In this study, we found that at costs of $285 per test, CTC screening would be a cost-effective alternative to and provide similar life-years gained as the currently recommended strategy of colonoscopy screening every 10 years, provided that CTC screening would be offered every 5 years with follow-up restricted to findings of 6 mm or larger. Our results were very robust for changes in CTC test characteristics and natural history assumptions. CTC with intermediate referral remained the most-cost-effective CTC screening strategy in the majority of sensitivity analyses. The threshold costs for this strategy varied from $260-$312, 53-61% lower than that of optical colonoscopy. Assuming differential adherence for CTC and colonoscopy, had more effect on threshold costs. In the extreme scenario in which CTC would be able to increase screening adherence with 25% compared to colonoscopy, the threshold costs for CTC still needed to be 30% lower than colonoscopy costs.
Our results support the expectations of clinicians that follow-up of small findings at CTC is not efficient.62
Small adenomas are common and most will never develop into CRC. Furthermore, small findings at CTC are often non-adenomatous polyps or even artifacts, negatively influencing the specificity of CTC. Of course, when ignoring small findings and because of the lower sensitivity of CTC for small adenomas, the preclinical screen-detectable period is shorter than with colonoscopy screening. We showed that with a mean dwelling time of 9.1 years for adenomas of 1-5 mm and of 7.3 years for an adenoma of 6 mm to preclinical cancer (which is less than the screening interval of 10 years), CTC should be offered at an interval of 5 years to be as effective as colonoscopy every 10 years. Some radiologists and gastroenterologists suggest that follow-up could be restricted to polyps of 10 mm or larger.62
They argue that dysplasia and malignancy occur too rarely in smaller adenomas to warrant diagnostic follow-up and polypectomy. The rate of malignant transformation may indeed be up to ten times higher in large polyps than in small polyps.63, 64
However, small and medium adenomas are almost ten times more prevalent than large adenomas,39, 48
making the CRC incidence from small and medium adenomas potentially as high as that from large adenomas.65, 66
This becomes clear from the results from our study: In none of the analyses was CTC screening cost-effective with only follow-up of lesions of 10mm or more.
The strength of CTC to be able to distinguish between low-risk and high-risk individuals for CRC, may also turn out to be its weakness. Despite the fact that small findings are ignored with CTC, they are present and will frequently be seen. Then questions of ethics arise: is it ethical not to register and/or to inform patients about this finding? Informing about these findings without taking action on them will induce anxiety in otherwise healthy individuals. The shorter screening interval in the strategy with a higher referral threshold takes away some of the concerns. The probability that adenomas less than 6 mm will grow into cancer within five years is small. The shorter interval further offers the possibility to detect previously missed lesions. Also, it should be noted that setting thresholds for further action is inherent to screening. Ignoring small findings with CTC is, in terms of risk management, not that different from the cut-off levels used for a positive test result with for example PSA testing or immunochemical FOBT. If, however, it would be decided that ignoring of small findings at CTC is unacceptable, this will further decrease the threshold costs to 33%-39% of colonoscopy costs, depending on the interval chosen.
In this analysis, we assumed that restriction of follow-up did not impair CTC sensitivity. However, radiologists may over- or underestimate the real size of an adenoma.67
When restricting follow-up to adenomas of 6 mm or 10 mm or larger, some lesions will be misclassified as smaller and wrongfully not be followed up. Some small lesions will also be overestimated in size and will be followed up, but the benefit of their removal is smaller than of removal of larger adenomas. Errors in size estimation are therefore likely to make intensive referral more favorable compared to intermediate or minimal referral.
CTC screening is a non-invasive alternative to colonoscopy screening, and is not associated with the major complications of colonoscopy such as perforations, serosal burns, and bleeds.52-54
A recent study comparing CTC and colonoscopy for CRC screening,68
reported seven serious adverse events in 3,163 people undergoing colonoscopy, and no complications in 3,120 people undergoing CTC. However, CTC is associated with exposure to radiation, which we did not consider in the current analysis. Brenner et al.69
estimated that the excess cancer risk from a pair of CTC scans using typical current scanner techniques is about 0.14% for a 50-year old and half that for a 70-year old. This estimate is controversial, because it was based on simulation calibrated to atomic bomb survivors. Multiple CTC screens will increase the radiation dose proportionally and most likely also the radiation risks. We found that CTC is only compatible to colonoscopy screening if offered seven times (every 5 years between ages 50 and 80), potentially leading to an excess cancer risk of approximately 0.47%. This will lead to life-years lost due to CTC which are not negligible compared to the life-years gained. We did not take these excess cancer cases into account, because there is good evidence that radiation dose with CTC can be reduced by at least a factor of 5 (and perhaps as much as 10), while still maintaining sensitivity and specificity for polyps larger than approximately 5 mm.69
With these dose reductions, excess risk of cancer from CTC becomes negligible.
Several other studies have been published on the cost-effectiveness of CTC screening in the general population (). In all these studies, the threshold costs for CTC screening were higher than the 43% of colonoscopy costs found in this study. An important reason for this is that we compared CTC screening with different intervals of colonoscopy screening, whereas the other studies compared CTC only to 10-yearly colonoscopy. Sonnenberg estimated that 10-yearly intensive CTC should cost 46% of colonoscopy costs to have the same costs per life-year gained.29
The same comparison in our study yields similar threshold costs (47%, footnote ). The estimated threshold costs from Ladabaum were slightly higher (60%), but he assumed better CTC test sensitivity.28
Vijan et al. compared CTC every 5 years (referral of all lesions) with 10-yearly colonoscopy.70
They found threshold costs of 75% of colonoscopy costs. The same comparison in our study yields costs of 33% (footnote ). This is explained by better test characteristics (especially for specificity) based on 3-dimensional (3D) CTC in Vijan’s assumptions. Using the performance characteristics of 2D CTC (which had slightly lower sensitivity than in this analysis, but still better specificity), Vijan found very low CTC threshold costs, which corresponds with our finding of 33%. Finally, Pickhardt compared 10-yearly CTC screening with a referral threshold of 6 mm to 10-yearly colonoscopy screening.30
He found that with CTC costs at 70% of colonoscopy costs, CTC screening with referral of lesions 6 mm or larger was cost-effective compared to colonoscopy. This is somewhat higher than the estimate from the same comparison in our study (62%). Our study adds that to compete with colonoscopy cost-effectiveness, one must consider different intervals of colonoscopy screening. This is necessary to ascertain that CTC screening is not dominated by colonoscopy screening. In , this is represented by the (incremental cost-effectiveness) lines connecting the colonoscopy strategies. It is harder for 5-yearly intermediate CTC screening to achieve a level on the cost-effectiveness frontier line connecting 15-yearly colonoscopy and 10-yearly colonoscopy than to get on the line connecting no screening (the origin) to 10-yearly colonoscopy. The 43% threshold for the CTC costs relative to the colonoscopy costs would increase to 62% with this more relaxed criterion.
Literature overview of studies estimating the cost-effectiveness of CTC screening in the average-risk population
CTC is still under development. The development of computer-assisted reading of the images and detection of lesions has potential for decreasing radiologists reading time and therewith reducing costs.71
Furthermore, the potential introduction of CTC without cathartic preparation will further reduce the inconvenience of patients, and therefore probably increase adherence with CTC.72, 73
These developments will have to be monitored for updating the comparative evaluation between CTC and other screening modalities. Our analysis shows that CTC can be a cost-effective alternative for CRC screening in the general population if offered every 5 years, diagnostic follow-up is restricted to those with polyps of 6 mm or larger and CTC costs less than 43% of colonoscopy costs. In view of the abovementioned developments, this level of CTC costs may be possible.