Abstract
Background
Organised programmes for colorectal cancer screening demand a high burden of medical and economic resources. The preferred methods are the faecal immunochemical test and primary colonoscopy.
Objective
The purpose of this study was to perform an economic analysis and comparison between these tests in Europe.
Methods
We used a Markov cost-utility analysis from a societal perspective comparing biennial faecal immunochemical test or colonoscopy every 10 years screening versus non-screening in Portugal. The population was screened, aged from 50–74 years, and efficacy was evaluated in quality-adjusted life years. For the base-case scenario, the faecal immunochemical test cost was €3 with 50% acceptance and colonoscopy cost was €397 with 38% acceptance. The threshold was set at €39,760/quality-adjusted life years and the primary outcome was the incremental cost-effectiveness ratio.
Results
Screening by biennial faecal immunochemical test and primary colonoscopy every 10 years resulted in incremental utilities of 0.00151 quality-adjusted life years and 0.00185 quality-adjusted life years at additional costs of €4 and €191, respectively. The faecal immunochemical test was the most cost-effective option providing an incremental cost-effectiveness ratio of €2694/quality-adjusted life years versus €103,633/quality-adjusted life years for colonoscopy. Colonoscopy capacity would have to increase 1.3% for a faecal immunochemical test programme or 31% for colonoscopy.
Conclusion
Biennial faecal immunochemical test screening is better than colonoscopy as it is cost-effective, allows more individuals to get screened, and provides a more rational use of the endoscopic capacity available.
Keywords
Key summary
Established knowledge on this subject
Colorectal cancer screening implementation is markedly different among countries. The two preferred methods are faecal immunochemical test (FIT) and primary colonoscopy. Many cost-effectiveness studies used unrealistic 100% adherence rates for the screening tests.
What are the significant and/or new findings of this study?
Under realistic worldwide adherence rates, biennial FIT screening is a more cost-effective choice than colonoscopy every 10 years. A FIT programme also allows more individuals to get screened and provides a more rational use of endoscopic capacity (13,050 colonoscopies/year/million screened) than a colonoscopy programme (47,500 colonoscopies/year/million screened). Our results support the progressive implementation of FIT-based programmes in Europe.
Introduction
Colorectal cancer (CRC) is a worldwide problem due to its high incidence and increasing burden reflecting population's growth, aging and lifestyle. 1 It is the second greatest cause of cancer mortality in Europe and the first in Portugal, representing nearly 16% of all cancer-related deaths. 2 Several European countries have already implemented population-based CRC screening programmes mainly based on the use of the faecal immunochemical test (FIT), due to higher accuracy and acceptability of such test, compared with previous guaiac-based faecal test. On the other hand, in the USA, as well as in a few European countries (such as Germany and Poland), a primary screening colonoscopy strategy is advocated at population level, due to the higher accuracy of such test for precancerous lesions.3–5
Accuracy, however, is not necessarily the main determinant when choosing between a FIT or a primary colonoscopy approach, as other factors such as the acceptability of the test, costs and limited endoscopic capacity may play a critical role in the decision-making process. In addition, available clinical evidence is generally restricted to one-time testing, either with FIT or colonoscopy, while these tests are expected to be repeated at regular intervals with cumulative estimates of efficacy that are too complex to be simply derived from the outcomes of such trials.
Simulation models may attempt to address such uncertainty, by simultaneously considering the key factors required in the decision process, allowing a long-term estimation of life expectancy increase, as well as budget savings between screening costs and decreasing treatments. 6 Although previous modelling has already addressed the comparison between FIT and colonoscopy, this was diluted in a more general comparison among several screening strategies, avoiding a clear and informative comparison between these two tests that are now implemented worldwide.7–15
Primary aim of our analysis was to perform a cost-utility analysis in a European country, to compare a population-based CRC screening programme with FIT or primary colonoscopy versus no screening. Secondary aims were to explore the influence of adherence rates and costs on such cost-utility ratio, and to evaluate its impact on health resources, namely on the annual capacity for performing colonoscopies.
Materials and methods
Study population
Portuguese adults from age 50–74 years were considered at risk for developing CRC and were modelled in a cost-utility analysis comparing colorectal screening on a population-based nationwide programme versus no screening, according to European Union recommendations.3,4 Two alternatives for screening were considered: biennial FIT followed by colonoscopy if positive (≥100 ng/ml or 20 µg/g) or primary colonoscopy every 10 years.3,4 This means that for every 10 years of the screening programme, a patient with consecutive negative FIT tests would account for the costs of five FIT tests while a patient with a negative primary colonoscopy would account for the cost of one colonoscopy.
A societal perspective was adopted by including the costs to the healthcare system, patients, families and employers, in accordance with recommendations for cost-effectiveness analysis reporting. 16
Model structure
A Markov model with a one-year cycle was chosen to compare both screening strategies (FIT or colonoscopy) versus no screening as reported in Supplementary Material Figure 1. Briefly, in the natural history model, we simulated three main states, namely no CRC, CRC and CRC death, progression from one status to the next being based on registry data. In the screening simulation, we used literature-based estimates from large cohort or randomised trials to estimate the reduction in CRC incidence and mortality, while we used endoscopic studies to provide an estimate of the prevalence of polyps at screening colonoscopy (either post-positive FIT or at primary colonoscopy screening). Such information on polyp prevalence was used only to assess the cost related to polypectomy while, as already outlined, estimates on efficacy were purely related to the degree of CRC prevention shown in already published cohorts.
Cost-utility analysis of faecal immunochemical test (FIT) or colonoscopy screening versus no screening. The 
The currency used is the Euro (€) and costs are given in 2017 prices. Prices from previous years were adjusted for inflation with an online conversion tool available from Pordata. 17 The discount rate was set at 3% for all cost and effectiveness data for the base-case scenario, ranging in sensitivity analysis between 0–5% in accordance with published guidelines that were used for reporting of this economic evaluation.16,18–21 The software used was TreeAge Pro 2009 (TreeAge Software, Williamstown, Massachusetts, USA).
Clinical data
Clinical probabilities were obtained after an extensive review of the literature to find the best available estimates for rates of adherence to screening tests; distribution by cancer stage; colonoscopy efficacy, polyp detection, removal and complications; colorectal cancer treatments and adverse events; and disease-specific stage survival rates. This included average realistic adherence rates for screening tests and available ranges, from European and North American publications, namely FIT adherence rates between 35–68% and colonoscopy adherence rates between 18–38%.7,22–24
Efficacy was evaluated in terms of CRC prevention and mortality reduction by detection of CRC in earlier stages of disease with better survival rates.
Cost data
Costs were estimated from Portuguese national sources for screening and surveillance costs (FIT, colonoscopy and bowel preparation, including the user fees if applicable, but without administrative related costs), healthcare state costs (depending on location of cancer in colon versus rectum, disease-stage and available treatments), adverse event costs (for colonoscopy, but also for colorectal cancer treatments such as surgery, chemotherapy or radiotherapy) and indirect costs (working days lost, visits to healthcare personnel and transport). No assumptions were made on issues such as dedicated nurse time, time lost for relatives or caregivers, or productivity changes.
For the current no screening strategy, costs are mainly derived from CRC treatments and further surveillance; for the FIT screening strategy, the FIT cost plus the colonoscopy cost (endoscopic exam plus bowel preparation) after a positive FIT test were added, while for the primary colonoscopy screening strategy the colonoscopy cost (endoscopic exam plus bowel preparation) was considered.
For the costs of both screening tests, some assumptions were made to allow a wide range of variation. As such, the colonoscopy cost was modelled with two values: €397 for the base-case setting (price already published to be paid for a colonoscopy with anaesthesia under a national screening colorectal cancer programme), 25 but also €150 which is the current price for an opportunistic colonoscopy with anaesthesia paid by the health service; FIT cost was modelled between €3–30, to accommodate a wider range with a very low base-case cost.
Assumptions were made on costs for employers and transportation expenses since no data were available for the Portuguese population. Accordingly, employers' costs were based on the cost per hour reported by the Portuguese Institute of Statistics, while transport expenses were based on a broad estimate of the distance between home and hospital for the general population.
Utility data
Utilities were obtained from the literature providing values for quality of life adjusted for disease location in terms of colon versus rectum, and by stage of disease from stage I–IV.26,27
Cost-utility analysis
The outcome measure was the incremental cost effectiveness ratio (ICER) between the screening strategies, FIT or colonoscopy, versus no screening. Costs were included in the numerator and effectiveness in the denominator, in terms of quality-adjusted life years (QALYs). The willingness to pay was set at €39,760/QALY adopting the threshold of twice the gross national income per capita, as recommended by the Commission for Macroeconomics and Health of the World Health Organization.28–30
Results of the cost-effectiveness model for the base-case scenario.
FIT: faecal immunochemical test; QALY: quality adjusted life year.
Results
According to our model, a FIT-based screening programme would provide a 30% reduction in CRC incidence and mortality, while a colonoscopy-based screening programme would provide a further 8% reduction with an average 38% reduction in the CRC incidence and mortality. In terms of effectiveness this means that a FIT screening programme would provide 0.00151 extra QALYs, while a colonoscopy screening programme would provide 0.00185 extra QALYs.
Regarding costs, the average cost for CRC per person with the current no screening strategy is €8 per person; with a FIT screening programme the average cost per person would be €12, while in a colonoscopy screening programme the average cost would be €199 per person. This means that a FIT-based screening programme would require an incremental cost of €4 per person while a colonoscopy-based programme would require an incremental €191 per person.
The ICERs of the model for the base-case scenario, comparing both screening strategies, are presented in Table 1. Compared to no screening, FIT screening at a cost of €3 per FIT test is cost-effective, presenting an ICER of €2694/QALY, well below the threshold set at €39,760/QALY. For colonoscopy at a price of €397, screening is not cost-effective due to its very high cost (although presenting more effectiveness), resulting in an ICER of €103,633/QALY, 2.5 times above the adopted threshold. These results are better represented in Figure 1, which demonstrates that FIT screening is the most cost-effective strategy. Even for a colonoscopy price of €150 (current price in Portugal), screening is not cost-effective providing an ICER of €48.285/QALY, still above the adopted threshold.
One-way sensitivity analysis according to the cut-off points defined for the FIT test, varying between (≥50 ng/ml or 10 µg/g) to (≥200 ng/ml or 30 µg/g), would make an ICER variation between €4653/QALY and €1530/QALY, respectively. Also, modelling the adherence rate for FIT showed that for rates between 35–62% the FIT screening is more cost-effective than primary colonoscopy but for rates ≥63%, the FIT option will dominate the colonoscopy option by providing even more QALYs than colonoscopy, at a lower cost.
Moreover, considering the need for repeating a colonoscopy until 10% (due to inability to reach the caecum or an inadequate bowel preparation), a sensitivity analysis shows that the ICER values would remain similar for both the FIT option (€2965/QALY instead of €2694) and the colonoscopy option (€549,252/QALY instead of €549,433).
Two-way sensitivity analysis on cost of both screening alternatives is shown in Figure 2(a), demonstrating that, to be cost-effective, the price for a primary colonoscopy would have to be below €95. Three-way sensitivity analysis on colonoscopy cost versus colonoscopy and FIT adherence rates is presented in Figure 2(b), showing that for colonoscopy to be cost-effective the acceptance rate would have to be 100% for a colonoscopy cost of €90. For a FIT acceptance above 55% or a colonoscopy price above €100, colonoscopy is never cost-effective.
(a) Sensitivity analysis on costs of both screening strategies. The 
Deterministic sensitivity analysis, representing the influence of each variable on the ICER is shown in Figure 3 as a tornado diagram. The results show that the most prominent variables in the model were the costs of screening tests (FIT and colonoscopy); the probabilities related to changes in stages of CRC (that relate to the efficacy of screening) and the performance of the FIT test in terms of sensitivity, specificity and adherence rate. For the base-case scenario with realistic ranges of adherence rates for both FIT and colonoscopy (35–68% for FIT and 18–38% for colonoscopy), neither of these values changed the model's conclusion, favouring FIT screening.
Tornado diagram. Variables tested in one-way sensitivity analysis are displayed on the 
Monte Carlo probabilistic multi-way analysis is shown in Figure 4, through 1000 simulations of the model comparing the FIT option versus no screening. Each point corresponds to one simulation, and cost-effective results for a FIT-based screening programme are reported as points below the willingness-to-pay dotted threshold line, comprising 96% of all simulations. Figure 5 represents the acceptability curves showing the probability of each option to be the best cost-effective strategy, comparing the 96% probability for FIT screening with a 4% probability for the no-screening strategy and 0% for colonoscopy screening.
Scatter plot for probabilistic Monte Carlo sensitivity analysis for the faecal immunochemical test (FIT) screening versus no screening. Representation of 1000 simulations where each dot means one simulation, the Acceptability curve comparing the screening strategies of faecal immunochemical test (FIT) or colonoscopy versus no screening. The 

Regarding the extra capacity in colonoscopy performance per year to accommodate the demands of a new screening programme, the increase of extra colonoscopies to perform per year, depending on the option of a FIT or colonoscopy screening test is shown in Figure 6. The actual number of colonoscopies performed per year in Portugal is 375,000 and most of them for symptoms or therapeutics; assuming that 5–10% of the actual colonoscopies are already performed for an opportunistic screening, the option of a FIT screening programme with a 50% adherence rate would represent an increase in extra colonoscopies capacity by just 1.3%, while for a colonoscopy screening programme with an adherence rate of 38%, extra colonoscopies capacity would have to increase by 31%.
Number of extra colonoscopies to perform per year depending on the option of faecal immunochemical test (FIT) or colonoscopy as a screening test. The lower brighter bar corresponds to the actual number of colonoscopies performed per year, most of them for symptoms, surveillance or therapeutics; the top darker bars corresponds to the increase in colonoscopies per year if a screening programme is in place, assuming that 5–10% of the colonoscopies are already performed for opportunistic screening. This means that for a FIT screening programme the extra colonoscopies capacity would rise just 1.3% while for a colonoscopy screening programme the extra colonoscopies capacity would have to rise by 31%.
An extrapolation on the extra capacity of colonoscopies per gastroenterologist, per week, according to the screening options is provided in Supplementary Material Tables 2.1 and 2.2, depending on the population aged 50–74 years-old and the number of available gastroenterologists. Both assume a mean of 48 working weeks per year and for the FIT screening every two years an adherence rate of 50%, a positivity rate of 6% and an adherence rate for colonoscopy after a positive test of 87%; for colonoscopy screening every 10 years a 38% adherence rate was used. In a country like Portugal, with around 3 m people aged 50–74 years and about 400 gastroenterologists, this means that a FIT screening programme would require an extra two colonoscopies per week per gastroenterologist (13,050 colonoscopies/year/m screened), while a colonoscopy screening programme would require seven extra colonoscopies per week per gastroenterologist (47,500 colonoscopies/year/m screened).
Discussion
CRC is particularly suitable for screening and prevention of death, considering its long latency of progression, providing an excellent window of opportunity for early detection. The existence of available screening methods with adequate sensitivity and specificity rates, acceptable by an asymptomatic population and with few side effects, makes it the perfect oncological disease to be detected early or even prevented by screening. In Portugal, three regional pilot programmes based on FIT-screening are currently in place while Health government decisions are waited for a national population-based CRC screening programme.
The choice between screening tests should take in to account costs for the society, due to the large number of negative tests in asymptomatic people. On the other hand, effectiveness of detection and removal of polyps, preventing the disease's natural progression and early detection of an asymptomatic cancer would allow less invasive and costly treatments.
The present model for the Portuguese population compared the two most-used screening strategies for CRC in Europe, FIT and colonoscopy, and our results show that both strategies are effective compared to no screening. Moreover, in our study both screening strategies provide clinical relevant reductions in CRC incidence and mortality after 25 years of a screening programme in place. These results are in accordance with published results that report for faecal tests screening reductions between 15–35% at 30 years of follow-up24,32–35 (30% in our model), while for primary endoscopic screening reduction rates are between 18–34% at 12 years for sigmoidoscopy and between 29–61% at 24 years for colonoscopy (38% in our model at 25 years).34–37
Additionally, biennial FIT screening is the most cost-effective option. The ICER of just €2,694/QALY is far below the threshold of €39,760/QALY, even for a colonoscopy cost of €397 per exam. Also, the increase in colonoscopy capacity warranted by such a screening programme would be only 1.3%. These outcomes assume realistic available adherence rates for both screening options, 50% for FIT and 38% for colonoscopy. Besides, they are based on the latest cost for a colonoscopy performed under a national screening programme defined by the Portuguese Government (€397).
Colonoscopy screening on the other hand, is very costly for its effectiveness, with an ICER of €103,633/QALY (at a cost of €397). Even if the current price of €150 for a colonoscopy under anaesthesia outside a screening programme was used, the corresponding ICER would be €48,285/QALY, still above the €39,760/QALY threshold. Also, such a screening programme would require an extra colonoscopy capacity of 31% compared to the actual capacity of the country.
Our conclusions were robust in sensitivity analyses as relevant variables such as costs of screening tests (FIT and colonoscopy), different FIT cut-offs, changes in stages of the detected cancers and performance of the screening tests (sensitivity, specificity or adherence rates) did not change the conclusions of the model, favouring FIT screening, as this programme remained cost-effective in 96% of the simulations.
Comparing our model to other relevant studies, the main difference relates to the assumed adherence rates in other models (Supplementary Material Table 3). All models that concluded in favour of colonoscopy screening, assumed perfect but unrealistic adherence rates of 100% for both FIT and colonoscopy,12,13,15 or equal but again unrealistic 50% adherence rates for both tests. 14 On the other hand, three models in favour of FIT screening used more realistic adherence rates of 50–68% for FIT and 38–40% for colonoscopy,6,7,9,10,16 while two others again used unrealistic similar adherence rates of 100% or 63% for both screening tests.8,11 Of all these studies, both from the European setting favoured FIT screening versus colonoscopy, similar to our conclusion.7,10 No screening programme exists with a perfect 100% adherence rate; also there is no published data with the same adherence rate for FIT and colonoscopy in the same population.
However, limitations to the present study need to be mentioned. Although an extensive literature research was performed for the best available evidence, studies on quality of life of patients with CRC specific for the Portuguese population are lacking. Ranges and distributions for some variables in sensitivity analysis are not available in the literature and estimates were used using the TreeAge software; it is crucial to recall that the model was conceived for the Portuguese population and adjustments need to be made for other populations to prove its generalisability.
In conclusion, biennial FIT screening for CRC is more cost-effective than primary colonoscopy screening in Portugal, presenting as a screening strategy affordable to the society, robust for a wide range of relevant clinical and cost variables and not requiring an extraordinary demand in extra colonoscopy capacity. This further supports the progressive implementation of FIT-based programmes in Europe. Future studies in other countries using realistic adherence rates are needed, to corroborate our conclusions.
Supplemental Material
Supplemental material for Cost-utility analysis of colonoscopy or faecal immunochemical test for population-based organised colorectal cancer screening
Supplemental material for Cost-utility analysis of colonoscopy or faecal immunochemical test for population-based organised colorectal cancer screening by Miguel Areia, Lorenzo Fuccio, Cesare Hassan, Evelien Dekker, António Dias-Pereira and Mário Dinis-Ribeiro in United European Gastroenterology Journal
Footnotes
Acknowledgements
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References
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