Comparing the Cost-Effectiveness of Innovative Colorectal Cancer Screening Tests

Elisabeth F. P. Peterse, PhD; Reinier G. S. Meester, PhD; Lucie de Jonge, MSc; Amir-Houshang Omidvari, MD; Fernando Alarid-Escudero, PhD; Amy B. Knudsen, PhD; Ann G. Zauber, PhD; Iris Lansdorp-Vogelaar, PhD


J Natl Cancer Inst. 2021;113(2):154-161. 

In This Article


New strategies are needed to increase CRC screening participation in the United States given rates reached a plateau of approximately 60%.[39] By comparing the incremental cost-effectiveness of CTC, PillCam, mtSDNA, and mSEPT9 from a societal perspective, this study revealed that of these alternatives, annual screening with mSEPT9 is cost-effective. Annual screening with the mSEPT9 had an ICER of $63 253 per QALYG. Other efficient strategies were CTC screening every 5 years (ICER = $1092 per QALYG) and annual mtSDNA screening (ICER = $214 974 per QALYG), which were not optimal given the willingness-to-pay threshold ($100 000 per QALYG).

The uncertainty of our conclusion is reflected in our probabilistic sensitivity analyses in which the mSEPT9 was the cost-effective strategy in 54% of our analyses. Test accuracy of the mSEPT9 is not as well established as for some of the other tests evaluated in this study. In line with requirements of the FDA, a prospective trial including 4500 participants is currently being performed that will provide essential additional information about test characteristics of the mSEPT9 and adherence to multiple rounds of testing and follow-up.[46]

Among the tests evaluated in this analysis, the mSEPT9 has the lowest sensitivity for both adenomas and CRC. Therefore, an important driver of its cost-effectiveness compared with CTC, PillCam, and mtSDNA is the substantially lower cost of the test. Similar as for FIT screening, the effectiveness of the mSEPT9 depends on annual repetition of the test and, similar to any other noncolonoscopy-based screening strategy, receipt of diagnostic follow-up colonoscopy. Due to the relatively low specificity of the mSEPT9 (79%) compared with the other tests, a high number of individuals are referred to a diagnostic follow-up colonoscopy regardless of disease status (51% after 3 years and 69% after 5 years with annual repetition of the test). Consequently, 21% of simulated individuals with a nonadvanced adenoma received a colonoscopy when screened with mSEPT9 in contrast with 7.6% when screened with FIT. Although nonadvanced adenomas generally confer low risk, they are more common than advanced adenomas and some may have aggressive biology. The detection of nonadvanced adenomas in these colonoscopies contributed to the slightly higher QALYG, CRC cases averted, and CRC deaths averted for mSEPT9 screening vs FIT screening despite its lower test sensitivity for advanced adenomas and cancers.

To our knowledge, this is the first study that simultaneously evaluated the PillCam, CTC, mSEPT9, and mtSDNA in a single cost-effectiveness analysis. In addition, it is the first cost-effectiveness analysis of these tests that uses updated test characteristics, CRC treatment costs, and CRC incidence. As expected, updated test characteristics, costs, and incidence levels have a substantial impact on cost-effectiveness outcomes. One cost-effectiveness analysis reported that mSEPT9 is less effective and more costly than FIT screening,[14] with costs of $8400 to $11 500 per QALYG compared with no screening. This study based the test characteristics of the mSEPT9 on the study by Church et al.,[34] which used an earlier version of the test. Changes that were made to the mSEPT9 as part of the development process for its premarket approval by the FDA resulted in the version used for the Potter et al. study,[27] which has an increased sensitivity but a decreased specificity compared with the version used by Church et al..[47] Our analyses suggest that with the current version of the mSEPT9, annual mSEPT9 screening is not less effective than annual FIT screening but is still more costly and requires considerably more colonoscopies. One previous study found a cost-effectiveness ratio of $29 244 per QALYG of 10-yearly PillCam screening vs no screening[15] compared with approximately $10 000 in our study with updated assumptions. Previous analyses that evaluated the cost-effectiveness of mtSDNA described that the mtSDNA is too expensive to be cost-effective compared with FIT and colonoscopy screening.[10,11,16] This study suggests that even when FIT and colonoscopy screening are not considered, the costs of mtSDNA screening are still too high compared with other alternative tests. Finally, our group's previous analyses on CTC suggested that CTC is not an efficient strategy compared with FIT and colonoscopy.[12,13] This study suggests that for individuals unwilling to undergo FIT and colonoscopy, CTC is an efficient strategy. However, annual screening with the mSEPT9 had an ICER of $63 253 per QALYG compared with 5-yearly CTC and is therefore preferred from a cost-effectiveness perspective.

Several limitations of our study are noteworthy. First, we assumed that no adenomas and cancers were systematically missed over time by a particular screening test. This assumption may not hold for the stool-based tests, because bleeding of a lesion is not necessarily a random event.[48] Furthermore, it may not hold for the mSEPT9 because approximately 18% of the tumors do not have methylation of the SEPT9 gene promoter[42] and will remain undetected at every subsequent mSEPT9 screening until their SEPT9 gene promoter is methylated. The systematic miss rates for the different screening tests are unknown. We performed a scenario analysis in which we assumed that 12% of advanced adenomas and 18% of CRCs are systematically missed by the mSEPT9, which minimally affected our results. This is in line with a previous study that suggested that incorporating systematically missing adenomas with a stool-based test has minimal impact on the effectiveness of FIT screening.[48]

Second, we assumed perfect adherence to screening, diagnostic follow-up, and surveillance in our base case analysis. This implies that the model predicted the maximum achievable benefit for all screening tests. Unfortunately, there are limited data on test-specific adherence to every step in the screening process (getting screening, diagnostic follow-up, treatment and/or surveillance) over multiple rounds of screening (eg, from ages 50 years to 75 years), making it impossible to inform our analyses with empirical evidence. We performed a scenario analysis that accounted for suboptimal adherence to follow-up and surveillance colonoscopies and for decreasing adherence over multiple screening rounds. Although the effectiveness of all screening modalities decreased with a lower adherence, the impact on ICERs was limited.

Third, the current lifetime risk of developing CRC in the absence of screening is uncertain. Our assumed CRC incidence is in line with previous analyses for the ACS and the observation that the increased CRC incidence in young adults is a cohort effect.[21,24] We explored the effect of a lower CRC incidence in a scenario analysis, which suggested that when CRC incidence resembles 1975–1979 data, CTC screening every 5 years is the cost-effective strategy because the ICER of annual screening with the mSEPT9 is approximately $120 000, just above the willingness-to-pay threshold.

Our study can be used to inform clinicians because it ranks the different CRC screening tests from a cost-effectiveness perspective. Individuals who are not willing to be screened with FIT or colonoscopy should be advised to undergo mSEPT9 screening if the high colonoscopy referral rate is acceptable to them. CTC should be the next test of choice. Ultimately, the best test is the "one that gets done." Although lack of participation may have various reasons, such as lack of resources in rural areas or more general reluctance against screening, previous studies suggest that the mSEPT9 has the potential to attract the population that currently does not participate in screening.[49,50] A recent study found substantially higher uptake of a blood-based test compared with a FIT in individuals who were overdue for screening,[49] and another study found that there was a 25% uptake of a blood-based test among people who declined stool-based tests.[50] This suggests that the mSEPT9 might be a suitable test to increase current CRC screening participation.

In conclusion, a well-established microsimulation model demonstrates that for people who are unwilling to be screened with FIT or colonoscopy, annual screening with the mSEPT9 is the test of choice given its cost-effectiveness profile compared with CTC, PillCam, and mtSDNA. The number of CRC cases and deaths averted and the number of QALYG from annual mSEPT9 screening are even higher than from annual FIT screening. However, the number of colonoscopies required for the mSEPT9 is 63% higher, and the total costs are 26% higher compared with annual FIT screening. Therefore, physicians should first offer individuals to participate in CRC screening using FIT or colonoscopy.