that, in the United States, 95% of primary care physicians recommend colonoscopy as the preferred CRC screening modality. Compared with FOBT, which primarily detects CRC and not adenomas, and FS, which mainly reduces distal CRC incidence and mortality, colonoscopy has the theoretic advantage of providing complete colonic examination and detecting and removing adenomas in both sides of the colon at the same time. In average-risk screening populations, colonoscopy has extremely low risk of serious adverse side effects. However, it is an invasive procedure and it has to be done at long intervals to maintain a risk/benefit ratio that is acceptable for a screening test.
This article discusses the effect of colonoscopy on CRC incidence and mortality. However, it first discusses the importance of evaluating CRC incidence and mortality as highlighted by the limitations of assessing surrogate markers such as detection of advanced adenomas and improved survival after detection of CRC on screening.
Introduction
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. It is estimated that up to 52,000 deaths will be attributed to CRC in the United States in 2012. There has been a steady decline in age-adjusted incidence rates of CRC in the US over the last 3 decades. A substantial recent decline in CRC incidence has been attributed to the removal of premalignant polyps detected on screening. In addition, the removal of the adenomatous colon polyps and early-stage detection of CRC by screening have been shown to lead to reduction in CRC mortality.
CRC screening with fecal occult blood testing (FOBT) or flexible sigmoidoscopy (FS) has been shown in randomized controlled trials (RCTs) to lead to reduction in CRC mortality. However, the benefits of primary screening colonoscopy for CRC have not yet been established in an RCT of colonoscopy, and there is indirect evidence for the role of colonoscopy in CRC screening. Three RCTs of primary screening colonoscopy have recently been launched to address the unresolved issues.
In the United States, colonoscopy has become the most commonly used modality for CRC screening. A recent survey found that, in the United States, 95% of primary care physicians recommend colonoscopy as the preferred CRC screening modality. Compared with FOBT, which primarily detects CRC and not adenomas, and FS, which mainly reduces distal CRC incidence and mortality, colonoscopy has the theoretic advantage of providing complete colonic examination and detecting and removing adenomas in both sides of the colon at the same time. In average-risk screening populations, colonoscopy has extremely low risk of serious adverse side effects. However, it is an invasive procedure and it has to be done at long intervals to maintain a risk/benefit ratio that is acceptable for a screening test.
This article discusses the effect of colonoscopy on CRC incidence and mortality. However, it first discusses the importance of evaluating CRC incidence and mortality as highlighted by the limitations of assessing surrogate markers such as detection of advanced adenomas and improved survival after detection of CRC on screening.
Colonoscopy and detection of advanced adenomas
Colonoscopy has dominated in the United States since Medicare’s decision to cover screening colonoscopy in average-risk persons in 2001, and similar decisions by other third-party payers. Endorsements by celebrities and heightened media attention have helped to increase public acceptance and demand for screening colonoscopy. These developments followed the landmark US Department of Veterans Affairs (VA) and Eli Lilly cohort studies published in 2000, which established that colonoscopy detects higher proportions of advanced adenomas than could be detected by FS or FOBT. In the VA cohort study, Lieberman and colleagues examined the role of colonoscopic screening to identify advanced colonic neoplasia in asymptomatic adults at 13 VA medical centers across the country. Advanced colonic neoplasia was defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. The study concluded that colonoscopy found advanced colonic neoplasia in 37.5% of asymptomatic adults. Imperiale and colleagues showed that asymptomatic adults 50 years of age or older who have polyps in the distal colon are more likely to have advanced proximal colon neoplasia than are adults without a distal colon polyp. In addition, 46% of asymptomatic adults with proximal colonic neoplasia did not have any distal polyps. Both studies showed that screening colonoscopy can identify additional advanced colonic neoplasia in asymptomatic adults, which would have not been detected by FOBT or FS. Because advanced adenomas are the precursor lesions for most CRCs, it is intuitive that higher detection rates of advanced adenomas will lead to greater reductions in CRC incidence and mortality. However, only a minority of advanced adenomas are estimated to develop into CRC and hence the magnitude of reduction in CRC incidence and mortality, due to higher detection rate of right-sided advanced adenomas at colonoscopy is not known. The modeling studies used to estimate the benefits of colonoscopy depend on the model assumptions and often do not model the natural history of right-sided adenomas separately. There are biological differences between right-sided and left-sided CRCs and the natural history of right-sided polyps (adenomatous and serrated) may also be different.
Survival after detection of CRC on screening
There are powerful biases such as lead-time bias, length-biased sampling, and overdiagnosis that can be associated with observational studies of screening tests and can confound assessment of screening-test efficacy. Early detection of cancer advances the date of diagnosis and adds apparent survival time compared with symptomatic detection. However, early detection of the disease, if it does not translate into an overall longer lifespan for a given individual, introduces lead-time bias. Lead-time bias has important implications for the use of 5-year survival as an indicator for screening effectiveness. Improved 5-year overall survival rate, without accompanying improvement in cause-specific mortality, is likely caused by lead-time bias or length-biased sampling. Screening tests tend to discover less aggressive, slow-growing lesions compared with cancers discovered as a result of symptoms (length-biased sampling). Individuals found to have less aggressive cancers have longer 5 year survival after cancer diagnosis than those with more aggressive cancers, which are more likely to be detected at the symptomatic stage. Overdiagnosis is an extreme form of length-bias sampling in which, despite its pathologic appearance, the cancer either has no malignant potential or is so indolent that it cannot alter the remaining lifespan because the person will die of another cause first.
Current evidence for CRC incidence and mortality after colonoscopy
Most of the current knowledge regarding effectiveness of screening colonoscopy is derived from follow-up of the cohorts in the National Polyp Study, Minnesota FOBT study, observational studies, and from the assumed extension of benefit with FS screening shown in several randomized trials.
National Polyp Study
The National Polyp Study (NPS) was an RCT designed to evaluate the appropriate timing of surveillance colonoscopy for the patients found to have one or more colorectal adenoma. The NPS cohort consisted of 3778 patients who underwent polypectomy. Of these, 2632 patients had one or more adenomatous polyps. After exclusions, 2602 patients with adenomas and 773 patients without adenoma were identified. Of the 2602 patients with adenoma, 1418 patients were randomized to surveillance colonoscopy at varying intervals (1 year vs 3 years). All of these patients subsequently underwent a second colonoscopy during an average follow-up of 5.9 years. The study also compared incidence of CRC with 3 reference groups, including 2 polyp bearing cohorts (Mayo Clinic in Rochester, and St Mark’s Hospital in London, United Kingdom ) and 1 general population registry (Surveillance, Epidemiology, and End Results [SEER] registry). During follow-up colonoscopy, 5 asymptomatic early-stage CRCs were detected; 3 at 3 years, 1 at 6 years, and 1 at 7 years. The observed incidence of CRC per 1000 person-years was 0.6 in the study cohort, whereas the expected incidence was 5.7 per Mayo Clinic data, 5.2 per the St Mark’s data, and 2.5 per the SEER data. The standardized incidence ratio (SIR) for CRC in the NPS cohort was 0.10 (95% confidence interval [CI], 0.03–0.24) compared with the Mayo Clinic group, 0.12 (95% CI, 0.04–0.27) compared with the St Mark’s group, and 0.24 (95% CI, 0.08–0.56) compared with the SEER group, suggesting a 76% to 90% reduction in CRC incidence after colonoscopic polypectomy. The cohort component of this study was the first to show that colonoscopic polypectomy resulted in a lower-than-expected incidence of CRC and supported the practice of searching for and removing adenomatous polyps to prevent CRC. Most recently, the NPS investigators examined the long-term risk of CRC mortality in 3 groups of patients: (1) NPS patients who had adenoma (n = 2602), (2) NPS patients who did not have adenoma (n = 773), and (3) the general US population using data from SEER registry. The investigators used the National Death Index (NDI) to identify deaths and determine the cause of death, and compared the CRC mortality in each of the two study groups with that expected from the SEER registry. Median follow-up period for the study was 16 years, with maximum follow-up as long as 23 years. In the adenoma cohort (n = 2602), 12 patients died of CRC compared with 25.4 expected CRC deaths based on SEER registry data, suggesting 53% reduction in CRC mortality (standardized mortality ratio [SMR], 0.47; 95% CI, 0.26–0.80) with colonoscopic polypectomy. In the nonadenoma cohort (n = 773), only 1 patient died of CRC at 7.7 years after index colonoscopy. These findings support the hypothesis that colonoscopic removal of adenomatous polyps prevents death from CRC.
Minnesota FOBT Study
Mandel and colleagues evaluated the efficacy of CRC screening by FOBT in a randomized trial. They randomly assigned 46,551 participants who were 50 to 80 years of age to screening for CRC once a year, or twice a year using FOBT, or to a control group. Participants who tested positive for FOBT underwent further diagnostic evaluation including colonoscopy. Over a 13-year follow-up period, cumulative mortality per 1000 from CRC was 5.88 (95% CI, 4.61–7.15) in the annually screened group, 8.33 (95% CI, 6.82–9.84) in the biennially screened group, and 8.83 (95% CI, 7.26–10.40) in the control group. The annual FOBT decreased the 13-year cumulative mortality from CRC by 33%. In addition to reduction in mortality, improved survival in those with CRC and a shift in detecting an earlier stage of cancer were noted in the annually screened group. Among the screening group with positive FOBT, more than 96% of those examined underwent colonoscopy at the University of Minnesota Hospital and a total of 12,246 colonoscopies were performed. Overall, 38% of the individuals undergoing FOBT annually had at least 1 colonoscopy during the course of the study, which resulted in a 20% reduction in CRC incidence after a follow-up of 18 years. This is the only FOBT trial that has shown a reduction in CRC incidence after FOBT screening. This reduction in CRC incidence (and higher reduction in CRC mortality than in any other FOBT trial) has been attributed to the high proportion of individuals undergoing colonoscopy after FOBT testing in the Minnesota study, which was much higher than in any of the other FOBT trials, a difference attributed to the high positive rates of rehydrated FOBT used in the trial leading to higher colonoscopy use. Although the primary focus of the study was to evaluate the reduced mortality from CRC with use of FOBT, the higher reduction in CRC mortality and the reduction in CRC incidence in this trial provided an early hint of the effectiveness of colonoscopy in CRC screening.
Observational Studies of the Effectiveness of Screening Colonoscopy
Incidence and risk of occurrence of CRC after colonoscopy
Müller and colleagues performed a case-control study of 32,702 veterans in the United States ( Table 1 ). They identified 8722 cases of colon cancer; 7629 cases of rectal cancer; and age-matched, sex-matched, and race-matched controls for each case. Exposure to endoscopic procedures including FS, colonoscopy, and polypectomy before development of CRC was evaluated. Compared with controls, patients with CRC were less likely to have undergone colonoscopy before being diagnosed with colon cancer (odds ratio [OR] 0.47; 95% CI, 0.37–0.58) or rectal cancer (OR, 0.61; 95% CI, 0.48–0.77). Kahi and colleagues assessed CRC incidence and mortality in a group of asymptomatic average-risk patients who underwent screening colonoscopy between 1989 and 1993 at a university hospital. Using the SIRs and SMRs, they compared the observed CRC rates with the expected rates from the SEER data. They found 12 cases of CRC in the cohort of 715 patients with 10,492 patient-years of follow-up. In their cohort, the SIR for CRC was 0.33 (95% CI, 0.10–0.62). Compared with SEER data, relative risk reduction for CRC incidence was 67%. Singh and colleagues performed a cohort study using an administrative claims database. After negative colonoscopy, they found an overall low incidence of CRC in men (SIR, 0.59; 95% CI, 0.50–0.70) and women (SIR, 0.71; 95% CI, 0.61–0.83). Brenner and colleagues compared a total of 1688 patients with CRC with 1932 control participants aged 50 years or older in a population-based case-control study in Germany. In this study, colonoscopy in the preceding 10 years was associated with strong risk reduction (OR, 0.23; 95% CI, 0.19–0.27) for CRC. The same group of investigators evaluated the risk of CRC after detection and removal of at least 1 adenoma at colonoscopy in 2582 cases of CRC against 1798 matched controls. Colonoscopy with polypectomy was associated with a strong risk reduction of CRC up to less than 3 years (OR, 0.2; 95% CI, 0.2–0.3) and 3 to 5 years (OR, 0.4; 95% CI, 0.3–0.6), even after detection and removal of high-risk polyps.
| Source | Location and Study Type | Study Database | Study Period | Number (N) | Follow-up (y) | CRC Risk | Other Details in the Study | |||
|---|---|---|---|---|---|---|---|---|---|---|
| Müller et al, 1995 | United States | VA | 1988–1993 | 16,351 with CRC vs general veterans population; exposure to endoscopic procedures including FS, colonoscopy and polypectomy | 10 | OR 0.47 (0.37–0.58) Colon cancer | Flexible sigmoidoscopy | |||
| Case control | OR 0.61 (0.48–0.77) rectal cancer | OR 0.56 (0.46–0.67) colon cancer | ||||||||
| OR 0.61 (0.49–0.75) rectal cancer | ||||||||||
| Singh et al, 2006 | Canada | Administrative claims data in Manitoba, Canada | 1989–2003 | 35,975 with negative colonoscopy compared with expected CRC rates in general population | >10 | Incidence SIR | The proportion of CRC located in the right side of the colon was significantly higher in the colonoscopy cohort than the rate in the Manitoba population (47% vs 28%; P <.001) | |||
| Cohort | >6 mo | 0.69 (0.59–0.81) | ||||||||
| >1 y | 0.66 (0.56–0.78) | |||||||||
| >2 y | 0.59 (0.48–0.72) | |||||||||
| >5 y | 0.55 (0.41–0.73) | |||||||||
| >10 y | 0.28 (0.09–0.65) | |||||||||
| Lakoff et al, 2008 | Canada | Administrative claims data in Ontario, Canada | 1992–1997 | 110,402 with negative colonoscopy compared with rates in population | Up to 14 | Incidence RR | Consistent reduction in risk of proximal CRC seen only from 10 to 14 y of follow-up | |||
| Cohort | Year 2 | 0.80 (0.66–0.93) | ||||||||
| Year 3 | 0.65 (0.54–0.77) | |||||||||
| Year 5 | 0.56 (0.46–0.67) | |||||||||
| Year 10 | 0.45 (0.34–0.55) | |||||||||
| Year 14 | 0.25 (0.12–0.37) | |||||||||
| Kahi et al, 2009 | United States | University Hospital Screening Colonoscopy Database vs SEER Registry | 1989–1993 | 715 patients with 10,492 patient-years follow-up | Up to 18 | SIR 0.33 (0.10–0.62) | — | |||
| Cohort | ||||||||||
| Singh et al, 2010 | Canada | Manitoba’s provincial physician’s billing claims database | 1989–2006 | 45,985 with negative colonoscopy compared with expected rates of CRC in population | >10 | — | SIR (Men) | SIR (Women) | Proximal vs distal CRC in men and women: There was no reduction in the risk of proximal CRC among men or women in the first 5 y following the index colonoscopy. Distal CRC risk was reduced in all of the follow-up time among both men and women. | |
| Cohort | 6–12 mo | 0.53 (0.25–0.98) | 1.27 (0.81–1.89) | Risk factors for early CRC (6–36 mo after index colonoscopy) included proximal site of CRC and specialty of endoscopist | ||||||
| 13–24 mo | 0.64 (0.40–0.97) | 0.97 (0.67–1.36) | ||||||||
| 25–36 mo | 0.71 (0.44–1.08) | 0.84 (0.55–1.23) | ||||||||
| 3–5 y | 0.59 (0.38–0.89) | 0.53 (0.35–0.77) | ||||||||
| 5–10 y | 0.55 (0.39–0.76) | 0.60 (0.45–0.80) | ||||||||
| >10 y | 0.53 (0.28–0.90) | 0.51 (0.28–0.83) | ||||||||
| Brenner et al, 2011 | Germany | Rhine-Neckar region population registry | 2003–2007 | 1945 CRC vs 2399 controls | Up to 20 | Incidence OR | Also examined the risk in smokers and men and women | |||
| Case control | 1–2 y | 0.14 (0.10–0.20) | ||||||||
| 3–4 y | 0.12 (0.08–0.19) | |||||||||
| 5–9 y | 0.26 (0.18–0.39) | |||||||||
| 10–19 y | 0.28 (0.17–0.45) | |||||||||
| 20+ y | 0.40 (0.24–0.66) | |||||||||
| Brenner et al, 2011 | Germany | Rhine-Neckar region population registry | 2003–2004 | 1688 CRC vs 1932 controls aged more than 50 y | 10 | OR 0.23 (0.19–0.27) | Proximal CRC OR 0.44 (0.35–0.55) | |||
| Case control | Distal CRC OR 0.16 (0.12–0.20) | |||||||||
CRC mortality after colonoscopy
Müller and Sonnenberg showed that colonoscopy reduced the mortality from CRC (OR, 0.45; 95% CI, 0.30–0.66) for the comparison with living control patients in a case-control study among veterans ( Table 2 ). Kahi and colleagues found 3 deaths from CRC in a cohort of 715 patients with 10,492 patient-years of follow-up. Compared with SEER data, they found 65% relative risk reduction in CRC mortality (SMR, 0.35; 95% CI, 0.0–1.06). Baxter and colleagues performed a population-based case-control study in Ontario, Canada. They evaluated prior exposure to complete colonoscopy in 10,292 cases of CRC and 51,460 controls matched by age, sex, geographic location, and socioeconomic status. Compared with controls, cases were less likely to have undergone complete colonoscopy (OR, 0.63; 95% CI, 0.57–0.69). Complete colonoscopy was strongly associated with fewer deaths from left-sided CRC (OR, 0.33; 95% CI, 0.28–0.39) but not from right-sided CRC (OR, 0.99; 95% CI, 0.86–1.14). Singh and colleagues showed a 29% reduction in overall CRC mortality (SMR, 0.71; 95% CI, 0.61–0.82) with the use of colonoscopy compared with the general population. Once again, colonoscopy was associated with fewer deaths from left-sided CRC (SMR, 0.53; 95% CI, 0.42–0.67) but not from right-sided CRC (SMR, 0.94; 95% CI, 0.77–1.17). Baxter and colleagues performed another case-control study using the SEER-Medicare data. They identified patients diagnosed with CRC (aged 70–89 years) who died as a result of CRC, and selected 3 matched controls without cancer for each case. They identified prior exposure to colonoscopy up to 6 months before the diagnosis of CRC in the case group and to the referent date of CRC in the control group. Overall, 11.3% of cases and 23.7% of controls underwent colonoscopy more than 6 months before the diagnosis. Compared with the controls, cases were less likely to have undergone colonoscopy (OR, 0.40; 95% CI, 0.37–0.43). The association was stronger for distal (OR, 0.24; 95% CI, 0.21–0.27) than proximal (OR, 0.58; 95% CI, 0.53–0.64) CRC.
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