A Targeted, Updated Systematic Review for the U.S. Preventive Services Task Force (USPSTF)
October 2008
Prepared by E.P. Whitlock, J.S. Lin, E. Liles, T.L. Beil, and R. Fu.
The information in this report is intended to help clinicians, employers, policymakers, and others make informed decisions about the provision of health care services. This report is intended as a reference and not as a substitute for clinical judgment.
This report may be used, in whole or in part, as the basis for the development of clinical practice guidelines and other quality enhancement tools, or as a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied.
This report was first published in Annals of Internal Medicine 2008;149:638-58.
Contents
Abstract
Introduction
Methods
Results
Discussion
Conclusion
References
Abstract
Background: In 2002, the U.S. Preventive Services Task Force (USPSTF) recommended colorectal cancer screening for adults 50 years of age or older but concluded that evidence was insufficient to prioritize among screening tests or evaluate newer tests, such as computed tomographic (CT) colonography.
Purpose: To review evidence related to knowledge gaps identified by the 2002 recommendation and to consider community performance of screening endoscopy, including harms.
Data Sources: MEDLINE, Cochrane Library, expert suggestions, and bibliographic reviews.
Study Selection: Eligible studies reported performance of colorectal cancer screening tests or health outcomes in average-risk populations and were at least of fair quality according to design-specific USPSTF criteria, as determined by 2 reviewers.
Data Extraction: Two reviewers verified extracted data.
Data Synthesis: Four fecal immunochemical tests have superior sensitivity (range, 61% to 91%), and some have similar specificity (97% to 98%), to the Hemoccult II fecal occult blood test (Beckman Coulter, Fullerton, California). Tradeoffs between superior sensitivity and reduced specificity occur with high-sensitivity guaiac tests and fecal DNA, with other important uncertainties for fecal DNA. In settings with sufficient quality control, CT colonography is as sensitive as colonoscopy for large adenomas and colorectal cancer. Uncertainties remain for smaller polyps and frequency of colonoscopy referral. We did not find good estimates of community endoscopy accuracy; serious harms occur in 2.8 per 1000 screening colonoscopies and are 10-fold less common with flexible sigmoidoscopy.
Limitation: The accuracy and harms of screening tests were reviewed after only a single application.
Conclusion: Fecal tests with better sensitivity and similar specificity are reasonable substitutes for traditional fecal occult blood testing, although modeling may be needed to determine all tradeoffs. Computed tomographic colonography seems as likely as colonoscopy to detect lesions 10 mm or greater but may be less sensitive for smaller adenomas. Potential radiation-related harms, the effect of extracolonic findings, and the accuracy of test performance of CT colonography in community settings remain uncertain. Emphasis on quality standards is important for implementing any operator-dependent colorectal cancer screening test.
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Introduction
Colorectal cancer ranks third in incidence and second in cause of cancer death for both men and women.1 Most cases of colorectal cancer occur in average-risk individuals (those without a family or predisposing medical history), and increasing age, male sex, and black race are associated with increased incidence.2 Black persons have the highest incidence of and mortality rates from colorectal cancer among all racial and ethnic subgroups.3-7 and nearly double the colorectal cancer-related mortality rate compared with other ethnic minorities.8
Colorectal cancer screening has been recommended by the U.S. Preventive Services Task Force (USPSTF) and many other organizations for more than 10 years.9 On the basis of evidence from multiple randomized, controlled trials (RCTs), a screening program with repeated annual or biennial guaiac fecal occult blood tests (FOBTs) and endoscopic follow-up of positive test results reduces colorectal cancer mortality; according to a recent update, colorectal cancer mortality was reduced 16% (CI, 10% to 22%) after 12 to 18 years.10 Extrapolating from trial evidence, clinical studies of test accuracy, and other supporting evidence, the USPSTF recognized flexible sigmoidoscopy (with or without FOBTs), colonoscopy, and double-contrast barium enema as other colorectal cancer screening options in 2002.11, 12 However, because colorectal cancer screening tests have potential harms, limited accessibility, or imperfect acceptability to patients, and no tests could be identified as superior in cost-effectiveness analysis.13, the USPSTF also recommended that choice among recommended methods for colorectal cancer screening to be individualized to patients or practice settings.14
Despite strong recommendations from the USPSTF and many others, serial national surveys document inadequate, slowly improving rates of colorectal cancer screening in the United States.15-20 In 2006, 60.8% of adults 50 years of age or older reported recent colorectal screening.20 Disparities in colorectal cancer screening exist, with lower rates of colorectal cancer screening in nonwhite and Hispanic populations16,21,22 and in areas with higher poverty rates.23
To increase the uptake of and benefits from recommended colorectal cancer screening, researchers have sought to improve the accuracy, acceptability, or accessibility of screening by introducing new tests or enhancing existing tests. However, the availability of additional options for colorectal cancer screening—including highly sensitive guaiac FOBT; fecal immunochemical testing; fecal DNA testing; and "virtual colonoscopy" approaches, such as computed tomographic (CT) colonography—has created uncertainty about what methods should be used for colorectal cancer screening in the general population.
To assist the USPSTF in updating its 2002 recommendation for colorectal cancer screening in average-risk adults age 50 years or older, we conducted a targeted systematic review primarily focused on evidence gaps or new evidence since the previous review. This approach updated what the USPSTF judged was the most important evidence for newer colorectal cancer screening tests and community-performed endoscopies, and it was supplemented by a companion decision analysis examining screening program performance and life-years gained by using different colorectal cancer screening tests, test intervals, and starting and stopping ages.24
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Methods
Under guidance from the USPSTF, this targeted review addressed only the first 3 questions of the full evidence chain in the analytic framework (Figure 1). From our larger report,25 we report here the accuracy (one-time test performance characteristics) and potential harms of newer colorectal cancer screening tests (high-sensitivity FOBTs, fecal immunochemical tests, fecal DNA testing, and CT colonography) in screening populations (key questions 2b and 3b) and the accuracy and harms of screening colonoscopy and flexible sigmoidoscopy in the community setting (key questions 2a and 3a). In the full report, we discuss lack of new data on the mortality benefits of colorectal cancer screening beyond FOBT programs (key question 1); race-, sex-, and age-related issues in colorectal cancer screening; considerations of targeted screening recommendations; and suggested future research. Detailed methods are provided in the Appendix and Appendix Tables 1, 2, and 3 and in the full report.25
Searches and Selection Process
In brief, we searched PubMed; Database of Abstracts of Reviews of Effects; Cochrane Database of Systematic Reviews; and the Institute of Medicine, National Institute for Health and Clinical Effectiveness, and Health Technology Assessment databases for recent systematic reviews (1999-2006) to support our review of all key questions.26 We found 11 existing systematic reviews for newer colorectal cancer screening tests (key question 2b). Using methods detailed in the Appendix, we selected 3 good-quality reviews of CT colonography27,28 or fecal DNA testing29 to locate relevant primary studies; we supplemented these with additional MEDLINE and Cochrane Library searches from January 2006 through January 2008 to locate additional studies published after the end date of the searches. Because there were no good-quality relevant systematic reviews for reports on fecal immunochemical tests (key questions 2b and 3b), we searched MEDLINE and the Cochrane Library (1990-2008) and from 2000 to 2008 to locate studies of the harms of screening tests (key questions 3a and 3b) since the 2002 report.
Abstracts and articles were dual-reviewed against inclusion criteria (Appendix) and required agreement of 2 reviewers. Eligible studies reported on the sensitivity and specificity of colorectal cancer screening tests or on health outcomes. We excluded studies that did not address average-risk populations for colorectal cancer screening, unless an average-risk subgroup was reported. We excluded case-control studies of screening accuracy because these may overestimate sensitivity as a design-related source of bias,30 as recently demonstrated for FOBTs.31 To avoid biases related to reference standards, we excluded studies of test accuracy that incompletely applied a valid reference standard or used an inadequate reference standard.32 For CT colonography, we considered only technologies that were compared with colonoscopy in average-risk populations, used a multidetector scanner,27 and reported per-patient sensitivity and specificity. In all, we evaluated 3948 abstracts and 490 full-text articles (Figure 2).
Quality Assessment and Data Abstraction
Two investigators critically appraised and quality-rated all eligible studies by using design-specific USPSTF criteria33 supplemented by other criteria (Appendix). Poor-quality studies were excluded. One investigator abstracted key elements of included studies into standardized evidence tables. A second reviewer verified these data. We resolved disagreements about data abstraction or quality appraisal by consensus. Evidence tables and tables of excluded studies for each key question are available in the full report.25
Data Synthesis and Analysis
We report qualitative synthesis of the results for most key questions because of study heterogeneity. The performance of screening tests is preferentially described per person (sensitivity and specificity), supplemented by per-polyp analyses (miss rates). Sensitivity for large adenomas from 2 similar studies of CT colonography screening was combined by using the inverse variance fixed-effects model because no heterogeneity was detected on the basis of the Cochran Q test and the I2 statistic.34 Because of the stringency of our inclusion criteria for studies to estimate rates of endoscopy harms in the community practice setting (key question 3a), included studies were clinically homogeneous enough to pool. A random-effects logistic model was used to evaluate statistical heterogeneity, estimate pooled rates, and explore potential sources of variation for complications from study-level characteristics.35,36 Model details and SAS PROC NLMIXED code are provided in the Appendix. Total serious adverse events required hospital admission (for example, perforation, major bleeding, severe abdominal symptoms, and cardiovascular events) or resulted in death. Results of exploratory analyses for potential sources of variation for pooled estimates are discussed in the full report, along with pooled estimates for individual complications, such as perforations.25
Role of the Funding Source
The Agency for Healthcare Research and Quality funded this work, provided project oversight, and assisted with internal and external review of the draft evidence synthesis but had no role in the design, conduct, or reporting of the review. The authors worked with 4 USPSTF members to develop the analytic framework, set the review scope, and resolve methodologic issues during the conduct of the review. The draft systematic review was reviewed by 8 external peer reviewers and was revised for the final version.
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Results
Our results are organized by screening method rather than key question, with newer tests discussed first. More detailed results, including evidence tables for each key question, are available in the full report.25
Fecal Immunochemical Tests, Hemoccult SENSA, Fecal DNA, and CT Colonography (Key Questions 2b and 3b)
We evaluated 3 categories of newer fecal colorectal cancer screening tests (fecal immunochemical testing, high-sensitivity guaiac FOBT, and fecal DNA testing) and CT colonography. Among these, the largest body of fair- or good-quality evidence with which to evaluate performance of colorectal cancer screening tests in average-risk screening populations was for several different fecal immunochemical tests, followed by Hemoccult SENSA (Beckman Coulter, Fullerton, California), CT colonography, and fecal DNA testing.
Accuracy of Newer FOBTs
Although we found 9 fair- or good-quality cohort studies evaluating fecal immunochemical tests in 86,498 average-risk persons, these tests cannot be clearly analyzed as a class.37 Therefore, we grouped results by test type for 4 different tests (Table 1). Limited data suggest better detection of colorectal cancer and large adenomas with 2 to 3 days of sample collection for FOBTs than with 1 day of sample collection. With few exceptions, studies did not directly compare fecal immunochemical tests with each other or with regular or high-sensitivity Hemoccult testing.
Overall, fecal immunochemical tests had higher sensitivity for colorectal cancer (61% to 91%).38-46 than was reported for nonrehydrated Hemoccult II (25% to 38%) in another recent systematic review31 and in the only study of fecal immunochemical testing that also evaluated Hemoccult II.39 Estimated specificity varied across fecal immunochemical tests (91% to 98%), and, in most studies, specificity appears lower than the reported specificity of nonrehydrated Hemoccult II (98% to 99%).39 Sensitivity for advanced neoplasia or large adenomas was less commonly reported but ranged from 27% to 67% for fecal immunochemical tests.39,40,43-45 The sensitivity of nonrehydrated Hemoccult II for large adenomas has been estimated at 16% to 31%.31 The single study directly comparing HemeSelect and nonrehydrated Hemoccult II reported twice the sensitivity for polyps 10 mm or greater for HemeSelect (SmithKline Diagnostics, San Jose, California) (67% vs. 31%).39 Currently, U.S. Food and Drug Administration (FDA)-approved fecal immunochemical tests with fair- or good-quality studies of screening test performance are largely not available on the U.S. market. Of the 4 fecal immunochemical tests discussed here, few were both FDA approved and on the U.S. market at the time this article was written.
Hemoccult SENSA had higher sensitivity for colorectal cancer (64% to 80%) than would be expected for Hemoccult II but lower specificity (87% to 90%)38,39 (Table 1). In direct comparisons, Hemoccult SENSA was less sensitive for colorectal cancer (64%) than was FlexSure OBT/Hemoccult ICT (82%) but more sensitive for large adenomas (41% vs. 30%). Hemoccult SENSA was more sensitive for colorectal cancer (79%) than HemeSelect (69%) but had similar sensitivity for large adenomas (69% vs. 67%, respectively). Hemoccult SENSA was less specific for colorectal cancer and for adenomas compared with both fecal immunochemical tests.38 More people would be referred for colonoscopy with Hemoccult SENSA than with fecal immunochemical tests because of 2- to 3-fold higher rates of positive test results with the former. A combination Hemoccult SENSA/FlexSure screening approach, in which the fecal immunochemical test was developed only if the guaiac-based test result was positive, had identical sensitivity and better specificity compared with Hemoccult SENSA alone (98.1% vs. 90.1%). These estimates provide relative rather than absolute sensitivity or specificity because patients with negative results underwent flexible sigmoidoscopy (or registry follow-up) only.
Accuracy of Fecal DNA Testing
Eligible fecal DNA screening studies were limited to a fair-quality large cohort study that used a multitarget fecal DNA panel test (the precommercial version of PreGen Plus, version 1 [Exact Sciences, Marlborough, Massachusetts], which tests for 21 DNA mutations in the K-ras, APC, and p53 genes, along with markers for microsatellite instability and long DNA) in average-risk patients undergoing colonoscopy,47 and a smaller cohort study that tested a single mutation of the K-ras gene.48 We will not further discuss the test for the single K-ras gene mutation because it showed zero sensitivity, testing positive in none of the 31 participants with advanced colorectal neoplasia, including 7 patients with invasive colorectal cancer.
Researchers compared a one-time application of PreGen Plus (version 1.0) with 3-card nonrehydrated Hemoccult II in a study that enrolled 5486 average-risk asymptomatic patients who were all to undergo colonoscopy47 (Table 1). Among the 4404 that adhered to all 3 tests, a subset (n = 2507; mean age, 69.5 years; 45% male; 87% white; 14% with a positive family history) was selected for fecal DNA testing on the basis of colonoscopic and histopathologic results.
Test performance for fecal DNA was compared with that for Hemoccult II in the selected subgroup; among these patients, 8.2% had positive results on the fecal DNA panel and 5.8% had positive Hemoccult II results. One-time fecal DNA testing was more sensitive for adenocarcinoma than was Hemoccult II (sensitivities of 51% [CI, 34.8% to 68.0%] and 12.9% [CI, 5.1% to 28.9%], respectively). Both fecal DNA testing and Hemoccult II had poor sensitivity for advanced carcinoma. Although specificity for minor polyps or no polyps did not differ between fecal DNA and Hemoccult II, power to detect a difference may have been limited because the full sample was not tested.
Serious Harms of Fecal Colorectal Cancer Screening
We found no studies addressing serious adverse effects from any type of fecal colorectal cancer screening tests. Risks are most likely related to false-positive test results and the associated risks from unnecessary colonoscopy screening.
Accuracy of CT Colonography
Although we located 7 fair- or good-quality cross-sectional studies49-55 examining a total of 4468 average-risk patients screened for colorectal cancer with both CT colonography and same-day colonoscopy, 3 of these50-52 did not contribute to our estimates of CT colonography test performance because of study limitations described in our larger report.25 The 4 remaining studies discussed here examined CT colonography screening in 4312 average-risk patients (Table 2); 3 of these studies also estimated colonoscopy sensitivity.49,53,54
The 2 largest and most comparable and applicable studies were conducted by Pickhardt and colleagues49 and the American College of Radiology Imaging Network (ACRIN)55 and together represent 87% of patients. These 2 studies found that CT colonography was comparable to colonoscopy for detecting large adenomas (≥10 mm), but not necessarily for smaller adenomas (≥6 mm). Pooled sensitivity for large adenomas in these 2 studies was 92% (CI, 87% to 96%), with no statistical heterogeneity detected between the studies (I2 = 0%; P = 0.42). Point estimates for the sensitivity of CT colonography for smaller adenomas in ACRIN (78% [CI, 71% to 85%]) were 11% lower than for Pickhardt and colleagues' study (88.7% [CI, 82.9% to 93.1%]) and significantly lower than estimates for optical colonoscopy obtained by using an enhanced reference standard of segmental unblinding.49 In addition, although CIs for sensitivity for detecting smaller adenomas overlap with those for the sensitivity for larger adenomas within both studies, intervals are wide. We did not pool sensitivity estimates for smaller adenomas because the 2 studies had quite different results, which were also statistically heterogeneous. This finding suggests uncertainty about the true sensitivity of CT colonography for smaller adenomas. Of note, the sensitivity of CT colonography for at least 1 of the studies55 is predicated on CT colonography-detected lesions that were 5 mm or greater, although these would not be the basis for referral for colonoscopy. The authors report that using a radiologic threshold of 6 mm for CT colonography-detected lesions reduced the sensitivity for large adenomas to 88%; similar data to estimate the change in sensitivity for smaller lesions are not provided. Sensitivity estimates for large adenomas or tumors for the 5-mm threshold varied among radiologists (from 67% to 100%), with fewer than half of radiologists detecting 100% of the 1 to 13 large adenomas in the cases they read. One of 7 colorectal tumors was missed on CT colonography in 1 study55, whereas both colorectal tumors were detected by CT colonography in the other.49
Per-patient specificity of CT colonography for small or large adenomas varied between the 2 largest studies. One study that used segmental unblinding to clearly distinguish false-positive CT colonography findings from false-negative colonoscopy findings had statistically significantly worse specificity (79.6% [CI, 77.0% to 82.0%]) for lesions 6 mm or greater, compared with 96% specificity for lesions 10 mm or greater.49 In contrast, ACRIN reported similar specificity for lesions regardless of size, with better specificity (88% [CI, 84% to 92%]) for lesions 6 mm or greater than reported by Pickhardt and colleagues.55 We did not pool specificity estimates because between-study results were too different and were statistically heterogeneous. In the ACRIN study, 40% (CI, 33.5% to 46.3%) of patients with lesions 6 mm or greater detected on CT colonography had lesions 6 mm or greater detected on colonoscopy.
Sensitivity and specificity estimates from 2 smaller fair-quality studies comparing CT colonography with colonoscopy are less informative because these studies detected relatively few lesions and their primary purposes were 1) to examine the relative accuracy of 2-dimensional vs. 3-dimensional methods for displaying and reviewing CT colonography images and 2) to compare radiologist performance.53,54 Thus, these studies do not provide overall results for the population but rather report subsets of data to compare readers or technologies. Results are generally consistent, with better sensitivity for larger (compared with smaller) lesions, no clear differences between 2- and 3-dimensional approaches (which was confirmed by ACRIN), and some degree of interreader variability (which seems exaggerated in these studies because of small numbers of lesions).
The pooled sensitivity estimates for large adenomas provided here might be considered best-case estimates because the studies had very low (<1%) rates of inadequate examinations, used standardized CT technologies, used fecal tagging and contrast-based luminal fluid opacification, and used a limited number of very experienced radiologists for all readings. In addition, we know little about the sensitivity of CT colonography for flat adenomas from these studies. In a related report from the study by Pickhardt and colleagues,56 the per-lesion sensitivity for flat adenomas 6 mm or greater (82.8%) was reported to be similar to the sensitivity for polypoid adenomas 6 mm or greater (86.2%). This determination, however, was based on a total of 29 flat adenomas 6 mm or greater, with flat polyps found in 52 of 1233 persons (4.9%).56
On the basis of a referral threshold of any polyp 6 mm or greater, these studies suggest that 1 in 3 to 1 in 8 persons screened with CT colonography would be referred for colonoscopy.
Serious Harms of CT Colonography
Few serious, procedure-related harms (for example, perforation, major events requiring medical attention) have been reported in 6 fair-quality cohort studies that addressed potential adverse effects with CT colonography screening.49,54,55,57-59 Overall, the risk for perforation with screening CT colonography in asymptomatic persons seems very low, with no perforations reported in 2 studies of 14,238 screening CT colonographies55,57 or in a study of 3120 CT colonographies.54 In 1 study, however, 1 person among 2531 persons undergoing both CT colonography and colonoscopy was hospitalized for bacteremia.55 Among 11,870 screening and diagnostic CT colonography examinations, researchers reported just 1 perforation in the subgroup of persons undergoing screening CT colonography, compared with 6 in the subgroup undergoing diagnostic CT colonography.59 Two small studies (n = 1587) did not report on perforation rates but did report that no major adverse events occurred.49,58
Harms related to bowel preparations required for CT colonography, colonoscopy, or flexible sigmoidoscopy are considered in the larger report.25
Uncertain Effects of CT Colonography Screening
Uncertainties associated with CT colonography screening include potential long-term harms from CT colonography-related radiation exposure. In addition, because CT colonography produces images of structures outside the colon, the implications of extracolonic findings that occur with CT colonography screening—including potential benefits from early disease detection as well as harms from unnecessary medical testing and anxiety—are unclear.
We identified no studies that directly measured harms caused by low-dose radiation exposure from CT. However, existing models can indirectly estimate potential adverse effects for lifetime attributable risk for cancer by extrapolating the cancer-related risks at the range of effective radiation doses reported for CT colonography from existing risk models based on much higher radiation exposure. On the basis of 2 reviews, total radiation exposure with CT colonography ranges from 1.6 to 24.4 mSV for dual positioning (both supine and prone), with a median dose estimate of 8.8 mSv or 10.2 mSv per examination.60,61 On the basis of the National Research Council's Biological Effects of Ionizing Radiation (BEIR) VII phase 2 report findings.62, the National Research Council predicts that approximately 1 additional individual per 1000 would develop cancer (solid cancer or leukemia) from exposure to 10 mSv above background (according to the linear no-threshold model). Because of limitations in the data used to develop this model, these risk estimates are uncertain and could vary by a factor of 2 or 3.62 In addition, some organizations believe that the linear no-threshold model is an oversimplification that may overestimate the risk for malignancy.63
Extracolonic findings detected by CT colonography are common, occurring in 27% to 69% of persons screened with CT colonography (Appendix Table 4). We identified 9 studies (n = 12,557) that reported estimates of extracolonic findings in asymptomatic persons.49,55,64-70 In these studies, classification of extracolonic findings varied but generally considered 3 types of clinical significance: high (findings that require surgical treatment, medical intervention, or further investigation), moderate (findings that would not require immediate medical attention but would probably require recognition, investigation, or future treatment), and low (findings that would not require further investigation or treatment). These 3 categories generally map to the CT Colonography Report and Data System (C-RADS).71, as described elsewhere.25 Extracolonic findings of high clinical significance (for example, indeterminate solid organ masses or chest nodules, abdominal aortic aneurysms ≥3 cm, aneurysms of the splenic or renal arteries, or adenopathy >1 cm) occurred in 4.5% to 11% of asymptomatic populations.49,65-67,69,70 Extracolonic findings of moderate clinical significance (such as renal calculi and small adrenal masses) were equally or more common and occurred in up to 27%.49,64,65,67-70 Because all extracolonic findings of high significance, along with some moderate findings, would require medical follow-up, these have the potential for additional morbidity and cost, as well as potential benefit. Across studies, approximately 7% to 16% of persons undergoing CT colonography were recommended to have additional diagnostic evaluation for extracolonic findings.55,64,65,67,68,70 Only a minority of these findings ultimately warranted definitive treatment (for example, repair of abdominal aortic aneurysm, resection of malignant lesions, or chemotherapy for metastatic lesions).64,65,68-70 Although these estimates provide important contextual information, they are limited by the available studies, which varied greatly in their ability to accurately assess follow-up and in the duration of follow-up, the longest of which was 2 years.
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