Janneke Wilschut

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/

Screening for colorectal cancer: random comparison of guaiac and immunochemical faecal occult blood testing at different cut-off levels

Immunochemical faecal occult blood testing (FIT) provides quantitative test results, which allows optimisation of the cut-off value for follow-up colonoscopy. We conducted a randomised population-based trial to determine test characteristics of FIT (OC-Sensor micro, Eiken, Japan) screening at different cut-off levels and compare these with guaiac-based faecal occult blood test (gFOBT) screening in an average risk population. A representative sample of the Dutch population (n=10 011), aged 50–74 years, was 1 : 1 randomised before invitation to gFOBT and FIT screening. Colonoscopy was offered to screenees with a positive gFOBT or FIT (cut-off 50 ng haemoglobin/ml). When varying the cut-off level between 50 and 200 ng ml−1, the positivity rate of FIT ranged between 8.1% (95% CI: 7.2–9.1%) and 3.5% (95% CI: 2.9–4.2%), the detection rate of advanced neoplasia ranged between 3.2% (95% CI: 2.6–3.9%) and 2.1% (95% CI: 1.6–2.6%), and the specificity ranged between 95.5% (95% CI: 94.5–96.3%) and 98.8% (95% CI: 98.4–99.0%). At a cut-off value of 75 ng ml−1, the detection rate was two times higher than with gFOBT screening (gFOBT: 1.2%; FIT: 2.5%; P<0.001), whereas the number needed to scope (NNscope) to find one screenee with advanced neoplasia was similar (2.2 vs 1.9; P=0.69). Immunochemical faecal occult blood testing is considerably more effective than gFOBT screening within the range of tested cut-off values. From our experience, a cut-off value of 75 ng ml−1 provided an adequate positivity rate and an acceptable trade-off between detection rate and NNscope.

Cost-effectiveness analysis of a quantitative immunochemical test for colorectal cancer screening.

BACKGROUND & AIMS Two European randomized trials (N = 30,000) compared guaiac fecal occult blood testing with quantitative fecal immunochemical testing (FIT) and showed better attendance rates and test characteristics for FIT. We aimed to identify the most cost-effective FIT cutoff level for referral to colonoscopy based on data from these trials and allowing for differences in screening ages. METHODS We used the validated MIcrosimulation SCreening ANalysis (MISCAN)-Colon microsimulation model to estimate costs and effects of different screening strategies for FIT cutoff levels of 50, 75, 100, 150, and 200 ng/mL hemoglobin. For each cutoff level, screening strategies were assessed with various age ranges and screening intervals. We assumed sufficient colonoscopy capacity for all strategies. RESULTS At all cost levels, FIT screening was most effective with the 50 ng/mL cutoff level. The incremental cost-effectiveness ratio of biennial screening between ages 55 and 75 years using FIT at 50 ng/mL, for example, was 3900 euro per life year gained. Annual screening had an incremental cost-effectiveness ratio of 14,900 euro per life year gained, in combination with a wider age range (between ages 45 and 80 years). In the sensitivity analysis, 50 ng/mL remained the preferred cutoff level. CONCLUSIONS FIT screening is more cost-effective at a cutoff level of 50 ng/mL than at higher cutoff levels. This supports the recommendation to use FIT at a cutoff level of 50 ng/mL, which is considerably lower than the values used in current practice.

At what costs will screening with CT colonography be competitive? A cost-effectiveness approach†

The costs of computed tomographic colonography (CTC) are not yet established for screening use. In our study, we estimated the threshold costs for which CTC screening would be a cost‐effective alternative to colonoscopy for colorectal cancer (CRC) screening in the general population. We used the MISCAN‐colon microsimulation model to estimate the costs and life‐years gained of screening persons aged 50–80 years for 4 screening strategies: (i) optical colonoscopy; and CTC with referral to optical colonoscopy of (ii) any suspected polyp; (iii) a suspected polyp ≥6 mm and (iv) a suspected polyp ≥10 mm. For each of the 4 strategies, screen intervals of 5, 10, 15 and 20 years were considered. Subsequently, for each CTC strategy and interval, the threshold costs of CTC were calculated. We performed a sensitivity analysis to assess the effect of uncertain model parameters on the threshold costs. With equal costs (

Diagnostic Yield Improves With Collection of 2 Samples in Fecal Immunochemical Test Screening Without Affecting Attendance

662), optical colonoscopy dominated CTC screening. For CTC to gain similar life‐years as colonoscopy screening every 10 years, it should be offered every 5 years with referral of polyps ≥6 mm. For this strategy to be as cost‐effective as colonoscopy screening, the costs must not exceed

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

285 or 43% of colonoscopy costs (range in sensitivity analysis: 39–47%). With 25% higher adherence than colonoscopy, CTC threshold costs could be 71% of colonoscopy costs. Our estimate of 43% is considerably lower than previous estimates in literature, because previous studies only compared CTC screening to 10‐yearly colonoscopy, where we compared to different intervals of colonoscopy screening.

Fecal Occult Blood Testing When Colonoscopy Capacity is Limited

BACKGROUND & AIMS The fecal immunochemical test (FIT) is superior to the guaiac-based fecal occult blood test in detecting neoplasia. There are not much data on the optimal number of FITs to perform. We conducted a population-based trial to determine attendance and diagnostic yield of 1- and 2-sample FIT screening. METHODS The study included 2 randomly selected groups of subjects aged 50-74 years (1-sample FIT, n=5007; 2-sample FIT, n=3197). The 2-sample group was instructed to collect fecal samples on 2 consecutive days. Subjects were referred for colonoscopy when at least 1 sample tested positive (≥50 ng hemoglobin/mL). RESULTS Attendance was 61.5% in the 1-sample group (2979 of 4845; 95% confidence interval, 60.1%-62.9%) and 61.3% in the 2-sample group (1875 of 3061; 95% confidence interval, 59.6%-63.0%; P=.84). In the 1-sample group 8.1% tested positive, and in the 2-sample group 12.8% had at least 1 positive test outcome and 5.0% had 2 positive test outcomes (P<.05). When the mean from both test results in the 2-sample group was used, 10.1% had a positive test outcome (P<.05). The detection rates for advanced neoplasia were 3.1% in the 1-sample group, 4.1% in the 2-sample group with at least 1 positive test outcome, 2.5% when both test results were positive, and 3.7% among subjects with the mean from both test results being positive. CONCLUSIONS There is no difference in attendance for subjects offered 1- or 2-sample FIT screening. The results allow for the development of efficient FIT screening strategies that can be adapted for local colonoscopy capacities, rather than varying the cut-off value in a 1-sample strategy.

Increased risk of adenomas in individuals with a family history of colorectal cancer: results of a meta-analysis.

BACKGROUND The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees. OBJECTIVE To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services. DESIGN Comparative microsimulation modeling study using 2 independently developed models. DATA SOURCES Derived from literature. TARGET POPULATION A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied. TIME HORIZON Lifetime. PERSPECTIVE Third-party payer. INTERVENTION Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies. OUTCOME MEASURES Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs. RESULTS OF BASE-CASE ANALYSIS Assuming a cost of

Advance notification letters increase adherence in colorectal cancer screening: A population-based randomized trial

350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of

A Decision-Analytic Evaluation of the Cost-Effectiveness of Family History–Based Colorectal Cancer Screening Programs

40 to