Colorectal Cancer Screening (PDQ®)—Health Professional Version - National Cancer Institute

Colorectal Cancer Screening (PDQ®)–Health Professional Version

Colonoscopy

Because there are no completed RCTs of colonoscopy, evidence of benefit is indirect. Most indirect evidence is about detection rate of lesions that may be clinically important (like early CRC or advanced adenomas). Some case-control results are available. Three RCTs (NCT01239082, NCT00883792, and NCT00906997) of colonoscopy have been initiated.

The Nordic-European Initiative on Colorectal Cancer (NordICC) is a population-based randomized trial to investigate the effectiveness of colonoscopy screening on CRC incidence and mortality in several European countries (Norway, Poland, Sweden, and the Netherlands). NordICC comprises 94,959 men and women aged 55 to 64 years who were randomly selected from population registers and randomly assigned in a 1:2 ratio to one time colonoscopy screening or no screening. Control participants were not contacted. The primary endpoint is a comparison of the 15-year CRC mortality rates. Participation rates, participant experience, lesion yield, and complications of colonoscopy screening in the participating countries have been reported.[46]

Among 31,420 eligible participants randomly assigned to colonoscopy, 12,574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8,816), 39.8% in Sweden (486 of 1,222), 33.0% in Poland (6,004 of 18,188), and 22.9% in the Netherlands (730 of 3,194). The cecum intubation rate of 97.2% was very similar across countries, with 9,726 participants (77.4%) not receiving sedation—10.8% in Norway rising to 90% in the Netherlands. Among the 12,574 screenees, there was one perforation (0.01%), two postpolypectomy serosal burns (0.02%), and 18 cases of bleeding caused by polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with CRC (50 distal and 14 proximal) and 3,861 (30.7%) had adenomas. There were 725 (5.8%) distal versus 562 (4.5%) high-risk adenomas, and 2,439 (19.4%) distal versus 1,078 (8.6%) proximal serrated polyps. Performance differed significantly among endoscopists; recommended benchmarks for cecal intubation (95%) were not met by 17.1% of endoscopists and benchmarks for adenoma detection (25%) were not met by 28.6% of endoscopists. Moderate or severe abdominal pain after colonoscopy was reported by 16.7% of participants examined with standard air insufflation versus 4.2% examined with carbon dioxide (CO2) insufflation.[46]

Prevalence of lesions in asymptomatic populations

In a colonoscopy study of 3,121 predominantly male U.S. veterans (mean age, 63 years), advanced neoplasia (defined as an adenoma that was ≥10.0 mm in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer) was identified in 10.5% of the individuals.[47] Among patients with no adenomas distal to the splenic flexure, 2.7% had advanced proximal neoplasia. Patients with large adenomas (≥10.0 mm) or small adenomas (<10.0 mm) in the distal colon were more likely to have advanced proximal neoplasia (OR, 3.4; 90% CI, 1.8–6.5) than were patients with no distal adenomas (OR, 2.6; 90% CI, 1.7–4.1). One-half of those with advanced proximal neoplasia had no distal adenomas. In a study of 1,994 adults (aged 50 years or older) who underwent colonoscopy screening (as part of a program sponsored by an employer), 5.6% had advanced neoplasms.[48] Forty-six percent of those with advanced proximal neoplasms had no distal polyps (hyperplastic or adenomatous). If colonoscopy screening is performed only in patients with distal polyps, about half the cases of advanced proximal neoplasia will not be detected.

A study of colonoscopy in women compared the yield of sigmoidoscopy versus colonoscopy. Of the 1,463 women, cancer was found in 1 woman and advanced colonic neoplasia was found in 72 women (4.9%), which is about 50% of the prevalence in men. The authors focused, however, on RR (i.e., RR of missing an advanced neoplasm) as the outcome, instead of absolute risk of such neoplasms, which is substantially lower in women. In addition, the natural history of advanced neoplasia is not known, so its importance as an outcome in studies of detection is not clear.[49]

Analysis of data from a colonoscopy-based screening program in Warsaw, Poland demonstrated higher rates of advanced neoplasia in men than in women. Of the 43,042 participants aged 50 to 66 years, advanced neoplasia was detected in 5.9% (5.7% in women with a family history of CRC, 4.3% in women without a family history of CRC, 12.2% in men with a family history of CRC, and 8.0% in men without a family history of CRC). Clinically significant complications requiring medical intervention were rare (0.1%), consisting of five perforations, 13 episodes of bleeding, 22 cardiovascular events, and 11 other events over the entire population of 50,148 screened persons. There were no deaths. The authors also reported that collection of 30-day complications data was not systematic; therefore, the data may not be reliable.[50]

Detection of right-sided versus left-sided lesions

Flat or difficult-to-detect lesions include serrated polyps, which may be more common in the right colon than in the left. The term serrated polyp is currently used to include hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed serrated polyps.[51,52] The clinical significance of these lesions is uncertain because the natural history of any polypoid lesion is difficult to learn. However, the histologic and molecular characteristics of some serrated lesions suggest possibly important malignant potential (e.g., mutations in the BRAF gene may be an early step toward carcinogenesis in serrated polyps).[53] This potential, along with the challenges of detecting flat lesions, may partially account for recent reports of a colonoscopy's lesser protective effect in the right colon compared to the left colon.

In 2011, authors of one study reported variability of detection rates for proximal serrated polyps. They studied 15 colonoscopists on faculty at one university and showed, during the years 2000 to 2009 and observed a wide variation in detection rates for proximal serrated polyps, ranging (per colonoscopy) from 0.01 to 0.26, suggesting that many proximal serrated lesions may be missed on routine exam.[51] The overall proportion of polyps that are serrated is unknown, in part because these lesions have been unappreciated and/or difficult to identify.

Adenoma detection rate (ADR)

Detection rates in colonoscopy screening vary with the rate at which the endoscopist examines the colon while withdrawing the scope. In one study, there were differences among gastroenterologists in the rates of detection of adenomas (range of the mean number of lesions per patient screened, 0.10–1.05; range of the percentage of patients with adenomas, 9.4%–23.7%) and the times of withdrawal of the scope (3.1–16.8 minutes for procedures not including polyp removal). Examiners whose mean withdrawal time was 6 minutes or more had higher detection rates than those with mean withdrawal times of less than 6 minutes (28.3% vs. 11.8%; P < .001 for any neoplasia and 6.4% vs. 2.6%; P < .005 for advanced neoplasia).[54]

In the first 10 years of the German CRC screening program, detection of nonadvanced adenomas increased in men from 13.3% to 22.3% and in women from 8.4% to 14.9%. The great majority of the nonadvanced adenomas, however, were small (<0.5 cm) and had uncertain clinical significance. The detection of advanced adenomas and CRC increased by a much smaller amount.[55]

Overall detection rate of adenomas and cancer may be affected by how thoroughly endoscopists search for flat adenomas and flat cancer. While the phenomenon of flat neoplasms has been appreciated for years in Japan, it has more recently been described in the United States. In a study in which endoscopists used high-resolution white-light endoscopes, flat or nonpolypoid lesions were found to account for only 11% of all superficial colon lesions, but these flat or nonpolypoid lesions were about 9.8 times as likely as polypoid lesions to contain cancer (in situ neoplasia or invasive cancer).[39] However, because the definition of flat or nonpolypoid was height less than one-half of the diameter, it is likely that many lesions classified as nonpolypoid in this study would be routinely found and described by U.S. endoscopists as sessile. The existence of very flat or depressed lesions—depressed lesions are very uncommon but are highly likely to contain cancer—requires that endoscopists pay increasing attention to this problem.[56] Flat lesions may play a role in the phenomenon of missed cancers.[57]

The impact of ADRs was assessed by a health maintenance organization in follow-up after 314,872 colonoscopies done from 1998 to 2010 by 136 gastroenterologists, each of whom had done at least 300 colonoscopies during that period. The goal was to determine rates of interval CRC, interval advanced CRC, and CRC death, and to relate those rates to a gastroenterologist’s ADR. There were 712 interval cancers (155 advanced) and 147 CRC deaths. The risk of interval cancer from lowest-to-highest quintile of ADR was 9.8, 8.6, 8.0, 7.0, and 4.8 per 10,000 person-years of follow-up. The adjusted HR, for physicians in the highest quintile compared with the lowest, was 0.52 for any interval CRC, 0.43 for advanced CRC, and 0.38 for fatal CRC. Each 1.0% increase in ADR was associated with a 3% decrease in risk of cancer, although the CI for each quintile was broad. Limitations of the study include the inability to determine which specific feature of ADR led to reduced interval cancer; for example, it is unclear whether it was due to the following:

Removal of small adenomas that may grow rapidly to become CRC.
ADR being a surrogate outcome for an endoscopist’s ability to more completely remove adenomas.
ADR being a surrogate outcome for an endoscopist’s ability to better detect large, flat, serrated lesions.
Higher ADR leading to recommendations for more frequent postpolypectomy surveillance colonoscopy.

Another limitation is that the harms of a colonoscopy associated with ADR could not be measured.[58]

Nonrandomized controlled trial evidence about colorectal cancer incidence or mortality reduction

Although there is no RCT to assess reduction of CRC incidence or mortality by colonoscopy, some case-control evidence is available. Based on case-control data about sigmoidoscopy, noted above, it has been speculated in the past that protection for the right colon might be similar to that found for the left colon. A 2009 case-control study of colonoscopy raised questions about whether the impact of colonoscopy on right-sided lesions might be different than the impact on left-sided lesions.[59] Using a province-wide administrative database in Ontario, Canada, investigators compared cases of persons who had received a diagnosis of CRC from 1996 to 2001 and had died by 2003. Controls were selected from persons who did not die of CRC. Billing claims were used to assess exposure to previous colonoscopy. The OR for the association between complete colonoscopy and left-sided lesions was 0.33, suggesting a substantial mortality reduction. For right-sided lesions, however, the OR of 0.99 indicated virtually no mortality reduction. However, this study had limited data about whether examinations were complete to the cecum and about bowel prep. Further, many endoscopists were nongastroenterologists.

A case-control study assessed CRC reduction (not CRC mortality reduction) in the right side versus the left side. In a population-based study from Germany, data were obtained from administrative records and medical records; 1,688 case patients (with CRC) were compared with 1,932 participants (without CRC), aged 50 years or older.[60] Data were collected about demographics, risk factors, and previous screening examinations. According to colonoscopy records, the cecum was reached 91% of the time. Colonoscopy in the previous 10 years was associated with an OR for any CRC of 0.23, for right-sided CRC of 0.44, and for left-sided CRC of 0.16. While this study did not assess CRC mortality, the results suggested that the magnitude of the right-side versus the left-side difference may be smaller than previously found.[59] It would be extremely useful to assess right side-versus left side differences in a RCT.

Other case-control data suggest a reduction of CRC incidence on the right-side of about 64% compared with about 74% on the left-side.[61]

Because there is no RCT evidence and case-control evidence is limited, it is important to consider the degree of mortality reduction from colonoscopy. While a figure of 90% is sometimes cited as the degree of mortality reduction,[62] the question will not be properly answered until the European RCT that has a control group of “routine care” that involves minimal screening of any kind is completed.[63] Until there are more reliable results from colonoscopy RCTs, studies of FS may provide the best estimate of CRC mortality incidence reduction, of at most 50% on the left-colon, by extending efficacy on the left-colon to the right-colon.

Virtual Colonoscopy (Computed Tomographic Colonography [CTC])

Virtual colonoscopy (also known as CTC or CT pneumocolon) refers to the examination of computer-generated images of the colon constructed from data obtained from an abdominal CT examination. These images simulate the effect of a conventional colonoscopy. Patients must take laxatives to clean the colon before the procedure, and the colon is insufflated with air (sometimes carbon dioxide) by insertion of a rectal tube just before radiographic examination.[64]

A large, paired-design study was conducted by the American College of Radiology Imaging Network group, with 2,531 average-risk people (prevalence of polyps or cancer ≥10 mm, 4%; mean age about 58 years) screened with both CTC and optical colonoscopy (OC). The gold standard was the OC, including repeat OC exams for people with lesions found by CTC but not by OC. Of 109 people with at least one adenoma or cancer 10 mm or larger, 98 (90%) were detected by CTC (referring everyone with a CTC lesion of ≥5 mm). Specificity was 86%, and PPV was 23%. There are several concerns from this study, including the following:

Most, but not all, lesions found by CTC and not by OC were followed up with repeat OC.
The design itself did not allow for following patients, thus potentially missing lesions that grow rapidly and would only be seen after follow-up.
Because the centers conducting the screening were primarily academic centers and the radiologists and endoscopists were carefully trained, the generalizability of the findings is not clear.
Sixteen percent of people had an extracolonic finding that required further evaluation.

Unknowns from the study include the following for either OC or CTC:[65]

The number of detected polyps that would have progressed to invasive cancer.
The number of people harmed by the screening process.

Another study reported similar sensitivity and specificity in persons with an increased risk of CRC.[66] In this study, the sensitivity of OC could not be determined because it was done in an unblinded manner. This study suggested that virtual colonoscopy might be an acceptable screening or surveillance test for persons with a high risk of CRC, but this cross-sectional study did not address outcome or frequency of testing in high-risk persons.

Some studies have assessed how well virtual colonoscopy can detect colorectal polyps without a laxative prep. The question is of great importance for implementation because the laxative prep required by both conventional colonoscopy and virtual colonoscopy is considered a great disadvantage by patients. By tagging feces with iodinated contrast material ingested during several days before the procedure, investigators in one study were able to detect lesions larger than 8 mm with 95% sensitivity and 92% specificity.[67] The particular tagging material used in this study caused about 10% of patients to become nauseated; however, other materials are being assessed.

Another study [68] utilized low-fiber diet, orally ingested contrast, and "electronic cleansing," a process that subtracts tagged feces. CTC identified 91% of persons with adenomas 10 mm or larger, but detected fewer (70%) lesions of at least 8 mm. Patients who received both CTC and OC preferred CTC to OC (290 vs. 175). This study shows that CTC without a laxative prep detects small 1 cm lesions with high sensitivity and is acceptable to patients. Long-term utilization of CTC will depend on several issues, including the frequency of follow-up exams that would be needed to detect smaller lesions that were undetected and may grow over time.

Extracolonic abnormalities are common in CTC. Fifteen percent of patients in an Australian series of 100 patients, referred for colonography because of symptoms or family history, were found to have extracolonic findings, and 11% of the patients needed further medical workups for renal, splenic, uterine, liver, and gallbladder abnormalities.[69] In another study, 59% of 111 symptomatic patients referred for clinical colonoscopy in a Swedish hospital between June 1998 and September 1999 were found to have moderate or major extracolonic conditions on CTC. CTC was performed immediately before a colonoscopy and these findings required further evaluation. The extent to which follow-up of these incidental findings benefited patients is unknown.[70]

Sixty-nine percent of 681 asymptomatic patients in Minnesota had extracolonic findings, of which 10% were considered to be highly important by the investigators, and required further medical workup. Suspected abnormalities involved kidney (34), chest (22), liver (8), ovary (6), renal or splenic arteries (4), retroperitoneum (3), and pancreas (1);[71] however, the extent to which these findings will contribute to benefits or harms is uncertain. Two other studies, one large (N = 2,195) and one small (n = 136) examined the moderate or high importance of extracolonic findings from CTC. The larger study [72] found that 8.6% of patients had an extracolonic finding of at least moderate importance, while 24% of patients in the smaller study [73] required some evaluation for an extracolonic finding. The larger study found nine cancers from these evaluations, at a partial cost (they did not include all costs) of $98.56 per patient initially screened. The smaller study found no important lesions from evaluation, at a cost of $248 per person screened. Both of these estimates of cost are higher than previous studies have found. The extent to which any patients benefited from the detection of extracolonic findings is not clear. Because both of these studies were conducted in academic medical centers, the generalizability to other settings is also not clear. Neither of these studies examined the effect of extracolonic findings on patient anxiety and psychological function.

Technical improvements involving both the interpretation methodology, such as three dimensional (3-D) imaging, and bowel preparation are under study in many centers. While specificity for detection of polyps is homogeneously high in many studies, sensitivity can vary widely. These variations are attributable to a number of factors including characteristics of the CT scanner and detector, width of collimation, mode of imaging (two dimensional [2-D] vs. 3-D and/or fly-through), and variability in the expertise of radiologists.[74]

Digital Rectal Examination

A case-control study reported that routine digital rectal examination was not associated with any statistically significant reduction in mortality from distal rectal cancer.[75]

Detection of DNA Mutations in the Stool

The molecular genetic changes that are associated with the development of colorectal adenomas and carcinoma have been well characterized.[76] Advanced techniques have been developed to detect several of these gene mutations that have been shed into the stool.[77-80] Stool DNA testing was recently assessed in a prospective study of asymptomatic persons who received colonoscopy, three-card FOBT (Hemoccult II), and stool DNA testing based on a panel of markers assessing 21 mutations. Conducted in a blinded way with prestated hypotheses and analyses, the study found that among 4,404 patients, the DNA panel had a sensitivity for CRC of 51.6% (for all stages of CRC) versus 12.9% for Hemoccult II, while the false-positive rates were 5.6% and 4.8%, respectively.[81,82]

A next-generation multitargeted stool test combined methylation markers for NDRG4 and BMP3, several KRAS mutations, and a human hemoglobin immunoassay. The markers, each quantitated separately, were combined using an algorithm in a prespecified multivariable analysis. The assay’s sensitivity and specificity were compared with a commercial FIT test (OC FIT-CHEK Polymedco), using colonoscopy as the gold standard. Among 12,776 participants who had colonoscopy screening, were enrolled from 2011 through 2012 at 90 sites in the United States and Canada, and were aged 50 to 84 years (and weighted toward >65 years), 9,989 had fully evaluable results. There were 65 CRC and 757 advanced adenomas or sessile serrated polyps 1 cm or greater. The sensitivity for CRC was 92.3% (60 of 65 CRC) for the multitargeted test and 73.8% for FIT. Sensitivity for advanced lesions was 42.4% for the multitargeted test and 23.8% for FIT. Sensitivity for high-grade dysplasia was 69.2% for the multitarget test and 46.2% for FIT. Sensitivity for serrated sessile polyps 1 cm or greater was 42.4% for the multitargeted test and 5.1% for FIT. Specificities were 86.6% for the multitargeted test and 94.9% for FIT, using nonadvanced or negative colonoscopy results, and were 89.8% and 96.4% for totally negative colonoscopy results. A receiver operating characteristic (ROC) analysis showed that the multitargeted test has higher sensitivity than FIT alone, even if the FIT cut-off is reduced to try to increase sensitivity. A limitation is that there were no data about performance of repeated testing over time and what may be an appropriate testing interval.[83]

Overall, the multitargeted test was more sensitive than FIT for both CRC and advanced precancerous lesions, but the test was less specific.[83] The U.S. Food and Drug Administration approved this multitargeted test for colorectal screening in 2014.

Adherence to Screening

Benefit from CRC screening can only occur if eligible people are actually screened. There have been problems with screening adherence, particularly for low income and uninsured people. There has also been concern that some people may adhere less to screening with a colonoscopy than with fecal tests. One well-conducted RCT found that, among an uninsured population, mailed FIT-kit outreach and follow-up reminder phone calls resulted in an adherence rate of 40.7%. Mailed colonoscopy invitations and follow-up phone reminders resulted in a 24.6% adherence rate. The usual-care adherence rate in this trial was 12.1%.[84]

Tailoring Screening to Risk

Benefit of screening might be improved by tailoring the recommended screening test to a person’s degree of CRC risk. For example, if a subgroup of young women were to have a substantially lower risk of proximal neoplasms, then recommending sigmoidoscopy instead of colonoscopy (both are recommended by the U.S. Preventive Services Task Force without preference, as part of a program of screening persons with average risk) might lead to higher compliance.

In a study to identify persons in an average-risk group who had a higher versus lower risk of advanced neoplasia (CRC and advanced adenomas) anywhere in the colon, 2,993 persons having a screening colonoscopy were stratified by age, gender, waist circumference, smoking, and family history (persons in high-risk family categories, e.g., Lynch syndrome or adenomatous polyposis coli, were excluded). In a classification system derived in a training set, the risks of advanced neoplasm in four groups were: 1.92%, 4.88%, 9.93%, and 24%. In the two lowest risk groups, sigmoidoscopy would have detected 51 (73%) of 70 advanced neoplasms. In the independent validation set, results were similar. Whether this system increases overall compliance has yet to be determined.[85]

A similar stratification system based on age, gender, smoking, and family history—and combined with FIT—was tested in Asia to determine whether use of the stratification system plus FIT could detect which persons need colonoscopy. If either the stratification system or FIT was positive, a person was recommended for colonoscopy. Using this strategy, 95% of persons with CRC were correctly told to have colonoscopy.[86]

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