Amy B. Knudsen

Evaluating Test Strategies for Colorectal Cancer Screening: A Decision Analysis for the U.S. Preventive Services Task Force

Despite recent declines in both incidence and mortality (1), colorectal cancer remains the second most common cause of death from cancer in the United States (2). Screening for colorectal cancer reduces mortality by allowing physicians to detect cancer at earlier, more treatable stages, as well as to identify and remove adenomatous polyps (asymptomatic benign precursor lesions that may lead to colorectal cancer). Many tests are available for screening, such as fecal occult blood tests (FOBTs), flexible sigmoidoscopy, and colonoscopy. Screening with FOBT (Hemoccult II, Beckman Coulter, Fullerton, California) has been shown to reduce colorectal cancer mortality by 15% to 33% in randomized, controlled trials (35), and screening with more sensitive FOBTs, flexible sigmoidoscopy, colonoscopy, or combinations of these tests may reduce the burden of colorectal cancer even more (6, 7). In the absence of adequate clinical trial data on several recommended screening strategies, microsimulation modeling can provide guidance on the risks, benefits, and testing resources required for different screening strategies to reduce the burden of colorectal cancer. In July 2002, the U.S. Preventive Services Task Force (USPSTF) concluded that there was sufficient evidence to recommend strongly that all average-risk adults 50 years of age or older should be offered colorectal cancer screening (8). However, the logistics of screening, such as the type of screening test, screening interval, and age at which to stop screening, were not evaluated in terms of the balance of benefits and potential harms. The USPSTF has again addressed recommendations for colorectal cancer screening with a systematic review of the evidence (9) on screening tests. For this assessment, the USPSTF requested a decision analysis to project expected outcomes of various strategies for colorectal cancer screening. Two independent microsimulation modeling groups from the Cancer Intervention and Surveillance Modeling Network (CISNET), funded by the National Cancer Institute, used a comparative modeling approach to compare life-years gained relative to resource use of different strategies for colorectal cancer screening. Methods We used 2 microsimulation models, MISCAN (MIcrosimulation Screening Analysis) (1012) and SimCRC (Simulation Model of Colorectal Cancer) (13), to estimate the life-years gained relative to no screening and the colonoscopies required (that is, an indicator for resource use and risk for complications) for different colorectal cancer screening strategies defined by test, age at which to begin screening, age at which to stop screening, and screening interval. We aimed to identify a set of recommendable strategies with similar clinical benefit and an efficient use of colonoscopy resources. Using 2 models (that is, a comparative modeling approach) adds credibility to the results and serves as a sensitivity analysis on the underlying structural assumptions of the models, particularly pertaining to the unobservable natural history of colorectal cancer. Microsimulation Models The Appendix describes the MISCAN and SimCRC models, and standardized model profiles are available at cisnet.cancer.gov/profiles/. In brief, both models simulate the life histories of a large population of individuals from birth to death. As each individual ages, there is a chance that an adenoma will develop. One or more adenomas can occur in an individual, and each adenoma can independently develop into preclinical (that is, undiagnosed) colorectal cancer (Figure 1). The risk for developing an adenoma depends on age, sex, and baseline individual risk. The models track the location and size of each adenoma; these characteristics influence disease progression and the chance that the adenoma will be found by screening. The size of adenomas can progress from small (5 mm) to medium (6 to 9 mm) to large (10 mm). Some adenomas eventually become malignant, transforming to stage I preclinical cancer. Preclinical cancer has a chance of progressing through stages I to IV and may be diagnosed by symptoms at any stage. Survivorship after diagnosis depends on the stage of disease. Figure 1. Natural history of disease as modeled by the Microsimulation Screening Analysis and Simulation Model of Colorectal Cancer models. The opportunity to intervene in the natural history through screening is noted. The natural history component of each model was calibrated to 19751979 clinical incidence data (14) and adenoma prevalence from autopsy studies in the same period (1524). We used this period because incidence rates and adenoma prevalence had not yet been affected by screening. We corrected the adenoma prevalence for studies of non-U.S. populations by using standardized colorectal cancer incidence ratios. The models use all-cause mortality estimates from the U.S. life tables and stage-specific data on colorectal cancer survival from the 19961999 Surveillance, Epidemiology, and End Results program (14). Table 1 compares outcomes from the natural history components of the models. Table 1. Comparison of the Natural History Outcomes from the Microsimulation Screening Analysis (MISCAN) and Simulation Model of Colorectal Cancer (SimCRC) Models The effectiveness of a screening strategy is modeled through a tests ability to detect lesions (that is, adenomas or preclinical cancer). Once screening is introduced, a simulated person who has an underlying lesion has a chance of having it detected during a screening round depending on the sensitivity of the test for that lesion and whether the lesion is within the reach of the test. Screened persons without an underlying lesion can have a false-positive test result and undergo unnecessary follow-up colonoscopy. Hyperplastic polyps are not modeled explicitly, but their detection is reflected in the specificity of the screening tests. The models incorporate the risk for fatal complications associated with perforation during colonoscopy. Both models have been validated against the long-term reductions in incidence and mortality of colorectal cancer with annual FOBT reported in the Minnesota Colon Cancer Control Study (3, 25, 26) and show good concordance with the trial results. Strategies for Colorectal Cancer Screening In consultation with the USPSTF, we included the following basic strategies: 1) no screening, 2) colonoscopy, 3) FOBT (Hemoccult II, Hemoccult SENSA [Beckman Coulter], or fecal immunochemical testing), 4) flexible sigmoidoscopy (with biopsy), and 5) flexible sigmoidoscopy combined with Hemoccult SENSA. For each basic strategy, we evaluated start ages of 40, 50, and 60 years and stop ages of 75 and 85 years. For the FOBT strategies, we considered screening intervals of 1, 2, and 3 years, and for the sigmoidoscopy and colonoscopy strategies, we considered intervals of 5, 10, and 20 years. These variations resulted in 145 strategies: 90 single-test strategies, 54 combination-test strategies, and 1 no-screening strategy. The stop age reflects the oldest possible age at which to screen, but the actual stopping age is dictated by the start age and screening interval. In the base case, we assumed 100% adherence for screening tests, follow-up of positive findings, and surveillance of persons found to have adenomas. Individuals with a positive FOBT result or with an adenoma detected by sigmoidoscopy were referred for follow-up colonoscopy. For years in which both tests were due for the combined strategy, the FOBT was performed first; if the result was positive, the patient was referred for follow-up colonoscopy. In those years, flexible sigmoidoscopy was done only for patients with a negative FOBT result. If findings on follow-up colonoscopy were negative, the individual was assumed to undergo subsequent screening with colonoscopy with a 10-year interval (as long as results of the repeated colonoscopy were negative) and did not return to the initial screening schedule, as is the recommendation of the U.S. Multi-Society Task Force and American Cancer Society (7, 27). All individuals with an adenoma detected were followed with colonoscopy surveillance per the Multi-Society guidelines (27, 28). The surveillance interval depended on the number and size of the adenomas detected on the last colonoscopy; it ranged from 3 to 5 years and was assumed to continue for the remainder of the persons lifetime. We estimated the test characteristics of colorectal cancer screening from a review of the available literature (Table 2) (29). We conducted this review independently of and parallel in time with the systematic evidence review performed for the USPSTF (9). Table 2. Test Characteristics Used in the Microsimulation Screening Analysis and Simulation Model of Colorectal Cancer Models Evaluation of Outcomes Determination of Efficient Strategies The most effective strategy was defined as the one with the greatest life-years gained relative to no screening. However, it is important to consider the relative intensity of test use required to achieve those gains. The more effective strategies tended to be associated with more colonoscopies on average in a persons lifetime, which translated into an increased risk for colonoscopy-related complications. We used an approach that mirrors that of cost-effectiveness analysis (30) to identify the set of efficient, or dominant, strategies within each test category. A strategy was considered dominant when no other strategy or combination of strategies provided more life-years with the same number of colonoscopies. We conducted this analysis separately for each of the 5 basic screening strategies because the number of noncolonoscopy tests differed by strategy. We then ranked the efficient screening strategies by increasing effectiveness and calculated the incremental number of colonoscopies (COL) per 1000, the incremental life-years gained (LYG) per 1000, and the incremental number of colonoscopies necessary to achieve 1 year of life (COL/

Cost-effectiveness of Colorectal Cancer Screening

Colorectal cancer is an important public health problem. Several screening methods have been shown to be effective in reducing colorectal cancer mortality. The objective of this review was to assess the cost-effectiveness of the different colorectal cancer screening methods and to determine the preferred method from a cost-effectiveness point of view. Five databases (MEDLINE, EMBASE, the Cost-Effectiveness Analysis Registry, the British National Health Service Economic Evaluation Database, and the lists of technology assessments of the Centers for Medicare and Medicaid Services) were searched for cost-effectiveness analyses published in English between January 1993 and December 2009. Fifty-five publications relating to 32 unique cost-effectiveness models were identified. All studies found that colorectal cancer screening was cost-effective or even cost-saving compared with no screening. However, the studies disagreed as to which screening method was most effective or had the best incremental cost-effectiveness ratio for a given willingness to pay per life-year gained. There was agreement among studies that the newly developed screening tests of stool DNA testing, computed tomographic colonography, and capsule endoscopy were not yet cost-effective compared with the established screening options.

Cost-Effectiveness of Computed Tomographic Colonography Screening for Colorectal Cancer in the Medicare Population

BACKGROUND The Centers for Medicare and Medicaid Services (CMS) considered whether to reimburse computed tomographic colonography (CTC) for colorectal cancer screening of Medicare enrollees. To help inform its decision, we evaluated the reimbursement rate at which CTC screening could be cost-effective compared with the colorectal cancer screening tests that are currently reimbursed by CMS and are included in most colorectal cancer screening guidelines, namely annual fecal occult blood test (FOBT), flexible sigmoidoscopy every 5 years, flexible sigmoidoscopy every 5 years in conjunction with annual FOBT, and colonoscopy every 10 years. METHODS We used three independently developed microsimulation models to assess the health outcomes and costs associated with CTC screening and with currently reimbursed colorectal cancer screening tests among the average-risk Medicare population. We assumed that CTC was performed every 5 years (using test characteristics from either a Department of Defense CTC study or the National CTC Trial) and that individuals with findings of 6 mm or larger were referred to colonoscopy. We computed incremental cost-effectiveness ratios for the currently reimbursed screening tests and calculated the maximum cost per scan (ie, the threshold cost) for the CTC strategy to lie on the efficient frontier. Sensitivity analyses were performed on key parameters and assumptions. RESULTS Assuming perfect adherence with all tests, the undiscounted number life-years gained from CTC screening ranged from 143 to 178 per 1000 65-year-olds, which was slightly less than the number of life-years gained from 10-yearly colonoscopy (152-185 per 1000 65-year-olds) and comparable to that from 5-yearly sigmoidoscopy with annual FOBT (149-177 per 1000 65-year-olds). If CTC screening was reimbursed at

Estimation of benefits, burden, and harms of colorectal cancer screening strategies: Modeling study for the US preventive services Task Force

488 per scan (slightly less than the reimbursement for a colonoscopy without polypectomy), it would be the most costly strategy. CTC screening could be cost-effective at

Radiation-Related Cancer Risks From CT Colonography Screening: A Risk-Benefit Analysis

108-

Contribution of Screening and Survival Differences to Racial Disparities in Colorectal Cancer Rates

205 per scan, depending on the microsimulation model used. Sensitivity analyses showed that if relative adherence to CTC screening was 25% higher than adherence to other tests, it could be cost-effective if reimbursed at

Calibration methods used in cancer simulation models and suggested reporting guidelines.

488 per scan. CONCLUSIONS CTC could be a cost-effective option for colorectal cancer screening among Medicare enrollees if the reimbursement rate per scan is substantially less than that for colonoscopy or if a large proportion of otherwise unscreened persons were to undergo screening by CTC.

Sensitivity of immunochemical faecal occult blood testing for detecting left- vs right-sided colorectal neoplasia

IMPORTANCE The US Preventive Services Task Force (USPSTF) is updating its 2008 colorectal cancer (CRC) screening recommendations. OBJECTIVE To inform the USPSTF by modeling the benefits, burden, and harms of CRC screening strategies; estimating the optimal ages to begin and end screening; and identifying a set of model-recommendable strategies that provide similar life-years gained (LYG) and a comparable balance between LYG and screening burden. DESIGN, SETTING, AND PARTICIPANTS Comparative modeling with 3 microsimulation models of a hypothetical cohort of previously unscreened US 40-year-olds with no prior CRC diagnosis. EXPOSURES Screening with sensitive guaiac-based fecal occult blood testing, fecal immunochemical testing (FIT), multitarget stool DNA testing, flexible sigmoidoscopy with or without stool testing, computed tomographic colonography (CTC), or colonoscopy starting at age 45, 50, or 55 years and ending at age 75, 80, or 85 years. Screening intervals varied by modality. Full adherence for all strategies was assumed. MAIN OUTCOMES AND MEASURES Life-years gained compared with no screening (benefit), lifetime number of colonoscopies required (burden), lifetime number of colonoscopy complications (harms), and ratios of incremental burden and benefit (efficiency ratios) per 1000 40-year-olds. RESULTS The screening strategies provided LYG in the range of 152 to 313 per 1000 40-year-olds. Lifetime colonoscopy burden per 1000 persons ranged from fewer than 900 (FIT every 3 years from ages 55-75 years) to more than 7500 (colonoscopy screening every 5 years from ages 45-85 years). Harm from screening was at most 23 complications per 1000 persons screened. Strategies with screening beginning at age 50 years generally provided more LYG as well as more additional LYG per additional colonoscopy than strategies with screening beginning at age 55 years. There were limited empirical data to support a start age of 45 years. For persons adequately screened up to age 75 years, additional screening yielded small increases in LYG relative to the increase in colonoscopy burden. With screening from ages 50 to 75 years, 4 strategies yielded a comparable balance of screening burden and similar LYG (median LYG per 1000 across the models): colonoscopy every 10 years (270 LYG); sigmoidoscopy every 10 years with annual FIT (256 LYG); CTC every 5 years (248 LYG); and annual FIT (244 LYG). CONCLUSIONS AND RELEVANCE In this microsimulation modeling study of a previously unscreened population undergoing CRC screening that assumed 100% adherence, the strategies of colonoscopy every 10 years, annual FIT, sigmoidoscopy every 10 years with annual FIT, and CTC every 5 years performed from ages 50 through 75 years provided similar LYG and a comparable balance of benefit and screening burden.

Stool DNA testing to screen for colorectal cancer in the medicare population: A cost-effectiveness analysis

OBJECTIVE The purpose of this study was to estimate the ratio of cancers prevented to induced (benefit-risk ratio) for CT colonography (CTC) screening every 5 years from the age of 50 to 80 years. MATERIALS AND METHODS Radiation-related cancer risk was estimated using risk projection models based on the National Research Councils Biological Effects of Ionizing Radiation (BEIR) VII Committees report and screening protocols from the American College of Radiology Imaging Networks National CT Colonography Trial. Uncertainty intervals were estimated using Monte Carlo simulation methods. Comparative modeling with three colorectal cancer microsimulation models was used to estimate the potential reduction in colorectal cancer cases and deaths. RESULTS The estimated mean effective dose per CTC screening study was 8 mSv for women and 7 mSv for men. The estimated number of radiation-related cancers resulting from CTC screening every 5 years from the age of 50 to 80 years was 150 cases/100,000 individuals screened (95% uncertainty interval, 80-280) for men and women. The estimated number of colorectal cancers prevented by CTC every 5 years from age 50 to 80 ranged across the three microsimulation models from 3580 to 5190 cases/100,000 individuals screened, yielding a benefit-risk ratio that varied from 24:1 (95% uncertainty interval, 13:1-45:1) to 35:1 (19:1-65:1). The benefit-risk ratio for cancer deaths was even higher than the ratio for cancer cases. Inclusion of radiation-related cancer risks from CT examinations performed to follow up extracolonic findings did not materially alter the results. CONCLUSION Concerns have been raised about recommending CTC as a routine screening tool because of potential harms including the radiation risks. Based on these models, the benefits from CTC screening every 5 years from the age of 50 to 80 years clearly outweigh the radiation risks.

A Systematic Comparison of Microsimulation Models of Colorectal Cancer The Role of Assumptions about Adenoma Progression

Background: Considerable disparities exist in colorectal cancer (CRC) incidence and mortality rates between blacks and whites in the United States. We estimated how much of these disparities could be explained by differences in CRC screening and stage-specific relative CRC survival. Methods: We used the MISCAN-Colon microsimulation model to estimate CRC incidence and mortality rates in blacks, aged 50 years and older, from 1975 to 2007 assuming they had: (i) the same trends in screening rates as whites instead of observed screening rates (incidence and mortality); (ii) the same trends in stage-specific relative CRC survival rates as whites instead of observed (mortality only); and (iii) a combination of both. The racial disparities in CRC incidence and mortality rates attributable to differences in screening and/or stage-specific relative CRC survival were then calculated by comparing rates from these scenarios to the observed black rates. Results: Differences in screening accounted for 42% of disparity in CRC incidence and 19% of disparity in CRC mortality between blacks and whites. Thirty-six percent of the disparity in CRC mortality could be attributed to differences in stage-specific relative CRC survival. Together screening and survival explained a little more than 50% of the disparity in CRC mortality between blacks and whites. Conclusion: Differences in screening and relative CRC survival are responsible for a considerable proportion of the observed disparities in CRC incidence and mortality rates between blacks and whites. Impact: Enabling blacks to achieve equal access to care as whites could substantially reduce the racial disparities in CRC burden. Cancer Epidemiol Biomarkers Prev; 21(5); 728–36. ©2012 AACR.