Cost‐effectiveness of preventive aspirin use and intensive downstaging polypectomy in patients with familial adenomatous polyposis: A microsimulation modeling study

Abstract Objective Although there is increasing evidence to suggest the cost‐effectiveness of aspirin use to prevent colorectal cancer (CRC) in the general population, no study has assessed cost‐effectiveness in patients with familial adenomatous polyposis (FAP), who are at high risk of developing CRC. We examined the cost‐effectiveness of preventive use of low‐dose aspirin in FAP patients who had undergone polypectomy in comparison with current treatment practice. Design We developed a microsimulation model that simulates a hypothetical cohort of the Japanese population with FAP for 40 years. Three scenarios were created based on three intervention strategies for comparison with no intervention, namely intensive downstaging polypectomy (IDP) of colorectal polyps at least 5.0 mm in diameter, IDP combined with low‐dose aspirin, and total proctocolectomy with ileal pouch‐anal anastomosis (IPAA). Cost‐effective strategies were identified using a willingness‐to‐pay threshold of USD 50,000 per QALY gained. Results Compared with no intervention, all strategies resulted in extended QALYs (21.01–21.43 QALYs per individual) and showed considerably reduced colorectal cancer mortality (23.35–53.62 CRC deaths per 1000 individuals). Based on the willingness‐to‐pay threshold, IDP with low‐dose aspirin was more cost‐effective than the other strategies, with an incremental cost‐effectiveness ratio of $57 compared with no preventive intervention. These findings were confirmed in both one‐way sensitivity analyses and probabilistic sensitivity analyses. Conclusion This study suggests that the strategy of low‐dose aspirin with IDP may be cost‐effective compared with IDP‐only or IPAA under the national fee schedule of Japan.


| INTRODUCTION
Familial adenomatous polyposis (FAP) is a genetic disease caused by germline mutations in the adenomatous polyposis coli (APC) gene and is characterized by the development of 100 or more adenomas (polyps) in the colorectum. 1 The incidence of FAP in the general population is estimated to be one to two in 20,000 individuals in Western countries, and one in 17,400 individuals in Japan. 2 Less than 1% of colorectal cancer patients are estimated to have FAP. 3 It has been reported that polyps found in the colorectum are likely to progress to adenocarcinoma in almost 50% of FAP patients by the age of 40 years and that if not treated, most patients with FAP develop colorectal cancer by the time they reach 60 years old. 1 While it is not possible to predict which among the 100 or more polyps will become malignant, in the case of colorectal cancer, polyp size is a significant risk factor associated with carcinogenesis.It is considered that polyps which increase in size with age are more likely to undergo malignant transformation. 4he standard treatment for FAP is prophylactic total colectomy with resection of the entire large intestine. 5Total colectomy often carries a poor prognosis and adversely impacts the quality of life due to frequent diarrhea and incontinence, 6 infecundity in women, 7 and the development of desmoid tumors. 8In Japan, total proctocolectomy combined with ileal pouch-anal anastomosis (IPAA) is currently considered the standard surgical procedure and has been increasingly implemented. 9Endoscopic management of FAP via repeated colonoscopies to remove polyps greater than 5 mm in size, called Intensive Downstaging Polypectomy (IDP), has been reported to reduce a polyp burden, 10,11 yet IDP has not been fully recommended as a prophylactic modality to date; nor has the use of non-surgical approaches to treat FAP, such as chemopreventive agents.
Recent clinical trials have consistently reported the effect of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, in preventing sporadic colorectal adenoma in Western 12 and Asian populations. 13Further, administration of low-dose aspirin has been shown to reduce recurrent adenomas of more than 5.0 mm in diameter in FAP patients who had previously undergone endoscopic removal of colorectal polyps of 5.0 mm or more. 14This suggests that aspirin inhibits the growth of colorectal polyps, which is a risk factor for the development of colorectal cancer.Given that aspirin is widely available at low cost, the prophylactic use of aspirin in preventing recurrent adenomas in FAP patients may be worth investigating in terms of cost-effectiveness.Although accumulating evidence has suggested the cost-effectiveness of aspirin use with colonoscopic surveillance in the chemoprevention of colorectal cancer in a general population, 15,16 no study has yet investigated the costeffectiveness of low-dose aspirin in FAP patients.
Microsimulation models are a convenient method that can estimate the long-term impact of different intervention strategies that cannot be compared in the real world, taking account of the heterogeneities in risks by participant background, mortality over time, and population dynamics. 17Here, we examined the potential cost-effectiveness of preventive use of low-dose aspirin in FAP patients who had undergone polypectomy in comparison with current treatment practice using microsimulation modeling.

| Model description
demographic component, we obtained information from nationally representative datasets on demographics, 18,19 cancer incidence, and mortality. 20We used this data to develop a microsimulation model of colorectal cancer in FAP patients and create a virtual population with sexand age-specific mortality from causes other than colorectal cancer.The natural history of disease progression was constructed following the adenoma-carcinoma sequence (Figure 2). 4 FAP patients carry a large number of colorectal polyps at the time of diagnosis, 1 and these polyps may develop into colorectal cancer at some point in life depending on the model input parameters (Table 1).
Preclinical colorectal cancer is an undetected cancer that may either become symptomatic, be detected by screening, or progress through stages I to IV. 21,22 Using long-term survival data from population-based cancer registries, the survival time of individuals after cancer diagnosis was simulated by sex, clinical stage at diagnosis, and years after diagnosis. 23Background mortality from causes other than colorectal cancer was also modeled by age, sex, and calendar year.
Because the model estimation needs to match the real-world incidence and mortality among FAP patients in Japan, we calibrated the natural history model against the absolute risk of colorectal cancer by age group provided by Iwama et al. (2004)  1 and evaluated the model fit by goodness-of-fit testing, and the best-fit parameter values were used in the final model (Supplemental Table S1). 24,25he model was then validated against the lifetime probability of colorectal cancer death in FAP patients derived from Iwama et al. (1993). 26The model was developed using Tree-Age Pro 2022 (TreeAge Software Inc).Data were analyzed using Stata 16.1 (Stata Corp.).The details of the model are described in Supplemental Document 1. 1,4,18,19,20,23,27

| Intervention strategies
We evaluated three intervention strategies as scenarios for comparison against the base case scenario, namely (1) the base case, in which no preventive intervention is performed; (2) intensive downstaging polypectomy

Input parameter Base-case analyses
One-way sensitivity analyses (range)

Probabilistic sensitivity analyses (distribution) Source
Natural history-transition probabilities (per year) Prevalence of FAP in the general population 0.00006 Fixed Fixed [2]   From high-risk polyp to preclinical stage I CRC in FAP patients a 0.015982 (<30 years); 0.113758 (30+ years) Fixed Fixed [24]   From preclinical stage I to preclinical stage II CRC a 0.24022 Fixed Fixed [24]   From preclinical stage II to preclinical stage III CRC a 0.22290 Fixed Fixed [24]   From preclinical stage III to preclinical stage IV CRC a 0.27487 Fixed Fixed [24]   From preclinical stage I to clinical stage I CRC a 0.07202 Fixed Fixed [25]   From preclinical stage II to clinical stage II CRC a 0.11011 Fixed Fixed [25]   From preclinical stage III to clinical stage III CRC a 0.18989 Fixed Fixed [25]   From preclinical stage IV to clinical stage IV CRC a 0.87577 Fixed Fixed [25]   Probability of survival in CRC patients b 0.0729-1.000Fixed Fixed [23]   Colonoscopy surveillance-test characteristics Sensitivity for 5-9 mm low-risk polyp 0.86500 Fixed Fixed [45]   Sensitivity for high-risk polyp (10+ mm) 0.97600 Fixed Fixed [45]   Specificity for colorectal polyps and CRC 1.00000 Fixed Fixed [45]   Probability of perforation after colonoscopy without polypectomy 0.00010 Fixed Fixed [46]   Effectiveness Probability of developing polyps (5+ mm) after IDP 0.554 Fixed Fixed [35]   Probability of developing polyps (5+ mm) after IPAA (once in a lifetime) 0.036 Fixed Fixed [47]   Relative risk of 1 or more polyps (5+ mm) incidence with aspirin and IDP 0.37 0.16-0.86Beta [14]   Adverse effects Probability of nausea, vomiting, stomach pain, and diarrhea grade 1-2 due to aspirin (for initial 3 days) 4.00% Fixed Fixed [14]   Probability of harms associated with IDP-perforation 0.40% Fixed Fixed [11, 35]   Probability of harms associated with IDPintestinal bleeding 2.30% Fixed Fixed [11, 35]   Utility loss (QALYs) Per colonoscopy c −0.003 Fixed Fixed [36]   Per complication of colonoscopy with polypectomy d −0.019Fixed Fixed [36]   Per LY with CRC care Stage I-initial care −0.120Fixed Fixed [36]  (IDP)-i.e.endoscopic removal of all colorectal polyps with a diameter of 5.0 mm or greater; (3) IDP combined with low-dose aspirin to prevent recurrent adenoma 14 ; and (4) total proctocolectomy with ileal pouch-anal anastomosis (IPAA). 5The baseline natural history was modeled to predict the probability of developing colorectal cancer in the absence of any preventive interventions.Any preventive intervention can alter the natural history of colorectal cancer by reducing the probability of recurrent adenoma and removing existing adenoma of 5.0 mm or greater in diameter; or by detecting preclinical cancer, depending on the sensitivity and specificity of the surveillance.All three

Input parameter Base-case analyses
One-way sensitivity analyses (range)
T A B L E 1 (Continued)  intervention strategies were administered to FAP patients aged 16 years and above.Individuals aged 16 years and above with IDP or IPAA were assumed to undergo annual surveillance colonoscopy after intervention.Perfect adherence to surveillance was assumed in all strategies.We assumed that low-dose aspirin use would be halted if gastrointestinal bleeding were observed, and that all colorectal cancer patients with FAP should undergo the standard treatment for sporadic colorectal cancer, which includes surgery and chemotherapy, or IPAA or IRA with regional lymph node dissection, in accordance with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines for the Clinical Practice of Hereditary Colorectal Cancer (2020). 5

| Cost-effectiveness analysis
The cost-effectiveness analysis was performed from a healthcare payer perspective, in which the model simulated a cohort of 100,000 individuals who were alive in 1963 and followed for 40 years (cycles) unless they died before the end of the simulation cycle.Effectiveness (quality-adjusted lifeyears [QALYs] gained) and costs were simulated for each intervention separately.Incremental cost-effectiveness ratios (ICER) were calculated by dividing the incremental cost by the QALYs gained.A strategy would be dominated if it were more costly but yielded fewer QALYs than the other strategies; or if it incurred greater cost but the same QALYs as the other strategies.Costs and QALYs were discounted at an annual rate of 3%. 28A willingness-to-pay (WTP) threshold of $50,000 US dollars per QALY gained was applied. 29Table 1 presents the main probabilities, relative risks, and costs used in the model.All costs were reported in 2020 US dollars at the average exchange rate of 106.725JPY/USD, and adjusted to the national fee schedule as of 2020.Supplemental Table S2 presents a Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklist. 30

| Sensitivity analysis
To assess the robustness of our modeled estimates to changes in model input parameters, we first performed one-way deterministic sensitivity analyses by changing the cost inputs of aspirin, IDP, cost of treatment for intestinal bleeding, cost of perforation treatment, cost of annual surveillance colonoscopy, and cost of IPAA by changing the respective costs by ±20%.We also assessed the effects of uncertainty surrounding the relative risk of polyp recurrence after IDP and low-dose aspirin.A discount rate of 3% per annum to both costs and effects was applied throughout all analyses, but we also explored a discount rate of 0% to 4% for both costs and effectiveness in our deterministic sensitivity analysis. 28Further, we evaluated the robustness of our results by changing the adherence rates of daily lowdose aspirin intake from 80% to 95% based on the results from a systematic review of clinical trials. 31 probabilistic sensitivity analysis was also performed using a Monte Carlo simulation to investigate the effect of parameter uncertainty on the results.The model was run 100,000 times, each taking a random draw from input values with the predefined uncertainty distributions listed in Table 1 (Probabilistic sensitivity analyses [distribution]).

| Calibration and validation results of the simulation model
Our microsimulation model accurately estimated the cumulative risk of colorectal cancer incidence throughout all age groups below 80 years.However, the middle-aged population (40-59 years old) showed estimates that were slightly more conservative than the CRC incidence reported by the Polyposis Committee of the Japanese Society for Cancer of the Colon and Rectum 1 (Figure 3).Our external validation using the lifetime probability of CRC death also showed a high level of concordance (modeled estimate; 0.31958) compared with the reported probability (Iwama et al. 0.31905). 26

| Incremental cost-effectiveness ratios
The model estimated that having no preventive intervention resulted in 325.3 colorectal cancer deaths per 1000 F I G U R E 3 Model calibration results comparing the cumulative probability of CRC incidence (observed) versus modeled estimates.The observed probability of CRC incidence is shown with a green line, while the modeled estimates are shown with red hollow dots.Incremental cost-effectiveness ratios (ICERs) showed that the IDP-only strategy was substantially less costeffective than the combined IDP and low-dose aspirin strategy.Specifically, the IDP-only strategy showed greater cost and a lower QALY gain than IDP with low-dose rin.Compared to no intervention, the IDP and low-dose aspirin strategy showed a minimal increase in average cost with increased QALYs, which resulted in an ICER of $59.The IPAA strategy had increased QALYs with a higher mean cost than the combined IDP and aspirin strategy, which resulted in an ICER of $122,796 for the IPAA strategy.Based on a willingness-to-pay (WTP) threshold of $50,000 per QALY gained, the IDP and low-dose aspirin strategy was cost-effective.

| Sensitivity analysis
In our one-way sensitivity analyses, the combined IDP and low-dose aspirin strategy remained cost-effective after changing the key parameters.The ICERs of the IPAA over the IDP and aspirin strategy varied from $-543,299 to $203,000 per QALY gained (Figure 4).The parameters that affected the ICERs of the IDP and aspirin strategy ranked from greatest to least effect, were relative risk of high-risk polyp recurrence with aspirin; discount rate; cost of IPAA; cost of IDP; cost of aspirin; cost of perforation treatment; cost of treating intestinal bleeding; and cost of screening.Our sensitivity analysis of changing the adherence rates of aspirin intake also showed consistent results given the WTP threshold of $50,000 (Supplemental Table S3).
In our probabilistic sensitivity analysis, the combined IDP and aspirin strategy was cost-effective over the IPAA strategy in 74.8% of simulations based on a WTP threshold of $50,000; and in 61.4% of simulations with a WTP threshold of $100,000 (Figure 5).Although 67.8% of the simulations yielded additional QALY gains for the IPAA strategy over the IDP and aspirin strategy (Figure 6), 43.5% of the simulations resulted in an ICER higher than $50,000, and 32.2% of the simulations showed that the IPAA strategy was absolutely dominated by the IDP and aspirin strategy.T A B L E 2 Estimated incremental cost-effectiveness of colorectal cancer prevention strategies in FAP patients.

F I G U R E 4
Tornado diagram showing ICER of IPAA over the strategy with IDP and low-dose aspirin from one-way sensitivity analyses.ICER from the base case analysis is shown in the straight black line.(Note: one-way sensitivity analysis by applying a lower range of the relative risk of having 1 or more polyps (5+ mm) recurrence by having aspirin with IDP resulted in negative ICERs because the IPAA strategy had fewer QALYs gained and higher costs than the strategy with IDP and low-dose aspirin).

| DISCUSSION
This study provides the first evidence for the costeffectiveness of prophylactic aspirin use in FAP patients who had previously undergone IDP.Our microsimulation analyses found that preventive use of low-dose aspirin combined with IDP was more cost-effective than IPAA in FAP patients given the willingness-to-pay threshold of $50,000 per QALY gained.The use of aspirin with IDP was also likely to be costeffective compared with the IDP-only strategy.
Our results are consistent with data from clinical trials, which showed the benefits of administering aspirin in suppressing recurrent adenomas in FAP patients. 14,32,33The mechanism by which a regular dose of aspirin inhibits tumorigenesis can be explained by the results of immunohistochemical staining that epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are concomitantly overexpressed in epithelial cells of the colorectal polyps of FAP patients, but that both overexpressions are attenuated by a regular dose of aspirin. 34Regarding the development of advanced cancer, a previous randomized control trial (RCT) that investigated the efficacy of aspirin use in FAP after IDP reported no occurrence of advanced cancer in either the control or intervention group due to frequent surveillance and endoscopic resection of polyps during the 8-month follow-up, 14 yet a single-arm intervention for FAP patients with IDP reported the occurrence of submucosal invasive CRC in 5 years (0.9%). 11he strategy with IDP and aspirin combined was found to produce greater cost saving per person on average than having no intervention, including with regard to daily use of aspirin, treatment of adverse effects, annual surveillance, and treatment of colorectal cancer.This is because the national fee schedule of Japan sets the cost of IDP in FAP patients at only around 1222.5 US dollars per surgery, regardless of the number of polyps removed, and also because aspirin is relatively inexpensive (19.5 US dollars per year).The high average cost per person for the IDP-only strategy is attributable to the cost of repeated IDP, and the increased incidence of colorectal cancer.As for the IPAA, the high cost of IPAA surgery has increased the average cost per person; and with an annual discount rate of 3% per year, the costs of intervention that takes place immediately-such as IPAA-outweighs the cost of cancer treatment that may occur in the distant future.
Our results also showed a large reduction in colorectal cancer deaths in all three preventive strategies.Nevertheless, the gains in QALYs were not as pronounced as that in the magnitude of deaths averted (19.19 QALYs per person in the no-intervention group vs. 21.07 to 21.43 QALYs per person in the intervention groups).This is partly due to discounting at an annual rate of 3%, which decreases the value of QALYs in the distant future.Furthermore, the expected QALY gains in the intervention groups were likely suppressed by utility loss due to adverse events, such as perforation and intestinal bleeding after IDP 35 ; nausea, vomiting, stomach pain, and diarrhea due to aspirin 13 ; utility loss per individual colonoscopy 36 ; and IPAA. 37Further, IDP, which requires advanced endoscopic techniques, has only recently been implemented. 10,11,38Given the possibility of future reports on adverse events, continuous monitoring and improvement of study accuracy are important considerations.
Preventive use of low-dose aspirin was initially recommended by the U.S. Preventive Services Task Force (USPSTF) in 2016 for the primary prevention of colorectal cancer, with specific targeting to those aged 50 to 59 years with high cardiovascular risk, no elevated bleeding risk, more than 10 years of life expectancy, and ability to use low-dose aspirin every day for 10 years. 39The updated USPSTF guideline in 2022 retracted this recommendation because of limited evidence of effectiveness and considerable variation in results. 40However, these USPSTF recommendations pertain to the general population with a given health condition and predefined age group and have not been specifically targeted to high-risk populations, such as patients with FAP or Hereditary Non-Polyposis Colorectal Cancer (HNPCC).In Japan, some prophylactic treatments of cancer -such as prophylactic mastectomy in patients with hereditary breast and ovarian cancer -have been listed in the national fee schedule, which regulates all medical costs for reimbursement and is revised on an item-by-item basis biennially. 41Although IDP has been listed in Japan's national fee schedule since 2022, the regulatory approval for the use of aspirin in FAP patients has not been granted.Given that cost-effectiveness plays a role in determining regulatory approval and the fee schedule, our findings, which highlight the cost-effectiveness of IDP combined with aspirin therapy, could potentially inform the approval procedure for aspirin use.
The strength of this study lies in its use of a wellvalidated microsimulation model that incorporated a natural history model of colorectal cancer in FAP patients, and the impact of preventive strategies on disease progression.This incorporation was achieved by synthesizing comprehensive evidence from nationally representative datasets and meta-analyses.The model has been calibrated to replicate the probability of colorectal cancer incidence in FAP patients.A further strength is our use of multiple sensitivity analyses to show that the cost-effectiveness of the combined IDP with low-dose aspirin strategy over other strategies is robust given the uncertain range of the input parameters.Some limitations also warrant mention.First, although we used postoperative utility scores and addressed a wider range of short-and long-term adverse effects, 37 this study did not consider the increased risk of desmoid tumor following surgery in FAP patients due to a paucity of data.It has been reported that 5% of male patients and 11% of female patients with FAP develop desmoid tumors postoperatively, 1 and that the risk of desmoid tumors is similar between IPAA and ileorectal anastomosis (IRA). 42Second, although duodenal adenomas of Spigelman Stage IV or higher in FAP patients pose a risk of developing duodenal cancer 43,44 which may require surgery, we were unable to include a scenario for duodenal adenomas in our analysis due to a lack of data.For the same reason, we were unable to assess the effect of low-dose aspirin after IRA or IPAA.Third, we based the effects of low-dose aspirin on a clinical trial that administered aspirin for 8 months in Japanese patients, and the effects and safety of aspirin in the longer term have not been considered, nor have those of other factors such as ethnicity or degree of obesity. 14Current smokers in the general population were reported to be at increased risk of colorectal tumor development with regular low-dose aspirin. 13However, we were unable to stratify our analyses by smoking status due to a paucity of data on FAP patients.However, we used the relative risk of recurrent tumor development by aspirin intake after adjustment of smoking status, and hence the possibility that we overestimated the benefit of aspirin is minimal.Finally, we modeled only the direct medical costs of colorectal cancer treatment and prevention and did not include societal costs associated with productivity loss.For the non-intervention group, colorectal cancer treatment would lead to a considerable loss of work days, whereas for the intervention groups, surveillance colonoscopy, IDP, and IPAA would lead to a loss of productivity.Future studies warrant further investigation into the effects of prevention strategies on the indirect costs of prevention of colorectal cancer in FAP patients.
In conclusion, the present study showed that a strategy of low-dose aspirin combined with IDP and annual surveillance colonoscopy is more cost-effective than IDP-only or IPAA under the framework of the national fee schedule of Japan.These findings highlight the need for further research on the prophylactic use of aspirin in people at high risk of colorectal cancer. 0

F I G U R E 5 6
Cost-effectiveness acceptability curves show the probability that a strategy is cost-effective given a range of threshold values.Incremental cost-effectiveness scatterplot estimated from the probabilistic sensitivity comparing the IPAA strategy against the strategy with IDP and aspirin.Each dot represents the discounted incremental cost and incremental QALYs of one bootstrap sample.The black line denotes the willingness-to-pay threshold at USD50,000 per QALY gained.
Structure of the microsimulation model.Key input parameters included in the analysis.