The Natural Disease Course of Pancreatic Cyst-Associated Neoplasia, Dysplasia, and Ductal Adenocarcinoma: Results of a Microsimulation Model.

BACKGROUND & AIMS: Estimates on the progression of precursor lesions to pancreatic cancer (PC) are scarce. We used microsimulation modeling to gain insight into the natural disease course of PC and its precursors. This information is pivotal to explore the efficacy of PC screening. METHODS: A Microsimulation Screening Analysis model was developed in which pancreatic intraepithelial neoplasms and cysts can evolve from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) to PC. The model was calibrated to Dutch PC incidence data and Japanese precursor prevalence data (autopsy cases without PC) and provides estimates of PC progression (precursor lesion onset and stage duration). RESULTS: Mean LGD state durations of cysts and pancreatic intraepithelial neoplasms were 15.8 years and 17.1 years, respectively. Mean HGD state duration was 5.8 years. For lesions that progress to PC, the mean duration was 4.8-4.9 years for LGD lesions and 4.0-4.1 years for HGD lesions. In 13.7% of individuals who developed PC, the HGD state lasted less than 1 year. The probability that an individual at age 50 years developed PC in the next 20 years was estimated to be 1.8% in the presence of any cyst and 6.1% in case of an LGD mucinous cyst. This 20-year PC risk was estimated to be 5.1% for individuals with an LGD pancreatic intraepithelial neoplasm. CONCLUSIONS: Mean duration of HGD lesions before development of PC was estimated to be 4.0 years. This implies a window of opportunity for screening, presuming the availability of a reliable diagnostic test. The probability that an LGD cyst will progress to cancer was predicted to be low.

Impact of surgical versus endoscopic management of complex nonmalignant polyps in a colorectal cancer screening program.

BACKGROUND: When complex nonmalignant polyps are detected in colorectal cancer (CRC) screening programs, patients may be referred directly to surgery or may first undergo additional endoscopy for attempted endoscopic removal by an expert. We compared the impact of both strategies on screening effectiveness and costs. METHODS: We used MISCAN-Colon to simulate the Dutch screening program, and projected CRC deaths prevented, quality-adjusted life-years (QALYs) gained, and costs for two scenarios: 1) surgery for all complex nonmalignant polyps; 2) attempted removal by an expert endoscopist first. We made the following assumptions: 3.9 % of screen-detected large nonmalignant polyps were complex; associated surgery mortality was 0.7 %; the rate of successful removal by an expert was 87 %, with 0.11 % mortality. RESULTS: The screening program was estimated to prevent 11.2 CRC cases (-16.7 %) and 10.1 CRC deaths (-27.1 %), resulting in 32.9 QALYs gained (+ 17.2 %) per 1000 simulated individuals over their lifetimes compared with no screening. The program would also result in 2.1 surgeries for complex nonmalignant polyps with 0.015 associated deaths per 1000 individuals. If, instead, these patients were referred to an expert endoscopist first, only 0.2 patients required surgery, reducing associated deaths by 0.013 at the expense of 0.003 extra colonoscopy deaths. Compared with direct referral to surgery, referral to an expert endoscopist gained 0.2 QALYs and saved €12 500 per 1000 individuals in the target population. CONCLUSION: Referring patients with complex polyps to an expert endoscopist first reduced some surgery-related deaths while substantially improving cost-effectiveness of the screening program.

The Optimal Age to Stop Endoscopic Surveillance of Patients With Barrett's Esophagus Based on Sex and Comorbidity: A Comparative Cost-Effectiveness Analysis.

BACKGROUND AND AIMS: Current guidelines recommend surveillance for patients with nondysplastic Barrett's esophagus (NDBE) but do not include a recommended age for discontinuing surveillance. This study aimed to determine the optimal age for last surveillance of NDBE patients stratified by sex and level of comorbidity. METHODS: We used 3 independently developed models to simulate patients diagnosed with NDBE, varying in age, sex, and comorbidity level (no, mild, moderate, and severe). All patients had received regular surveillance until their current age. We calculated incremental costs and quality-adjusted life-years (QALYs) gained from 1 additional endoscopic surveillance at the current age versus not performing surveillance at that age. We determined the optimal age to end surveillance as the age at which incremental cost-effectiveness ratio of 1 more surveillance was just less than the willingness-to-pay threshold of $100,000/QALY. RESULTS: The benefit of having 1 more surveillance endoscopy strongly depended on age, sex, and comorbidity. For men with NDBE and severe comorbidity, 1 additional surveillance at age 80 years provided 4 more QALYs per 1000 patients with BE at an additional cost of $1.2 million, whereas for women with severe comorbidity the benefit at that age was 7 QALYs at a cost of $1.3 million. For men with no, mild, moderate, and severe comorbidity, the optimal ages of last surveillance were 81, 80, 77, and 73 years, respectively. For women, these ages were younger: 75, 73, 73, and 69 years, respectively. CONCLUSIONS: Our comparative modeling analysis illustrates the importance of considering comorbidity status and sex when deciding on the age to discontinue surveillance in patients with NDBE.

The Differential Risk of Cervical Cancer in HPV-Vaccinated and -Unvaccinated Women: A Mathematical Modeling Study.

BACKGROUND: With increased uptake of vaccination against human papillomavirus (HPV), protection against cervical cancer will also increase for unvaccinated women, due to herd immunity. Still, the differential risk between vaccinated and unvaccinated women might warrant a vaccination-status-screening approach. To understand the potential value of stratified screening protocols, we estimated the risk differentials in HPV and cervical cancer between vaccinated and unvaccinated women. METHODS: We used STDSIM, an individual-based model of HPV transmission and control, to estimate the HPV prevalence reduction over time, after introduction of HPV vaccination. We simulated scenarios of bivalent or nonavalent vaccination in females-only or females and males, at 20% coverage increments. We estimated relative HPV-type-specific prevalence reduction compared with a no-vaccination counterfactual and then estimated the age-specific cervical cancer risk by vaccination status. RESULTS: The relative cervical cancer risk for unvaccinated compared with vaccinated women ranged from 1.7 (bivalent vaccine for females and males; 80% coverage) to 10.8 (nonavalent vaccine for females-only; 20% coverage). Under 60% vaccination coverage, which is a representative coverage for several western countries, including the United States, the relative risk (RR) varies between 2.2 (bivalent vaccine for females and males) and 9.2 (nonavalent vaccine for females). CONCLUSIONS: We found large cervical cancer risk differences between vaccinated and unvaccinated women. In general, our model shows that the RR is higher in lower vaccine coverages, using the nonavalent vaccine, and when vaccinating females only. IMPACT: To avoid a disbalance in harms and benefits between vaccinated and unvaccinated women, vaccination-based screening needs serious consideration.

Cost-effectiveness analysis of colorectal cancer screening in a low incidence country: The case of Saudi Arabia.

Background: Colorectal cancer (CRC) screening is cost-effective in many Western countries, and many have successfully implemented CRC screening programs. For countries with a lower CRC incidence, like Saudi Arabia, the value of CRC screening is less evident and requires careful weighing of harms, benefits, and costs. Methods: We used the MISCAN-Colon microsimulation model to simulate a male and female cohort with life expectancy and CRC risk as observed in Saudi Arabia. For both cohorts, we evaluated strategies without screening, with annual or biennial faecal immunochemical testing (FIT), and with 10-yearly or once-only colonoscopy. We also considered different start and end ages of screening. For both cohorts, we estimated lifetime costs and effects of each strategy. We then identified a set of potentially cost-effective strategies using incremental cost-effectiveness ratios (ICERs) defined as the additional cost per additional quality-adjusted life year (QALY). Results: Without CRC screening, an estimated 14 per 1,000 males would develop CRC during their lifetime and 9 would die from CRC. Several strategies proved potentially cost-effective including biennial FIT at ages 55-65 (ICER of $7,400), once-only colonoscopy at age 55 (ICER of $7,700), and 10-yearly colonoscopy at ages 50-65, 45-65, and 45-75 (ICERs of $34,000, 71,000, and 375,000, respectively). For females, risk of CRC was lower and CRC screening was therefore less cost-effective, but efficient strategies were largely similar. Conclusions: Despite low CRC incidence in Saudi Arabia, some FIT or colonoscopy screening strategies may meet reasonable thresholds of cost-effectiveness. The optimal strategy will depend on multiple factors including the willingness to pay per QALY, the colonoscopy capacity, and the accepted budget impact.

Identifying key factors for the effectiveness of pancreatic cancer screening: A model-based analysis.

Pancreatic cancer (PC) survival is poor, as detection usually occurs late, when treatment options are limited. Screening of high-risk individuals may enable early detection and a more favorable prognosis. Knowledge gaps prohibit establishing the effectiveness of screening. We developed a Microsimulation Screening Analysis model to analyze the impact of relevant uncertainties on the effect of PC screening in high-risk individuals. The model simulates two base cases: one in which lesions always progress to PC and one in which indolent and faster progressive lesions coexist. For each base case, the effect of annual and 5-yearly screening with endoscopic ultrasonography/magnetic resonance imaging was evaluated. The impact of variance in PC risk, screening test characteristics and surgery-related mortality was evaluated using sensitivity analyses. Screening resulted in a reduction of PC mortality by at least 16% in all simulated scenarios. This reduction depended strongly on the natural disease course (annual screening: -57% for "Progressive-only" vs -41% for "Indolent Included"). The number of screen and surveillance tests needed to prevent one cancer death was impacted most by PC risk. A 10% increase in test sensitivity reduced mortality by 1.9% at most. Test specificity is important for the number of surveillance tests. In conclusion, screening reduces PC mortality in all modeled scenarios. The natural disease course and PC risk strongly determines the effectiveness of screening. Test sensitivity seems of lesser influence than specificity. Future research should gain more insight in PC pathobiology to establish the true value of PC screening in high-risk individuals.

Reducing unnecessary referrals for colposcopy in hrHPV-positive women within the Dutch cervical cancer screening programme: A modelling study.

BACKGROUND: With the implementation of primary high-risk human papillomavirus (hrHPV) screening in the Netherlands, an increase was observed in the number of unnecessary referrals (≤Cervical Intraepithelial Neoplasia (CIN) 1) to colposcopy. We aimed to investigate which alternative triage strategies safely reduce unnecessary referrals in HPV-based cervical cancer screening programmes. METHODS: Microsimulation model MISCAN was used to simulate an unvaccinated cohort of ten million 30-year old Dutch women. We calculated unnecessary referrals, cervical cancer incidence, mortality, costs and QALYs for 24 triage strategies. Condition for direct referral (atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), conditional on HPV-genotype 16/18/other high risk (OHR)), type of triage test (cytology alone or combined with hrHPV) and time to triage test (6 or 12 months) was varied. RESULTS: The 24 triage strategies had varying effects on the number of unnecessary referrals ranging from -72% to +35%. Adjusting conditions for referral to 'HPV16/18+ and ASC-US+' and 'HPVOHR+ and HSIL+' and extending the interval between tests to 12 months resulted in a reduction in unnecessary referrals of 40% (incidence +0%, mortality -1%). Reduction in unnecessary referrals without genotyping was achieved by adjusting conditions for direct referral to LSIL (12 months to repeat test) (unnecessary referrals -37%, incidence +2%, mortality +0%). CONCLUSIONS: To reduce the number of unnecessary referrals without increasing incidence and mortality by more than 2% in the Dutch cervical cancer screening programme, genotyping for HPV16 or HPV16/18 should be implemented with 12 months to repeat testing.

Calculation of Stop Ages for Colorectal Cancer Screening Based on Comorbidities and Screening History.

BACKGROUND & AIMS: Routine screening for colorectal cancer typically is recommended until age 74 years. Although it has been proposed that a screening stop age could be determined based on sex and comorbidity, less is known about the impact of screening history. We investigated the effects of screening history on the selection of an optimal age to stop screening. METHODS: We used the Microsimulation Screening Analysis-Colon model to estimate the harms and benefits of screening with biennial fecal immunochemical tests by sex, comorbidity status, and screening history. The optimal screening stop age was determined based on the incremental number needed for 1 additional life-year per 1000 screened individuals compared with the threshold provided by stopping screening at 76 years in the average-health population with a perfect screening history (attended all required screening, diagnostic, and follow-up tests) to biennial fecal immunochemical testing from age 50 years. RESULTS: For persons age 76 years, 157 women and 108 men with a perfect screening history would need to be screened to gain 1 life-year per 1000 screened individuals. Previously unscreened women with no comorbid conditions and no history of screening could undergo an initial screening through 90 years, whereas unscreened men could undergo initial screening through 88 years, before this balance is reached. As screening adherence improved or as comorbidities increased, the optimal age to stop screening decreased to a point that, regardless of sex, individuals with severe comorbidities and a perfect screening history should stop screening at age 66 years or younger. CONCLUSIONS: Based on the harm-benefit balance, the optimal stop age for colorectal cancer screening ranges from 66 years for unhealthy individuals with a perfect screening history to 90 years for healthy individuals without prior screening. These findings can be used to assist patients and clinicians in making decisions about screening participation.

The Impact of the Policy-Practice Gap on Costs and Benefits of Barrett's Esophagus Management.

INTRODUCTION: Clinical guidelines recommend surveillance of patients with Barrett's esophagus (BE). However, the surveillance intervals in practice are shorter than policy recommendations. We aimed to determine how this policy-practice gap affects the costs and benefits of BE surveillance. METHODS: We used the Netherlands as an exemplary Western country and simulated a cohort of 60-year-old patients with BE using the Microsimulation Screening Analysis model-esophageal adenocarcinoma (EAC) microsimulation model. We evaluated surveillance according to the Dutch guideline and more intensive surveillance of patients without dysplastic BE and low-grade dysplasia. For each strategy, we computed the quality-adjusted life years (QALYs) gained and costs compared with no surveillance. We also performed a budget impact analysis to estimate the increased costs of BE management in the Netherlands for 2017. RESULTS: Compared with no surveillance, the Dutch guideline incurred an additional &OV0556;5.0 ($5.7) million per 1,000 patients with BE for surveillance and treatment, whereas 57 esophageal adenocarcinoma (EAC) cases (>T1a) were prevented. With intensive and very intensive surveillance strategies for both nondysplastic BE and low-grade dysplasia, the net costs increased by another &OV0556;2.5-5.6 ($2.8-6.5) million while preventing 10-19 more EAC cases and gaining 33-60 more QALYs. On a population level, this amounted to &OV0556;21-47 ($24-54) million (+32%-70%) higher healthcare costs in 2017. DISCUSSION: The policy-practice gap in BE surveillance intervals results in 50%-114% higher net costs for BE management for only 10%-18% increase in QALYs gained, depending on actual intensity of surveillance. Incentives to eliminate this policy-practice gap should be developed to reduce the burden of BE management on patients and healthcare resources.

The Impact of Different Screening Model Structures on Cervical Cancer Incidence and Mortality Predictions: The Maximum Clinical Incidence Reduction (MCLIR) Methodology.

Background. To interpret cervical cancer screening model results, we need to understand the influence of model structure and assumptions on cancer incidence and mortality predictions. Cervical cancer cases and deaths following screening can be attributed to 1) (precancerous or cancerous) disease that occurred after screening, 2) disease that was present but not screen detected, or 3) disease that was screen detected but not successfully treated. We examined the relative contributions of each of these using 4 Cancer Intervention and Surveillance Modeling Network (CISNET) models. Methods. The maximum clinical incidence reduction (MCLIR) method compares changes in the number of clinically detected cervical cancers and mortality among 4 scenarios: 1) no screening, 2) one-time perfect screening at age 45 that detects all existing disease and delivers perfect (i.e., 100% effective) treatment of all screen-detected disease, 3) one-time realistic-sensitivity cytological screening and perfect treatment of all screen-detected disease, and 4) one-time realistic-sensitivity cytological screening and realistic-effectiveness treatment of all screen-detected disease. Results. Predicted incidence reductions ranged from 55% to 74%, and mortality reduction ranged from 56% to 62% within 15 years of follow-up for scenario 4 across models. The proportion of deaths due to disease not detected by screening differed across the models (21%-35%), as did the failure of treatment (8%-16%) and disease occurring after screening (from 1%-6%). Conclusions. The MCLIR approach aids in the interpretation of variability across model results. We showed that the reasons why screening failed to prevent cancers and deaths differed between the models. This likely reflects uncertainty about unobservable model inputs and structures; the impact of this uncertainty on policy conclusions should be examined via comparing findings from different well-calibrated and validated model platforms.

Cost-effectiveness of inactivated influenza vaccination in children with medical risk conditions in the Netherlands.

BACKGROUND: In many countries, annual immunization with inactivated influenza vaccine (IIV) is recommended for children with medical risk conditions. Prior cost-effectiveness analyses found such immunization to be cost saving, but assumed effectiveness against non-severe influenza outcomes and a higher effectiveness against severe influenza outcomes than recent studies would suggest. However, recent vaccine studies do not indicate any reduction in community or outpatient disease episodes in IIV immunized individuals. We therefore evaluated cost-effectiveness of IIV immunization in children with medical risk conditions in the Netherlands, assuming that IIV reduces influenza-related hospitalization and death, but has no meaningful impact on non-severe health outcomes. METHODS: A health economic decision tree model was developed to evaluate health effects and costs of annual IIV immunization versus no immunization. Model inputs were based on our study on influenza-related primary care visits and other literature. Immunization was considered cost effective if associated costs were less than €20,000 per quality-adjusted life year (QALY) gained. Probabilistic sensitivity analyses were performed to assess robustness of results, and one-way sensitivity analyses and scenario analyses were done to assess the influence of individual parameters. RESULTS: Annual IIV prevents an average of 1.59 influenza-related hospitalizations and 0.02 deaths per 1,000 children with medical risk conditions. This results in an expected QALY gain of 0.43 at incremental costs of €21,564 per 1,000 children, corresponding to an incremental cost-effectiveness ratio (ICER) of €50,297/QALY compared to no immunization. Under base case assumptions, immunization had a 5% probability of being cost effective. Results were most influenced by vaccine efficacy against fatal influenza, QALY loss due to death, and mortality rate. CONCLUSIONS: If IIV only reduces severe disease outcomes, as current evidence suggests, annual immunization of medical risk children is unlikely to be cost effective. Results should however be interpreted with caution as cost-effectiveness is largely dependent on incidence and QALY losses for fatal influenza, for which evidence is scarce.

Cost-Effectiveness of Risk-Stratified Colorectal Cancer Screening Based on Polygenic Risk: Current Status and Future Potential.

BACKGROUND: Although uniform colonoscopy screening reduces colorectal cancer (CRC) mortality, risk-based screening may be more efficient. We investigated whether CRC screening based on polygenic risk is a cost-effective alternative to current uniform screening, and if not, under what conditions it would be. METHODS: The MISCAN-Colon model was used to simulate a hypothetical cohort of US 40-year-olds. Uniform screening was modeled as colonoscopy screening at ages 50, 60, and 70 years. For risk-stratified screening, individuals underwent polygenic testing with current and potential future discriminatory performance (area under the receiver-operating curve [AUC] of 0.60 and 0.65-0.80, respectively). Polygenic testing results were used to create risk groups, for which colonoscopy screening was optimized by varying the start age (40-60 years), end age (70-85 years), and interval (1-20 years). RESULTS: With current discriminatory performance, optimal screening ranged from once-only colonoscopy at age 60 years for the lowest-risk group to six colonoscopies at ages 40-80 years for the highest-risk group. While maintaining the same health benefits, risk-stratified screening increased costs by $59 per person. Risk-stratified screening could become cost-effective if the AUC value would increase beyond 0.65, the price per polygenic test would drop to less than $141, or risk-stratified screening would lead to a 5% increase in screening participation. CONCLUSIONS: Currently, CRC screening based on polygenic risk is unlikely to be cost-effective compared with uniform screening. This is expected to change with a greater than 0.05 increase in AUC value, a greater than 30% reduction in polygenic testing costs, or a greater than 5% increase in adherence with screening.

Optimizing Management of Patients With Barrett's Esophagus and Low-Grade or No Dysplasia Based on Comparative Modeling.

BACKGROUND & AIMS: Endoscopic treatment is recommended for patients with Barrett's esophagus (BE) with high-grade dysplasia, yet clinical management recommendations are inconsistent for patients with BE without dysplasia (NDBE) or with low-grade dysplasia (LGD). We used a comparative modeling analysis to identify optimal management strategies for these patients. METHODS: We used 3 independent population-based models to simulate cohorts of 60-year-old individuals with BE in the United States. We followed up each cohort until death without surveillance and treatment (natural disease progression), compared with 78 different strategies of management for patients with NDBE or LGD. We determined the optimal strategy using cost-effectiveness analyses, at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). RESULTS: In the 3 models, the average cumulative incidence of esophageal adenocarcinoma was 111 cases, with costs totaling $5.7 million per 1000 men with BE. Surveillance and treatment of men with BE prevented 23% to 75% of cases of esophageal adenocarcinoma, but increased costs to $6.2 to $17.3 million per 1000 men with BE. The optimal strategy was surveillance every 3 years for men with NDBE and treatment of LGD after confirmation by repeat endoscopy (incremental cost-effectiveness ratio, $53,044/QALY). The average results for women were consistent with the results for men for LGD management, but the optimal surveillance interval for women with NDBE was 5 years (incremental cost-effectiveness ratio, $36,045/QALY). CONCLUSIONS: Based on analyses from 3 population-based models, the optimal management strategy for patient with BE and LGD is endoscopic eradication, but only after LGD is confirmed by a repeat endoscopy. The optimal strategy for patients with NDBE is endoscopic surveillance, using a 3-year interval for men and a 5-year interval for women.

Cost-Effectiveness of Personalized Screening for Colorectal Cancer Based on Polygenic Risk and Family History.

BACKGROUND: There is growing evidence for personalizing colorectal cancer screening based on risk factors. We compared the cost-effectiveness of personalized colorectal cancer screening based on polygenic risk and family history to uniform screening. METHODS: Using the MISCAN-Colon model, we simulated a cohort of 100 million 40-year-olds, offering them uniform or personalized screening. Individuals were categorized based on polygenic risk and family history of colorectal cancer. We varied screening strategies by start age, interval and test and estimated costs, and quality-adjusted life years (QALY). In our analysis, we (i) assessed the cost-effectiveness of uniform screening; (ii) developed personalized screening scenarios based on optimal screening strategies by risk group; and (iii) compared the cost-effectiveness of both. RESULTS: At a willingness-to-pay threshold of $50,000/QALY, the optimal uniform screening scenario was annual fecal immunochemical testing (FIT) from ages 50 to 74 years, whereas for personalized screening the optimal screening scenario consisted of annual and biennial FIT screening except for those at highest risk who were offered 5-yearly colonoscopy from age 50 years. Although these scenarios gained the same number of QALYs (17,887), personalized screening was not cost-effective, costing an additional $428,953 due to costs associated with determining risk (assumed to be $240 per person). Personalized screening was cost-effective when these costs were less than ∼$48. CONCLUSIONS: Uniform colorectal cancer screening currently appears more cost-effective than personalized screening based on polygenic risk and family history. However, cost-effectiveness is highly dependent on the cost of determining risk. IMPACT: Personalized screening could become increasingly viable as costs for determining risk decrease.

Cost-effectiveness of Active Identification and Subsequent Colonoscopy Surveillance of Lynch Syndrome Cases.

BACKGROUND & AIMS: The province of Ontario, Canada is considering immunohistochemical followed by cascade analyses of all patients who received a diagnosis of colorectal cancer (CRC) at an age younger than 70 years to identify individuals with Lynch syndrome. We evaluated the costs and benefits of testing for Lynch syndrome and determined the optimal surveillance interval for first-degree relatives (FDRs) found to have Lynch syndrome. METHODS: We developed a patient flow diagram to determine costs and yield of immunohistochemical testing for Lynch syndrome in CRC cases and, for those found to have Lynch syndrome, their FDRs, accounting for realistic uptake. Subsequently, we used the MISCAN-colon model to compare costs and benefits of annual, biennial, and triennial surveillance in FDRs identified with Lynch syndrome vs colonoscopy screening every 10 years (usual care for individuals without a diagnosis of Lynch syndrome). RESULTS: Testing 1000 CRC cases was estimated to identify 20 CRC index cases and 29 FDRs with Lynch syndrome at a cost of $310,274. Despite the high cost of Lynch syndrome tests, offering the FDRs with Lynch syndrome biennial colonoscopy surveillance was cost-effective at $8785 per life-year gained compared with usual care because of a substantial increase in life-years gained (+122%) and cost savings in CRC care. Triennial surveillance was more costly and less effective, and annual surveillance showed limited additional benefit compared with biennial surveillance. CONCLUSIONS: Immunohistochemical testing for Lynch syndrome in persons younger than 70 years who received a diagnosis of CRC and then testing FDRs of those found to have Lynch syndrome provide a good balance between costs and long-term benefits. Colonoscopy surveillance every 2 years is the optimal surveillance interval for patients with Lynch syndrome.

Cost-effectiveness of a multitarget stool DNA test for colorectal cancer screening of Medicare beneficiaries.

BACKGROUND: In 2014, the Centers for Medicare and Medicaid Services (CMS) began covering a multitarget stool DNA (mtSDNA) test for colorectal cancer (CRC) screening of Medicare beneficiaries. In this study, we evaluated whether mtSDNA testing is a cost-effective alternative to other CRC screening strategies reimbursed by CMS, and if not, under what conditions it could be. METHODS: We use three independently-developed microsimulation models to simulate a cohort of previously unscreened US 65-year-olds who are screened with triennial mtSDNA testing, or one of six other reimbursed screening strategies. Main outcome measures are discounted life-years gained (LYG) and lifetime costs (CMS perspective), threshold reimbursement rates, and threshold adherence rates. Outcomes are expressed as the median and range across models. RESULTS: Compared to no screening, triennial mtSDNA screening resulted in 82 (range: 79-88) LYG per 1,000 simulated individuals. This was more than for five-yearly sigmoidoscopy (80 (range: 71-89) LYG), but fewer than for every other simulated strategy. At its 2017 reimbursement rate of $512, mtSDNA was the most costly strategy, and even if adherence were 30% higher than with other strategies, it would not be a cost-effective alternative. At a substantially reduced reimbursement rate ($6-18), two models found that triennial mtSDNA testing was an efficient and potentially cost-effective screening option. CONCLUSIONS: Compared to no screening, triennial mtSDNA screening reduces CRC incidence and mortality at acceptable costs. However, compared to nearly all other CRC screening strategies reimbursed by CMS it is less effective and considerably more costly, making it an inefficient screening option.

Modeling in Colorectal Cancer Screening: Assessing External and Predictive Validity of MISCAN-Colon Microsimulation Model Using NORCCAP Trial Results.

BACKGROUND: Microsimulation models are increasingly being used to inform colorectal cancer (CRC) screening recommendations. MISCAN-Colon is an example of such a model, used to inform the Dutch CRC screening program and US Preventive Services Task Force guidelines. Assessing the validity of these models is essential to provide transparency regarding their performance. In this study, we tested the external and predictive validity of MISCAN-Colon. METHODS: We validated MISCAN-Colon using the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, a randomized controlled trial that examined the effectiveness of once-only flexible sigmoidoscopy (FS) screening. We simulated the study population and design of the NORCCAP trial in MISCAN-Colon and compared 10- to 12-year model-predicted hazard ratios (HRs) for overall and distal CRC incidence and mortality to those observed. In addition, we compared the numbers of screen-detected neoplasia. Finally, we predicted the trial's future results to allow for the assessment of predictive validity. RESULTS: MISCAN-Colon predicted an HR for overall CRC incidence (0.85), distal CRC incidence (0.82), overall CRC mortality (0.68), and distal CRC mortality (0.62). These were within the limits of the 95% confidence intervals of the NORCCAP trial results. Similar results were observed for the number of screen-detected cancers. The model significantly underestimated the number of screen-detected adenomas. Model-predicted HRs for CRC incidence and mortality up to 15- to 17-year follow-up were 0.84 and 0.72, respectively. CONCLUSION: Although the underestimation of screen-detected adenomas requires further investigation, MISCAN-Colon is able to make a valid replication of the CRC incidence and mortality reduction of an FS screening trial, which suggests that it can be considered a useful tool to support decision making on CRC screening.

The health impact of human papillomavirus vaccination in the situation of primary human papillomavirus screening: A mathematical modeling study.

BACKGROUND: Human papillomavirus (HPV) vaccination and the implementation of primary HPV screening in the Netherlands will lead to a lower cervical disease burden. For evaluation and further improvement of prevention, it is important to estimate the magnitude and timing of health benefits of current and alternative vaccination strategies such as vaccination of boys or adults. METHODS AND FINDINGS: We evaluated the impact of the current girls-only vaccination program and alternative strategies on cervical disease burden among the first four vaccinated five-year birth cohorts, given the context of primary HPV screening. We integrated the existing microsimulation models STDSIM (HPV transmission model) and MISCAN-Cervix (cervical cancer screening model). Alternative vaccination strategies include: improved vaccination uptake, including routine boys vaccination, and offering adult vaccination at sexual health clinics. Our models show that the current vaccination program is estimated to reduce cervical cancers and cancer deaths by about 35% compared to primary HPV screening in the absence of vaccination. The number needed to vaccinate (NNV) to gain 1 life year is 45. The most efficient alternative vaccination strategies are: 1) improving coverage of girls to 80% (NNV = 42); and 2) routine vaccination for girls and boys at 80% coverage (incremental NNV = 155), with cervical cancer mortality reductions estimated at 50% and 60% respectively. CONCLUSIONS: While the current program already substantially reduces cervical cancer incidence and mortality, prevention can be further improved by increasing vaccination uptake and extending vaccination to boys. As not all cervical cancer deaths will be prevented, screening participation should still be encouraged.