We used 2 independent microsimulation models to evaluate different strategies for colorectal cancer screening defined by screening test, age at which to begin screening, interval to repeat screening, and age at which 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 (colonoscopy every 10 years, high-sensitivity FOBT performed annually, and flexible sigmoidoscopy every 5 years with Hemoccult SENSA every 2 to 3 years) that provide similar gains in life-years—if there is equally high adherence for all aspects of the screening process. Our analysis also found that annual FOBT with a lower-sensitivity test (for example, 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 for 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 at which to stop screening (6
). Although randomized, controlled trials are the preferred method for establishing effectiveness of (screening) interventions, they are expensive, require long follow-up, and can address only 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 colorectal cancer screening with high-sensitivity FOBT (Hemoccult SENSA or fecal immunochemical test) provided similar life-years gained as colonoscopy, even though the individual test characteristics were substantially better for colonoscopy (). This finding was partially due to the fact the FOBT must be performed every year compared with every 10 years for colonoscopy, and the test characteristics are assumed to remain unchanged with each subsequent screening. 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 examination 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. In addition, a substantial percentage of individuals on annual FOBT screening will eventually have a false-positive screening test with referral for colonoscopy. Once confirmed to be negative by colonoscopy they are then place on colonoscopy screening every 10 years, as per guidelines. For example, with a specificity of 92.5% for Hemoccult SENSA, the percentage of people in a colonoscopy screening program is about 54% after 10 FOBTs and about 79% after 20 FOBTs.
There has been no recommended stopping age for colorectal cancer screening (7
). However, our results indicate that continued screening in 75-year-old persons after consecutive negative screenings since age 50 will add little benefit. Individuals with continuous negative findings by age 75 are unlikely to have a missed adenoma at their last screening or to develop an adenoma that progresses to cancer and subsequent cancer death after their last screening. Surveillance colonoscopies for patients with adenomas detected are continued without a stopping age. We note that our analysis used chronologic 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 for men and 12.5 years for women, respectively (32
A few findings can be explained by model differences. Both models incorporate assumptions about the adenoma--carcinoma sequence (that is, the development of colorectal cancer 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 colorectal cancer diagnosis is 10 years among individuals with colorectal cancer diagnosed (that is, dwell time), whereas in the SimCRC model this value is about 22 years. The implications of these differences were more 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 effect 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 the Appendix
and ). In the MISCAN model, adenomas are assumed to have the same distribution as colorectal cancers, 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 did 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 strategy of sigmoidoscopy every 5 years was not as effective as annual screening with a sensitive FOBT or with colonoscopy every 10 years.
There are several limitations and caveats to consider. First, we evaluated only colorectal cancer strategies requested by the USPSTF on the basis of their review of the evidence in 2002 (8
), and we did not include newer screening tests, such as computed tomographic colonography or the DNA stool test (9
). 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 nonfatal adverse effects from screening. However, this does not capture all resources required per scenario, although we report the numbers of non-colonoscopy tests (that is, FOBT or flexible sigmoidoscopy) required for each strategy. Third, we assumed 100% adherence with screening, follow-up (that is, chance of undergoing diagnostic colonoscopy if a screening test result is positive), and surveillance for all scenarios 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 that varied 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 noninvasive but more frequent testing, or invasive but less frequent testing. Because we considered 3 different adherence scenarios in , readers can compare different adherence levels themselves. We emphasize that in practice adherence is critical and that ultimately the best option for a patient is the one that he or she will attend (7
). In addition, issues pertaining to the implementation of a screening program, including endoscopy capacity (33
), professional qualification (36
), insurance coverage, shared decision making, and how to increase adherence with colorectal cancer screening (38
), are important considerations for implementing recommendations in practice.
In conclusion, our results support colorectal cancer screening with colonoscopy every 10 years, a sensitive FOBT annually, or high sensitive FOBT every 2 to 3 years with a -yearly flexible sigmoidoscopy from ages 50 to 75 years. Our findings in general support the 2002 USPSTF recommendations for colorectal cancer screening, with a few exceptions. First, while there is currently no recommended stopping age for colorectal cancer screening, we found that continuing screening after age 75 in 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 5 years does not provide effectiveness similar to that of screening annually with a sensitive FOBT or every 10 years with colonoscopy. Finally, if a sensitive FOBT is used, the FOBT screening interval can be extended to 3 years when used in combination with flexible sigmoidoscopy every 5 years. These conclusions were corroborated by 2 independent microsimulation models.
From Memorial Sloan-Kettering Cancer Center, New York, New York; Erasmus Medical Center, Rotterdam, the Netherlands; Massachusetts General Hospital, Boston, Massachusetts; and University of Minnesota, Minneapolis, Minnesota