Our analysis showed that 3- and 5-yearly stool DNA testing were both more costly and less effective than annual screening with a sensitive FOBT. Screening with a stool DNA test would be an efficient strategy at a per-test cost of $34–$60, depending on the screening interval (3 or 5 years) and model used. Only if the relative adherence with stool DNA testing were 50% better than other screening tests, would the test be cost-effective at current test costs. These results hold both for the Medicare-eligible population, as well as the general screening population. The fact that two independently-developed models come to similar conclusions with respect to cost-effectiveness and threshold costs of stool DNA screening shows the robustness of the results for model uncertainties, particularly pertaining to the natural history of colorectal disease.
We had anticipated that stool DNA testing would be dominated by screening with a sensitive FOBT given that the stool DNA test has similar sensitivity and specificity as Hemoccult SENSA with a cost that is almost 80 times greater. Consequently the aim of our analysis was to explore the conditions under which stool DNA testing could compete with the existing screening tests. We have only explored the potential of stool DNA testing for colorectal cancer screening. The test might also have prognostic or even treatment implications, for example through risk stratification based on genetic markers or by guiding the use of genomic-targeted therapies. However, in this case the test becomes a diagnostic tool that can be administered at the time of diagnosis of colorectal cancer rather than a pre-symptomatic screening test. The evaluation of the cost-effectiveness of a stool DNA test as a diagnostic test is beyond the scope of our analysis.
Because stool DNA testing is still evolving,(3
) we evaluated threshold costs for improved test characteristics. Such improvements can be expected, given technological advances in the form of more sensitive polymerase chain reaction strategies.(3
) However, the threshold costs for the latest published version of the stool DNA test (version 2.0),(39
) are lower than the threshold costs for the base-case stool DNA test (version 1.1) due to the many unnecessary colonoscopies brought about by the considerably lower specificity. Even under the extreme assumption of perfect sensitivity and specificity, the threshold cost for the stool DNA test remained below $350 at intervals of 3 or 5 years.
Substantially higher adherence with stool DNA testing would make stool DNA screening cost-effective at $350. However, while it has been shown that the stool DNA test is acceptable to patients who have already agreed to participate in a screening program,(51
) there is no evidence that screening adherence with stool DNA testing would be substantially better than with other tests. Adherence needs to be 50% better than even FOBT and since both types of tests are non-invasive, this is unlikely. In the absence of this adherence benefit, stool DNA remains dominated.
Stool DNA testing is currently included in the American Cancer Society (ACS) guidelines for colorectal cancer screening (24
). Twelve US states and the District of Columbia have legislative mandates requiring that certain insurers should offer all screening options of the current ACS guidelines. As a consequence, coverage of stool DNA screening is now mandated in these states.(53
) For every 65-year-old person switching from Hemoccult SENSA or colonoscopy screening to stool DNA screening, colorectal cancer screening costs would increase on average by $750–$1250 (results not shown), while the life-years saved would on average decrease. In the US, there currently are 2.6 million 65-year olds,(54
) so on a national level stool DNA screening could potentially lead to an unnecessary expenditure of $3 billion per year. These figures would be even higher, when considering the complete target population for screening from age 50.
Our findings are comparable to two published cost-effectiveness analysis of stool DNA screening.(55
) Like ours, both analyses concluded that the stool DNA test was dominated by currently recommended colorectal cancer screening tests. Wu et al. found threshold costs that were slightly higher ($57–$70) than the threshold costs in this analysis. However, those threshold costs were based on a willingness to pay of $13,000 per life-year gained compared to no screening. Song et al. found threshold costs of $195 when comparing 2-yearly stool DNA testing to 10-yearly colonoscopy and assuming considerably higher colonoscopy costs. A similar comparison in the MISCAN and SimCRC models yielded threshold costs of $205–$213.
There are several limitations of the models. First, the models simulate the progression from adenoma to colorectal cancer by increasing the size of the adenomas over time. Because adenoma size and the presence of villous components or high-grade dysplasia are highly correlated,(57
) size indirectly represents histology and grade. However, neither model separately simulates the step from adenoma with low-grade dysplasia to an adenoma with high-grade dysplasia. If the advantage of a stool DNA test is detection of a smaller adenoma at the stage of high-grade dysplasia, we may underestimate its effectiveness. Second, we assumed that all colorectal cancers arise through the traditional adenoma-carcinoma sequence, with a linear sequence of mutations in the APC, KRAS and TP53 genes. Recent data indicate the probable existence of at least one alternative pathway to colorectal cancer through a mutation of the BRAF gene.(58
) Existence of different pathways will probably not influence the performance of FOBT because bleeding of a lesion is unlikely to be related to the pathway. It may influence sensitivity of endoscopy, as lesions from this pathway are more likely to be proximal and sessile or flat and therefore more difficult to find. However for the stool DNA test, the lesion in question may have acquired a gene mutation not assessed by the test. In this case, a person with a false-negative result on such a test will have a higher than average probability of having a negative test with subsequent screens. Consequently, we may have overestimated the benefit and the threshold cost of this test.
In conclusion, our analysis shows that future developments of the stool DNA test should not only focus on improving test characteristics but also on reducing test cost. The first stool DNA assay that reached the market was expensive ($795); a more recent stool assay for vimentin methylation alone was introduced this year at a cost of $220.(3
) These numbers offer hope that further technological refinements will permit significant cost reductions. We are currently lacking good information on the performance characteristics of these new tests. When the performance levels of newer versions of the stool DNA test become available, the results of our sensitivity analysis can be used to determine their cost-effectiveness. If the cost of the test is higher than the threshold costs associated with the level of performance of the new test, it will not be cost-effective. Our analysis shows, that improving tests characteristics alone is insufficient to make stool DNA testing cost-effective. Without further cost reductions, stool DNA screening will not be a cost-effective alternative for average-risk colorectal cancer screening in the Medicare population or the general screening population.
Reproducible Research Statement
Models are available to approved individuals with written agreement.