Colonoscopy and Flexible Sigmoidoscopy in Community Settings (Key Questions 2a and 3a)

Accuracy of Colonoscopy

Evaluating the accuracy of screening colonoscopy in average-risk participants, particularly in community settings, is challenging because of the lack of an independent gold standard and very few applicable studies. As detailed in the full report,²⁵ we found no studies of miss rates after tandem screening colonoscopy in average-risk patients to fairly represent performance of community endoscopists, and no studies of repeated colonoscopy within 3 years after screening colonoscopy in a representative sample of average-risk community-based patients.

Researchers have used CT colonography screening studies already discussed^49,53,54 to estimate the sensitivity of colonoscopy for colorectal cancer and for adenomas of various sizes detected using either CT colonography or colonoscopy. Two of these studies conducted CT colonography followed by colonoscopy with segmental unblinding to recheck CT colonography-located lesions not seen on first-pass colonoscopy;^49,53 1 of these provides the single best estimate for community performance of colonoscopy⁴⁹ (Table 2). In this good-quality study of 1233 average-risk persons, colonoscopy by 1 of 17 experienced colonoscopists missed 10% of adenomas 6 mm or greater and 12% of adenomas 10 mm or greater. Sensitivity (per-person detection rate) of colonoscopy for adenomas 6, 8, or 10 mm or greater did not statistically significantly differ from sensitivity of CT colonography. Colonoscopy missed 1 of 2 colorectal lesions detected, whereas CT colonography detected both. In the second study using segmental unblinding, no colorectal cancer was detected in 96 average-risk patients using either test, and colonoscopy by 1 of 5 gastroenterologists missed 10% of polyps 6 mm or greater but no polyps 10 mm or greater. Colonoscopy was much less accurate in the third study of 452 asymptomatic, average-risk patients, detecting only 77% (20 of 26) of neoplasms 10 mm or greater and just 1 of 5 colorectal lesions detected by CT colonography.⁵³ This study, however, evaluated the performance of more than 50 experienced endoscopists, whereas CT colonography was conducted by 3 very experienced radiologists.

Taken together, these data are insufficient to provide precise estimates of the sensitivity of colonoscopy in community settings, particularly for colorectal cancer detection, because of the small number of patients studied (n = 1781) and the relatively few lesions (7 total colorectal lesions). They do, however, confirm that colonoscopy misses some polyps and may also miss colorectal cancer.

Serious Harms from Colonoscopy

We found 17 fair- or good-quality, primarily prospective, studies evaluating clinically significant adverse events from screening colonoscopy conducted in predominantly asymptomatic persons.^{49,55,67,72-85} Only 1 of these studies.⁸¹ was included in the 2002 systematic review for the USPSTF. Seven of these 16 studies were conducted in community settings.^{55,73,75,77,79,81-83} Using a random-effects logistic model to pool data from the 12 studies (n = 57,742)^{49,55,73-76,79,80,82-85} reporting this outcome, we found 2.8 total serious complications (including perforations, hemorrhage, diverticulitis, cardiovascular events, severe abdominal pain, and death) per 1000 procedures (CI, 1.5 to 5.2 per 1000 procedures; test for heterogeneity; P = 0.13) (Appendix Figure 1). When we limited the model just to the 7 studies conducted in the United States, serious complications were nonsignificantly reduced (2.5 per 1000 procedures [CI, 1.0 to 6.1 per 1000 procedures]). Because of reporting limitations, complication rates could not be calculated for colonoscopies with and without polypectomy. Only 3 of these 11 studies reported the proportion of colonoscopies in which polypectomies were performed—the proportions ranged from 41% to 68%.^79,80,82 In these 3 studies, more than 85% of serious complications, perforations, and major bleeding incidents occurred during colonoscopies that required polypectomies. We could not estimate complications by age because of limitations in study reporting.

Accuracy of Flexible Sigmoidoscopy

We found no studies that estimated accuracy of flexible sigmoidoscopy in average-risk patients undergoing screening with both flexible sigmoidoscopy and colonoscopy. We report here the accuracy of screening with simulated flexible sigmoidoscopy reported in 6 large cohort studies of screening colonoscopy in a total of 14,938 average-risk patients.^86-91 Elsewhere.²⁵, we describe 3 studies—1 tandem flexible sigmoidoscopy study that reported adenoma miss rates⁹² and 2 prospective studies that reported distal advanced neoplasia or colorectal cancer on flexible sigmoidoscopy repeated 3 years after negative results on screening flexible sigmoidoscopy^93,94—that do not provide any greater precision than these estimates.

The estimated sensitivity of flexible sigmoidoscopy (using either biopsy or visual inspection to determine colonoscopy referral) for colorectal cancer throughout the entire colon was 58% to 75%, based on small numbers of colorectal lesions, with an estimated sensitivity of 72% to 86% for advanced neoplasia. Variations in these estimates are probably due to differences in examiner skill and the patient's risks for proximal lesions in the unexamined colon. These estimates are further limited because they simulate flexible sigmoidoscopy results by using colonoscopy examinations. This approach presumes that all lesions are detected if they are within the insertion depth for flexible sigmoidoscopy and ignores differences introduced through the more thorough bowel preparation used for colonoscopy or through colonoscopists' skill. The community performance of flexible sigmoidoscopy screening and its effect on health outcomes, including mortality from colo-rectal cancer, will become clearer after current RCTs are reported.

Serious Harms from Flexible Sigmoidoscopy

We found 8 fair- or good-quality studies that evaluated clinically significant adverse events from flexible sigmoidoscopy for colorectal cancer screening in an average-risk population.^{72,74,84,85,95-98} Only 1 of these studies was included in the previous 2002 review.⁷²

Using a random-effects logistic model to pool data from the 6 studies^{72,74,84,85,95,96} reporting this outcome (n = 126,985), we found 0.34 serious complication per 1000 procedures (CI, 0.06 to 1.9 per 1000 procedures; test for heterogeneity, P = 0.26) (Appendix Figure 2). Serious complications were defined the same as for screening colonoscopy but excluded complications from follow-up colonoscopy. Per protocol, all of these studies performed polypectomy during flexible sigmoidoscopy; based on 2 studies, polypectomies were conducted in 20% to 22% of flexible sigmoidoscopy examinations.^72,74 We could not estimate complications by age because of limitations in study reporting.

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Discussion

Since 2002, research on colorectal cancer screening has grown substantially as researchers have investigated the accuracy of novel screening approaches and have continued examining already recommended approaches. As discussed in our full report,²⁵ we found no new reports of the mortality impact of colorectal cancer screening (besides FOBT programs); however, results from several trials of flexible sigmoidoscopy that will report mortality effects are pending.^84,99-101 In addition, although we found many studies addressing test performance of newer FOBTs, fecal DNA screening tests, or CT colonography,²⁵ relatively few addressed average-risk screening populations and used minimally acceptable study designs and methods. Table 3 summarizes review findings about the performance and harms of new fecal screening tests, CT colonography, colonoscopy, and flexible sigmoidoscopy by key question, with newer tests reported first.

Recent guidance articulates evidence requirements to justify replacing a currently recommended diagnostic (or screening) test with a newer test in the absence of RCTs showing benefit;^102,103 this pertains to replacing existing colorectal cancer screening tests with newer ones. Accordingly, researchers should evaluate the comparative accuracy of newer and older tests by using the same reference standard as trials that showed treatment benefit in the same (or similar) patients representing the appropriate disease spectrum.¹⁰³ If the newer test has increased sensitivity—with similar specificity and patient safety—or similar sensitivity but other advantages (for example, improved specificity, acceptability, or accessibility), studies of test accuracy alone may support substituting this test in the absence of trial data.¹⁰³ However, when new tests offer tradeoffs between desirable and undesirable attributes (for example, improved sensitivity but reduced specificity), a decision analytic model or new research may be needed. When data on new tests are incomplete or uncertain, and the costs or consequences of making assumptions from such data are potentially severe, clinicians may require further research before acting.¹⁰³

Fecal Screening Tests

As determined primarily through indirect comparisons, several fecal immunochemical tests had superior single-test sensitivity for colorectal cancer and possibly for advanced neoplasia compared with Hemoccult II. Fecal immunochemical tests had similar or somewhat lower specificity, suggesting that test choice might be important when considering substituting fecal immunochemical tests in a fecal screening program. For one quantitative fecal immunochemical test (Magstream, Fujirebio Inc., Tokyo, Japan), choice of positive cutoff values would allow programs to determine the appropriate tradeoff between improved sensitivity and specificity. Limited evidence suggested better test performance with 2- or 3-day sample collection than with 1-day collection. Ease of administration may work in favor of some fecal immunochemical tests,³¹ although their increased costs may reduce acceptability for payers. The relatively small increase in Medicare reimbursement for fecal immunochemical tests (exceeding those for Hemoccult II)¹⁰⁴ may be affecting market availability. Not all well-studied fecal immunochemical tests were both FDA approved and on the U.S. market at the time this article was written.

On the basis of fewer data and less precise estimates, Hemoccult SENSA also had increased sensitivity for colorectal cancer compared with Hemoccult II but reduced specificity. Direct comparisons with fecal immunochemical tests were few, with mixed results for sensitivity and consistently lower specificity for Hemoccult SENSA. The tradeoffs from improved sensitivity with reduced specificity in a screening program of repeated testing is best evaluated through modeling.²⁴

One study on screening test performance of the precommercial version of a multitarget fecal DNA test (PreGen Plus) showed improved sensitivity for colorectal cancer but not adenomas, similar or slightly reduced specificity, and higher positive rates compared with Hemoccult II.⁴⁷ Test accuracy estimates for colorectal cancer were imprecise for both tests because of power, and sensitivity and specificity of Hemoccult II in this study were lower than generally reported in higher-quality studies.^31,105 In addition, this study's findings may not be generalizable to population screening because participants were relatively older (three quarters were >65 years of age, compared with screening beginning at age 50 years) and the version of PreGen Plus tested has been supplanted by other versions (1.1 and higher) for which there are no screening population studies (Table 3). Commercial availability of fecal DNA tests may be further affected by the recent FDA requirement for premarket review of this test, which was previously considered to be outside FDA jurisdiction.^106,107 Furthermore, in the absence of trial data or modeling, fecal DNA could be considered only as a substitute for an annual or biennial FOBT in established screening programs. This could be cost-prohibitive given the relative cost for fecal DNA compared with guaiac or immunochemical tests.¹⁰⁴ Cost concerns may underlie recommendations by the manufacturer to repeat fecal DNA screening at 5-year intervals.¹⁰⁸ Data on health outcomes are insufficient, however, to support this interval recommendation.¹⁰⁹

Accuracy, Harms, and Uncertainties with CT Colonography

Computed tomographic colonography has been studied as a diagnostic test (for patients with symptoms) and, less frequently, as a screening test in average-risk asymptomatic patients. Recent publication of the ACRIN study has more than doubled the number of average-risk patients studied to determine the accuracy of CT colonography for colorectal cancer screening,⁵⁵ with only 1 smaller screening study (n = 300) still pending.¹¹⁰ On the basis of published studies in 4312 average-risk screening patients, CT colonography screening by trained and experienced radiologists had sensitivity similar to that of colonoscopy for colorectal cancer and large adenomas (≥10 mm). However, estimates of sensitivity of CT colonography for smaller adenomas (≥6 mm) was more variable between studies (with point estimates of 78% and 88.7% and wide CIs) and was not clearly comparable to the sensitivity of colonoscopy for smaller adenomas. The health impact of potentially reduced sensitivity for smaller polyps is unclear.¹¹¹ Specificity estimates for CT colonography were also quite variable between studies; for lesions 6 mm or greater, point estimates ranged from 79.6% to 88%.

Beyond issues of test accuracy, other uncertainties may affect considerations of whether this test is ready for widespread population screening. These include questions about potential harms from radiation exposure, uncertainty about extracolonic findings, uncertainty about test referral thresholds and repeat test intervals, and judgments about how the test performance seen in clinical studies will translate to the conduct of CT colonography screening examinations in community settings. Most important is how clinicians and policymakers value these remaining uncertainties and whether the costs or consequences of making assumptions from incomplete data are viewed as potentially severe, thus requiring further research before acting.¹⁰³

Immediate procedure-related harms with CT colonography appear to be minimal. The risk for perforation with air insufflation is very low, particularly in asymptomatic persons undergoing screening. Uncertainty remains about delayed harms associated with CT-related radiation exposure, an area of growing concern with more widespread use of CT for diagnostics and screening.¹¹² The estimate of 1/1000 excess lifetime tumors in a 50-year-old after a single CT colonography examination is uncertain and could vary 2- to 3-fold. Radiation-related cancer risks could decrease if newer technologies reduce average radiation exposure (that is, from 10 mSv to about 5 mSv).¹¹³ A recent survey of 22 institutions conducting CT colonography found a total median radiation dose per screening protocol of 5.6 mSv (range, 2.6 to 14.7 mSv).¹¹⁴ Thus, because radiation doses depend on factors associated with the technology used and with decisions by the technician,¹¹² higher radiation exposure might persist in some settings. Even assuming a 10-fold lower risk (1/10,000 excess cancer risk), a recent modeling exercise¹¹⁵ found that lifetime CT colonography screening (starting at age 50 years and repeated every 10 years) produced 36/100,000 radiation-induced cases of cancer with 8 deaths, which offset some of the modeled mortality benefits from reductions in colonoscopy-associated complications.

Extracolonic findings that may require clinical follow-up occur relatively commonly (up to 1 in 4 asymptomatic persons undergoing CT colonography screening), with 7% to 16% clearly receiving recommendations for further diagnostic imaging tests or surgery.^55,67 Whether these extracolonic findings will ultimately provide additional benefit or harm to those undergoing CT colonography screening for colorectal cancer, and at what additional cost to the health care system, is unknown. A recent modeling study that attempted to address extracolonic findings found a net benefit,¹¹⁵ although the range of these findings was restricted to considering cancer and abdominal aortic aneurysms (reducing the estimated prevalence of extracolonic findings from <1% to at most 5% of the screened population). Other limitations and concerns about the assumptions underpinning this modeling exercise have been noted elsewhere.¹¹⁶

The referral threshold for colonoscopy (size of lesions detected by CT colonography) is largely based on expert opinion rather than clinical outcomes. Most, but not all,¹⁰⁹ experts currently suggest colonoscopy referral for a polyp 6 mm or greater. This makes referral to colonoscopy relatively common, with as many as 1 in 3 persons, to as few as 1 in 8, referred after CT colonography (Table 2). An ongoing nonrandomized comparative study of colonoscopy and CT colonography screening is offering patients with only 1 or 2 polyps 6 to 9 mm in size on CT colonography the option of CT colonography surveillance instead of immediate colonoscopy, under an institutional review board-approved protocol.^67,117 Under this protocol, fewer patients (1 in 13) have been referred to colonoscopy, compared with referring all those with polyps 6 mm or greater (1 in 8). The safety of this approach is still being determined. Variability in polyp measurement due to differences among readers, CT measurement approaches, and viewing displays further complicates considerations of appropriate polyp size for colonoscopy referral after CT colonography examination.^118-120

An important question for those considering implementing population colorectal cancer screening using CT colonography is whether test accuracy for this technology-dependent, operator-dependent test will be the same in nonresearch settings as in clinical studies. Studies on the accuracy of CT colonography have generally used an enhanced reference standard, which allows the separation of false-positive CT colonography results from false-negative colonoscopy results by reconciling differences with second-look colonoscopy. These studies have confirmed that colonoscopy and CT colonography miss adenomas and colorectal cancer, although reliable estimates of colonoscopy accuracy are limited by very small numbers of lesions. When considering the comparative accuracy between 2 operator-dependent technologies (CT colonography and colonoscopy), current studies are further limited by using designs that compared a larger number of experienced colonoscopists (5 to 50) to a much smaller number of experienced or very experienced radiologists (2 to 15).

As others have stated, "Accurate CT colonography with high sensitivity and specificity for polyps ≥ 6 mm in size depends on meticulous technique".⁶⁷ Differences in the experience and training of radiologist readers has been cited as the major factor underlying discrepant test accuracy estimates for CT colonography in nonscreening populations.¹²¹ Radiologists in nonacademic settings who read a validated set of 15 CT colonographies exhibited considerable individual variability in accuracy (53% to 93%),¹²² consistent with our findings from 2 smaller CT screening studies comparing readers,^53,54 as well as from ACRIN, which used trained and certified readers.⁵⁵ The challenges of adequately ensuring high-quality CT colonography readings are further illustrated by reports from ACRIN that half of the radiologists did not pass the initial certifying examination (after either 1.5 days of training or experience with ≥500 cases), although all did pass after further training.¹²³ Clearly, specification, implementation, and monitoring of quality standards will be needed before widespread population screening with CT colonography. Activities are reported to be under way to upgrade quality metrics and training for CT colonography through the American College of Radiology.¹⁰⁹

Little is known about relative patient preferences for CT colonography compared with colonoscopy in average-risk screening populations, and preferences may differ from those of high-risk or symptomatic patients undergoing diagnostic CT colonography. Some data suggest that average-risk patients may prefer CT colonography for convenience, and slightly more (49.8%) would prefer CT colonography for future screening compared with those preferring colonoscopy (41.1%).⁴⁹ Issues about patient preferences will become particularly important once considerations of benefits, harms, and community accuracy are resolved. At that point, patient acceptability should also consider the 2-step process (CT colonography followed by referral colonoscopy as needed), with a second bowel preparation for colonoscopy potentially required. Same-day colonoscopy may make repeated bowel preparation unnecessary but requires coordination between radiology and gastroenterology services.¹²⁴

Availability of accurate CT colonography screening examinations that do not require any (or full) bowel preparation could greatly influence patient preferences and willingness to be screened.^125,126

Accuracy and Harms with Colonoscopy and Flexible Sigmoidoscopy in Community Settings

Colonoscopy has presumed accuracy given its position in the diagnostic evaluation of patients screened by other colorectal cancer methods, although gastroenterologists have explicitly recognized that accuracy is highly dependent on the quality of the bowel preparation and endoscopic examination.¹²⁷ Recent CT colonography studies using an enhanced standard of repeating colonoscopy examination for discordant colonoscopy-CT colonography findings have confirmed that screening colonoscopy can miss colorectal tumors as well as adenomas. Related data from tandem colonoscopy in diagnostic or high-risk screening populations suggest reasonably low miss rates for large adenomas (2.1% [CI, 0.3% to 7.3%]);¹²⁸ similarly, new or missed colorectal tumors occurred in 3.4% of a population-based cohort (n = 12,487) who had previously undergone colonoscopy for any reason up to 3 years before a new diagnosis of colorectal cancer.¹²⁹ Although available studies do not precisely estimate the risk for missed lesions with screening colonoscopy, all underscore the importance of quality initiatives for the performance of colonoscopy or any operator-dependent technological screening tool.¹²⁷

Colonoscopy presents a higher risk for immediate harms than do other tests. Serious harms from community endoscopies are about 10 times more common with colonoscopy (2.8 per 1000 procedures) than with flexible sigmoidoscopy (3.4 per 10,000 procedures). The estimates for harms from flexible sigmoidoscopy, however, have much wider CIs. Age-specific harm rates were sought but could not be determined.

Limitations

We reviewed the accuracy and harms of newer colorectal cancer screening tests as potential replacements for currently recommended tests. The USPSTF commissioned a separate, simultaneous decision analysis comparing different colorectal cancer screening programs to consider tradeoffs in test accuracy, repeated screening, and starting and stopping ages. Because of the targeted nature of this review, we did not formally update or address test acceptability (preferences, costs, adherence) issues; however, the importance of these issues for new technologies, such as CT colonography, may be considered as secondary to establishing the accuracy, harms, and community performance of the screening tests.

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Conclusion

Some newer fecal screening tests with better sensitivity and similar specificity are reasonable substitutes for Hemoccult II testing to improve annual or biennial fecal screening programs for colorectal cancer. Modeling can help determine tradeoffs in fecal tests with improved sensitivity but reduced specificity and to compare results from screening programs. Colorectal cancer screening with CT colonography in average-risk populations is likely to detect larger adenomas and colorectal cancers as well as colonoscopy does, but it is not clear that CT colonography is as sensitive for smaller adenomas (≥6 mm) or what proportion of positive CT colonography results will be false positive. We did not evaluate the clinical benefit of detecting smaller polyps in this report. In addition, uncertainties about potential radiation-related harms, the effect of extracolonic findings, and test performance in community settings still remain. Given potential harms and observed variability in test accuracy, emphasis on quality standards for implementation of any operator-dependent colorectal cancer screening tests appears prudent. Considerations about colorectal cancer screening are affected by its rapidly evolving clinical science base, by the ongoing evolution of colorectal cancer screening technologies, and by a marketplace that continues to change. Thus, frequent reconsideration of available evidence and updating of recommendations is warranted.

Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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Acknowledgment:

The authors thank the following peer reviewers for the evidence report (alphabetical)—James Allison, MD, Carrie Klabunde, PhD, Ted Levin, MD, Perry Pickhardt, MD, Margaret Piper, PhD, MPH, David Ransohoff, MD, Robert Smith, PhD, and Steve Woolf, MD, MPH; Oregon Evidence-based Practice Center staff—Kevin Lutz, MA, Taryn Cardenas, BA, Rebecca Newton-Thompson, MD, MPH, Elizabeth O'Connor, PhD, Mark Helfand, MD, MS, MPH, and Daphne Plaut, MLS; and Centers for Disease Control and Prevention staff—Laura Seeff, MD.

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Current as of October 2008

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Internet Citation:

Whitlock EP, Lin JS, Liles E, Beil TK, Fu R. Screening for Colorectal Cancer: A Targeted, Updated Systematic Review for the U.S. Preventive Services Task Force. October 2008. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf08/colocancer/coloartwhit.htm

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