4Discussion

We used two independent microsimulation models to evaluate different CRC screening strategies defined by screening test, age to begin, interval to repeat, and age to stop screening. Our goal was to provide the USPSTF with information that synthesizes and translates multiple sources of data, such as screening test characteristics, into projections of clinical benefit and resource utilization for multiple screening options. We found several screening strategies (high sensitivity FOBT performed annually, flexible sigmoidoscopy every 5 years with Hemoccult SENSA every 2 to 3 years, and colonoscopy every 10 years) that provide similar gains in life-years - provided equally high adherence for all aspects of the screening process. Our analysis also found that annual FOBT with a lower-sensitivity test (e.g., Hemoccult II) and flexible sigmoidoscopy alone resulted in fewer life-years gained relative to other strategies. Our analysis confirmed the current recommendation to begin screening at age 50 in an asymptomatic general population and showed that stopping at age 75 after consecutive negative screenings since age 50 provides almost the same benefit as stopping at age 85 but with substantially fewer colonoscopy resources and risk of complications.

Our decision analysis represents the first time that the USPSTF has included simulation modeling to help inform their decision on recommendations. The USPSTF had previously recommended screening for all asymptomatic persons beginning at age 50 but did not recommend one test over another or an age to stop screening (8). Although randomized controlled trials are the preferred method for establishing effectiveness of (screening) interventions, they are expensive and require long follow-up and can only address a limited number of comparison groups. However, well-validated microsimulation models may be used to highlight the tradeoff between clinical benefit and resource utilization from different screening policies and inform decision making with standardized comparisons of net benefits and risks. The process with which our analysis was conducted represents an important advancement from evidence-based to evidence-informed medicine, and the use of more than one model, as advocated by CISNET, adds credibility when model results agree.

We found that CRC screening with high sensitivity FOBT (Hemoccult SENSA or FIT) provided comparable life-years gained as colonoscopy, even though the individual test characteristics were substantially better for colonoscopy (Table 2). This finding was partially due to the fact the FOBT needs to be performed every year compared with every ten years for colonoscopy, and the test characteristics are assumed to remain unchanged with each subsequent screen. For example, if an adenoma was missed by a screening test in one cycle then the chance that it would be missed again on the next exam is still based on the false-negative rate (1 - sensitivity for adenomas). There is little evidence on whether test sensitivity varies with increasing rounds of testing. Also, a substantial percentage of individuals initially ‘assigned’ to annual FOBT screening switch to a strategy of colonoscopy screening every ten years because of false-positive FOBT results. For example, with a specificity of 92.5% for Hemoccult SENSA, the percentage of people in a colonoscopy screening program after 10 FOBTs is about 54%, and after 20 FOBTs is about 79%.

Previously there has been no recommended stopping age for CRC screening (7, 30). However, our results indicate that continued screening in 75-year-old persons after consecutive negative screens since age 50 will add little benefit. Individuals with continuous negative findings by age 75 are unlikely to either have a missed adenoma at their last screen or to develop an adenoma that progresses to cancer and subsequent cancer death after their last screen. Surveillance colonoscopies for those with adenomas detected are continued without a stopping age. We note that our analysis used chronological age rather than comorbidity-adjusted life expectancy and that the decision to stop screening in practice should consider the age and health of the patient. As a guide, life expectancy at age 75 is 10.5 and 12.5 years for men and women, respectively (36).

There were a few findings that can be explained by model differences. Both models incorporate assumptions about the adenoma-carcinoma sequence (i.e., the development of CRC from adenomas), for which limited data are available to estimate the time that it takes (on average) for an adenoma to develop into preclinical cancer. For example, in the MISCAN model the average time from adenoma development to CRC diagnosis is 10 years among those individuals with CRC diagnosed (i.e., dwell time), whereas in the SimCRC model this value is about 22 years. The implications of these differences were higher life-years gained with screening in general, and more favorable results for beginning screening at age 40, with the SimCRC model. The former implication had minimal impact on our conclusions because the relative findings were consistent across models. The latter implication resulted in eliminating the start age of 40 from consideration. Another difference between the models is the distribution of adenomas in the colorectal tract (see Appendix 1 and Table 1). In the MISCAN model, adenomas are assumed to have the same distribution as CRCs, while the SimCRC model is calibrated to the distribution of adenomas from autopsy studies. As a result, the MISCAN model found strategies involving sigmoidoscopy to be more effective than the SimCRC model because a larger proportion of adenomas are within the reach of the sigmoidoscope. Despite this difference, both model results found that the 5-yearly sigmoidoscopy strategy was not as effective as annual screening with a sensitive FOBT or 10-yearly colonoscopy.

There are several limitations and caveats to consider. First, we only evaluated CRC strategies requested by the USPSTF based on their review of the evidence in 2002 (8) and did not include newer screening tests such as CT colonography or the DNA stool test (9, 10, 30). Second, because we were not asked to provide a cost-effectiveness analysis we used the number of colonoscopies as a proxy for resource utilization, as well as non-fatal adverse effects from screening. However, this does not capture all resources required per scenario, although we report the numbers of FOBT and flexible sigmoidoscopy tests required for each strategy. Third, we assumed 100% adherence with screening, follow-up (i.e., chance of getting a diagnostic colonoscopy if a screening test is positive), and surveillance for all scenarios in order to provide outcomes associated with the strategies as they were specified. In practice, adherence is much lower than 100% and varies across type of screening test. We conducted a sensitivity analysis varying overall adherence but not differentially across strategies. We chose to evaluate strategies assuming equivalent adherence because it is uncertain whether adherence will be higher with non-invasive but more frequent testing, or invasive but less frequent testing. Because we considered three different adherence scenarios in Figure 3, readers are able to compare different adherence levels themselves. We emphasize that in practice adherence is critical and ultimately the best option for a patient is the one that he or she will attend (7, 30). In addition, issues pertaining to the implementation of a screening program, including endoscopy capacity (37–39), professional qualification (40, 41), insurance coverage, shared decision making, and how to increase adherence with CRC screening (42) are important considerations for implementing recommendations in practice.

In conclusion, our results support CRC screening from ages 50 to 75 with a high sensitivity FOBT annually, 10-yearly colonoscopy, or high sensitivity FOBT every 2 to 3 years with a 5-yearly flexible sigmoidoscopy. Our findings were in general support of the 2002 USPSTF CRC screening recommendations with a few exceptions. First, while there is currently no recommended stopping age for CRC screening, we found that continuing screening after age 75 in those individuals who have had regular, consistently negative, screenings since age 50 provides minimal benefit for the resources required. Second, we found that screening with Hemoccult II annually and flexible sigmoidoscopy alone every five years does not provide comparable effectiveness to screening annually with a sensitive FOBT or every ten years with colonoscopy. Lastly, if a sensitive FOBT is used the FOBT screening interval can be extended to three years when used in combination with flexible sigmoidoscopy every five years. These conclusions were corroborated by two independent microsimulation models.