The present study is a formal economic evaluation of DNA3
, and DNA10
in relation to several alternatives (No Screening, FOBT1
, and COLO10
) using Taiwanese data on colorectal cancer incidence and disease natural history, sub-classified by adenoma size and Dukes' stage in invasive carcinoma. The findings from this study suggest that all of the screening strategies are reasonably cost-effective in relation to No Screening. However, the stool DNA testing strategies were the least cost-effective. COLO10
are the most cost-effective strategy. Nevertheless, the feasibility of opting for colonoscopy as screening tool for average-risk groups may be questionable due to the shortage of medical endoscopic manpower and the risk of perforation associated with colonoscopy. Stool DNA testing would be preferable to the other screening strategies if the sensitivity for both adenoma and CRC were high enough, as seen in the best case scenario of sensitivity analysis from the Ahlquist study [10
], and if the cost of the test could be lowered through economies of scale like the example of hepatitis B vaccination the price of which has dramatically fallen due to the advent of universal program in 1990s [43
]. However, the interpretation of the finding in the best case scenario should be taken with great caution because subjects enrolled in Ahlquist study [10
] was based on clinical series patients rather than asymptomatic subjects from average-risk population [16
It should be noted that our focus on this study was to assess whether stool DNA testing was cost-effective provided stool DNA testing can be used as another alternative choice for population-based screening. The incremental cost-effectiveness analysis by pairwise comparison across different screening tools (i.e. colonoscopy vs. stool DNA testing) was therefore not attempted.
Although stool DNA testing has been proposed in recent years its application to mass screening for colorectal cancer has not been evaluated. The major deterrent has been doubt over the performance of test. Previous studies show a wide range of sensitivities for stool DNA testing, ranging from 15% to 82% for large adenoma and from 50% to 100% for invasive CRC [10
]. This variation may often be attributed to differences in the way asymptomatic subjects or symptomatic cases were selected, although this was not the case in the Imperiale et al study [16
]. The largest study to focus on asymptomatic subjects (the major target of mass screening) showed 8% sensitivity for small adenoma, 15% for large adenoma and 52% for invasive CRC [16
]. False negative cases, as a result of low sensitivity, may lower its effectiveness as a tool for screening asymptomatic subjects in the general population. However, to integrate state-of-world information obtained form previous studies, we used the meta-analysis to obtain the estimate by taking all previous studies into account as the moderate case scenario. However, the estimate of sensitivity of adenoma has been largely affected by the Imperial study [16
] because it is the largest study up to date on screening for colorectal cancer with stool DNA testing. The estimate based on meta-analysis for the sensitivity of cancer has been estimated as 85% by weighting the inverse variance of each study.
It could be argued that stool DNA testing screening is to be more expensive than other screening tools. This may be true at the inception of screening strategy but with widespread use, we might reasonably expect savings due to economies of scale. Genetic epidemiology is still in its infancy but the development of genetic chip technology and DNA testing advances may soon facilitate the development of simple commercial stool DNA testing kits, which would be considerably cheaper.
Very few studies have addressed the economic aspects of adopting stool DNA testing as screening tool for use in the general population. Only Song et al [44
] and Leshno et al [45
] have performed a study on cost-effectiveness, comparing fecal DNA testing with conventional CRC screening. The parameters in the former study are based on Western countries with a high prevalence of CRC, and the parameters in the latter study are based on Israel which also has a high incidence rate of CRC [46
]. To the best of our knowledge, no similar studies on stool DNA testing have been conducted in countries with low or intermediate incidence of CRC. Furthermore, the base-case estimates of sensitivity and specificity for stool DNA testing may vary across studies. The sensitivity and the specificity used in Leshno study are 70%, 82%, 91%, and 90% for small adenoma, large adenoma, preclinical CRC, and specificity, respectively, which were similar to our best case scenario, and only annual stool DNA testing has been considered [45
]. The corresponding estimates in Song study are 40%, 40%, 65%, and 95%, respectively [44
]. Compared with the two previous studies [44
], the base-case estimates in our study are the most conservative ones which only base on the population-based study [16
]. However, despite the diversified parameter regarding sensitivity and specificity, our findings that stool DNA testing is cost-effective compared to No Screening but inferior to conventional screening methods such as FOBT and colonoscopy are consistent with Song et al's and Leshno et al's findings [44
The reported ICERs in this study are much lower than that reported in other cost-effectiveness analysis [44
]. This discrepancy can be explained by the low cost of screening tool, and other relevant cost for CRC treatment and diagnosis used in this study which represents the reality in Taiwan. When we used the cost based on the Western country as our base-case parameters [44
], given perfect compliance and perfect referral rate as assumed in the previous studies, the ICERs are comparable with the previous studies [44
]. The ICER for FOBT1
, and COLO10
compared with No Screening are estimated as $2,376, $20,206 and $13,831 per life-year saved, respectively. However, all the stool DNA testing strategies are not cost-effective and the ICERs inflate to approximately $115,000 per life-year saved for DNA10
compared with No Screening.
The compliance may have large influence on the cost and the effectiveness of a screening program. Nevertheless, the compliance may vary widely by different screening tool and population [49
], therefore, the decision should be made by the preference of each population. Figure has shown the influence of different compliance level of each screening tool on the cost-effectiveness which allows the assessment for various compliance rates to each screening tool. For example, for a population with the compliance of 40% with FOBT1
and of 20% with SIGM5
would save more lives and less costly than all the other screening strategies. However, for a population with the compliance of 50% with FOBT1
and of 40% with SIGM5
would have more life-year gained than FOBT1
but with higher cost.
As far as the validity of our simulation model is concerned, our results obviously depend on the parameters chosen for the natural history part of the model. Three findings lead us to believe that our simulated model is adequate. Firstly, the predicted cumulative incidence of CRC in our study, 34 per 1,000, is close to the observed one, 37 per 1,000 [17
]. Secondly, our sensitivity analyses demonstrates that changes to the upper and lower bounds of our estimates do not lead to substantial changes in our results. Thirdly, to check whether our simulated results on the effectiveness of FOBT test are consistent with those reported in several randomized trials [1
], we applied 60% (56.5%~67%) compliance rate of FOBT and 85% referral rate to diagnostic colonoscopy and identical transition parameters based on base-case parameters, and shortened follow-up year to 10 years as seen in randomized trial, the predicted mortality reduction for annual FOBT screening and biennial FOBT screening is 20% and 13%, respectively, the latter of which is close to the findings from several randomised trials with two-yearly inter-screening interval, indicating 16%, 21%, and 15% mortality reduction conducted in Burgundy (France) [4
], Funen (Denmark) [3
], and Nottingham (UK) [2
], respectively. For the incidence, the incidence ratio was estimated as 0.80 (annual FOBT) after follow-up for 18 years, which was close to the estimate reported in randomized trial [1
Since this study was conducted from a third-party payer perspective, we therefore adopted the price mandated by the Bureau of National Health Insurance (95% population covered) as the cost and only direct costs were included. However, indirect costs such as production loss due to attending to screening or due to disease should be considered from the societal viewpoint. This could be the subject of future studies.
Our study has, however, one limitation as our proposed model assumes an adenoma to carcinoma sequence, which accounts for the majority of CRCs. Non-polypoid cases are not taken into account. However, as only a fraction of CRCs are non-polypoid and the cost-effectiveness analysis addresses the relative comparisons across screening strategies, the incorporation of the occurrence of non-polypoid tissue is unlikely to substantially affect the results.