Exploring the Cost Effectiveness of a Whole-Genome Sequencing-Based Biomarker for Treatment Selection in Patients with Advanced Lung Cancer Ineligible for Targeted Therapy.

OBJECTIVE: We aimed to perform an early cost-effectiveness analysis of using a whole-genome sequencing-based tumor mutation burden (WGS-TMB), instead of programmed death-ligand 1 (PD-L1), for immunotherapy treatment selection in patients with non-squamous advanced/metastatic non-small cell lung cancer ineligible for targeted therapy, from a Dutch healthcare perspective. METHODS: A decision-model simulating individual patients with metastatic non-small cell lung cancer was used to evaluate diagnostic strategies to select first-line immunotherapy only or the immunotherapy plus chemotherapy combination. Treatment was selected using PD-L1 [A, current practice], WGS-TMB [B], and both PD-L1 and WGS-TMB [C]. Strategies D, E, and F take into account a patient's disease burden, in addition to PD-L1, WGS-TMB, and both PD-L1 and WGS-TMB, respectively. Disease burden was defined as a fast-growing tumor, a high number of metastases, and/or weight loss. A threshold of 10 mutations per mega-base was used to classify patients into TMB-high and TMB-low groups. Outcomes were discounted quality-adjusted life-years (QALYs) and healthcare costs measured from the start of first-line treatment to death. Healthcare costs includes drug acquisition, follow-up costs, and molecular diagnostic tests (i.e., standard diagnostic techniques and/or WGS for strategies involving TMB). Results were reported using the net monetary benefit at a willingness-to-pay threshold of €80,000/QALY. Additional scenario and threshold analyses were performed. RESULTS: Strategy B had the lowest QALYs (1.84) and lowest healthcare costs (€120,800). The highest QALYs and healthcare costs were 2.00 and €140,400 in strategy F. In the base-case analysis, strategy A was cost effective with the highest net monetary benefit (€27,300), followed by strategy B (€26,700). Strategy B was cost effective when the cost of WGS testing was decreased by at least 24% or when immunotherapy results in an additional 0.5 year of life gained or more for TMB high compared with TMB low. Strategies C and F, which combined TMB and PD-L1 had the highest net monetary benefit (≥ €76,900) when the cost of WGS testing, immunotherapy, and chemotherapy acquisition were simultaneously reduced by at least 47%, 39%, and 43%, respectively. Furthermore, strategy C resulted in the highest net monetary benefit (≥ €39,900) in a scenario where patients with both PD-L1 low and TMB low were treated with chemotherapy instead of immunotherapy plus chemotherapy. CONCLUSIONS: The use of WGS-TMB is not cost effective compared to PD-L1 for immunotherapy treatment selection in non-squamous metastatic non-small cell lung cancer in the Netherlands. WGS-TMB could become cost effective provided there is a reduction in the cost of WGS testing or there is an increase in the predictive value of WGS-TMB for immunotherapy effectiveness. Alternatively, a combination strategy of PD-L1 testing with WGS-TMB would be cost effective if used to support the choice to withhold immunotherapy in patients with a low expected benefit of immunotherapy.

Development and validation of a decision model for the evaluation of novel lung cancer treatments in the Netherlands.

Recent discoveries in molecular diagnostics and drug treatments have improved the treatment of patients with advanced (inoperable) non-squamous non-small cell lung cancer (NSCLC) from solely platinum-based chemotherapy to more personalized treatment, including targeted therapies and immunotherapies. However, these improvements come at considerable costs, highlighting the need to assess their cost-effectiveness in order to optimize lung cancer care. Traditionally, cost-effectiveness models for the evaluation of new lung cancer treatments were based on the findings of the randomized control trials (RCTs). However, the strict RCT inclusion criteria make RCT patients not representative of patients in the real-world. Patients in RCTs have a better prognosis than patients in a real-world setting. Therefore, in this study, we developed and validated a diagnosis-treatment decision model for patients with advanced (inoperable) non-squamous NSCLC based on real-world data in the Netherlands. The model is a patient-level microsimulation model implemented as discrete event simulation with five health events. Patients are simulated from diagnosis to death, including at most three treatment lines. The base-model (non-personalized strategy) was populated using real-world data of patients treated with platinum-based chemotherapy between 2008 and 2014 in one of six Dutch teaching hospitals. To simulate personalized care, molecular tumor characteristics were incorporated in the model based on the literature. The impact of novel targeted treatments and immunotherapies was included based on published RCTs. To validate the model, we compared survival under a personalized treatment strategy with observed real-world survival. This model can be used for health-care evaluation of personalized treatment for patients with advanced (inoperable) NSCLC in the Netherlands.

Development of a data-driven case-mix adjustment model for comparison of hospital performance in hip fracture care.

To compare hospitals' hip fracture patient mortality in a quality of care registry, correction for patient characteristics is needed. This study evaluates in 39,374 patients which characteristics are associated with 30 and 90-day mortality, and showed how using these characteristics in a case mix-model changes hospital comparisons within the Netherlands. PURPOSE: Mortality rates after hip fracture surgery are considerable and may be influenced by patient characteristics. This study aims to evaluate hospital variation regarding patient demographics and disease burden, to develop a case-mix adjustment model to analyse differences in hip fracture patients' mortality to calculate case-mix adjusted hospital-specific mortality rates. METHODS: Data were derived from 64 hospitals participating in the Dutch Hip Fracture Audit (DHFA). Adult hip fracture patients registered in 2017-2019 were included. Variation of case-mix factors between hospitals was analysed, and the association between case-mix factors and mortality at 30 and 90 days was determined through regression models. RESULTS: There were 39,374 patients included. Significant variation in case-mix factors amongst hospitals was found for age ≥ 80 (range 25.8-72.1% p < 0.001), male gender (12.0-52.9% p < 0.001), nursing home residents (42.0-57.9% p < 0.001), pre-fracture mobility aid use (9.9-86.7% p < 0,001), daily living dependency (27.5-96.5% p < 0,001), ASA-class ≥ 3 (25.8-83.3% p < 0.001), dementia (3.6-28.6% p < 0.001), osteoporosis (0.0-57.1% p < 0.001), risk of malnutrition (0.0-29.2% p < 0.001) and fracture types (all p < 0.001). All factors were associated with 30- and 90-day mortality. Eight hospitals showed higher and six showed lower 30-day mortality than expected based on their case-mix. Six hospitals showed higher and seven lower 90-day mortality than expected. The specific outlier hospitals changed when correcting for case-mix factors. CONCLUSIONS: Dutch hospitals show significant case-mix variation regarding hip fracture patients. Case-mix adjustment is a prerequisite when comparing hospitals' 30-day and 90-day hip fracture patients' mortality. Adjusted mortality may serve as a starting point for improving hip fracture care.

Economic Evaluation of Population-Based BRCA1/BRCA2 Mutation Testing across Multiple Countries and Health Systems.

Clinical criteria/Family history-based BRCA testing misses a large proportion of BRCA carriers who can benefit from screening/prevention. We estimate the cost-effectiveness of population-based BRCA testing in general population women across different countries/health systems. A Markov model comparing the lifetime costs and effects of BRCA1/BRCA2 testing all general population women ≥30 years compared with clinical criteria/FH-based testing. Separate analyses are undertaken for the UK/USA/Netherlands (high-income countries/HIC), China/Brazil (upper-middle income countries/UMIC) and India (low-middle income countries/LMIC) using both health system/payer and societal perspectives. BRCA carriers undergo appropriate screening/prevention interventions to reduce breast cancer (BC) and ovarian cancer (OC) risk. Outcomes include OC, BC, and additional heart disease deaths and incremental cost-effectiveness ratio (ICER)/quality-adjusted life year (QALY). Probabilistic/one-way sensitivity analyses evaluate model uncertainty. For the base case, from a societal perspective, we found that population-based BRCA testing is cost-saving in HIC (UK-ICER = $-5639/QALY; USA-ICER = $-4018/QALY; Netherlands-ICER = $-11,433/QALY), and it appears cost-effective in UMIC (China-ICER = $18,066/QALY; Brazil-ICER = $13,579/QALY), but it is not cost-effective in LMIC (India-ICER = $23,031/QALY). From a payer perspective, population-based BRCA testing is highly cost-effective in HIC (UK-ICER = $21,191/QALY, USA-ICER = $16,552/QALY, Netherlands-ICER = $25,215/QALY), and it is cost-effective in UMIC (China-ICER = $23,485/QALY, Brazil-ICER = $20,995/QALY), but it is not cost-effective in LMIC (India-ICER = $32,217/QALY). BRCA testing costs below $172/test (ICER = $19,685/QALY), which makes it cost-effective (from a societal perspective) for LMIC/India. Population-based BRCA testing can prevent an additional 2319 to 2666 BC and 327 to 449 OC cases per million women than the current clinical strategy. Findings suggest that population-based BRCA testing for countries evaluated is extremely cost-effective across HIC/UMIC health systems, is cost-saving for HIC health systems from a societal perspective, and can prevent tens of thousands more BC/OC cases.

Fecal occult blood testing when colonoscopy capacity is limited.

BACKGROUND: Fecal occult blood testing (FOBT) can be adapted to a limited colonoscopy capacity by narrowing the age range or extending the screening interval, by using a more specific test or hemoglobin cutoff level for referral to colonoscopy, and by restricting surveillance colonoscopy. Which of these options is most clinically effective and cost-effective has yet to be established. METHODS: We used the validated MISCAN-Colon microsimulation model to estimate the number of colonoscopies, costs, and health effects of different screening strategies using guaiac FOBT or fecal immunochemical test (FIT) at various hemoglobin cutoff levels between 50 and 200 ng hemoglobin per mL, different surveillance strategies, and various age ranges. We optimized the allocation of a limited number of colonoscopies on the basis of incremental cost-effectiveness. RESULTS: When colonoscopy capacity was unlimited, the optimal screening strategy was to administer an annual FIT with a 50 ng/mL hemoglobin cutoff level in individuals aged 45-80 years and to offer colonoscopy surveillance to all individuals with adenomas. When colonoscopy capacity was decreasing, the optimal screening adaptation was to first increase the FIT hemoglobin cutoff value to 200 ng hemoglobin per mL and narrow the age range to 50-75 years, to restrict colonoscopy surveillance, and finally to further decrease the number of screening rounds. FIT screening was always more cost-effective compared with guaiac FOBT. Doubling colonoscopy capacity increased the benefits of FIT screening up to 100%. CONCLUSIONS: FIT should be used at higher hemoglobin cutoff levels when colonoscopy capacity is limited compared with unlimited and is more effective in terms of health outcomes and cost compared with guaiac FOBT at all colonoscopy capacity levels. Increasing the colonoscopy capacity substantially increases the health benefits of FIT screening.

Cost-effectiveness analysis of a quantitative immunochemical test for colorectal cancer screening.

BACKGROUND & AIMS: Two European randomized trials (N = 30,000) compared guaiac fecal occult blood testing with quantitative fecal immunochemical testing (FIT) and showed better attendance rates and test characteristics for FIT. We aimed to identify the most cost-effective FIT cutoff level for referral to colonoscopy based on data from these trials and allowing for differences in screening ages. METHODS: We used the validated MIcrosimulation SCreening ANalysis (MISCAN)-Colon microsimulation model to estimate costs and effects of different screening strategies for FIT cutoff levels of 50, 75, 100, 150, and 200 ng/mL hemoglobin. For each cutoff level, screening strategies were assessed with various age ranges and screening intervals. We assumed sufficient colonoscopy capacity for all strategies. RESULTS: At all cost levels, FIT screening was most effective with the 50 ng/mL cutoff level. The incremental cost-effectiveness ratio of biennial screening between ages 55 and 75 years using FIT at 50 ng/mL, for example, was 3900 euro per life year gained. Annual screening had an incremental cost-effectiveness ratio of 14,900 euro per life year gained, in combination with a wider age range (between ages 45 and 80 years). In the sensitivity analysis, 50 ng/mL remained the preferred cutoff level. CONCLUSIONS: FIT screening is more cost-effective at a cutoff level of 50 ng/mL than at higher cutoff levels. This supports the recommendation to use FIT at a cutoff level of 50 ng/mL, which is considerably lower than the values used in current practice.

How much colonoscopy screening should be recommended to individuals with various degrees of family history of colorectal cancer?

BACKGROUND: Individuals with a family history of colorectal cancer (CRC) are at increased risk for CRC. Current screening recommendations for these individuals are based on expert opinion. The authors investigated optimal screening strategies for individuals with various degrees of family history of CRC based on a cost-effectiveness analysis. METHODS: The MISCAN-Colon microsimulation model was used to estimate costs and effects of CRC screening strategies, varying by the age at which screening was started and stopped and by screening interval. The authors defined 4 risk groups, characterized by the number of affected first-degree relatives and their age at CRC diagnosis. For all risk groups, the optimal screening strategy had an incremental cost-effectiveness ratio of approximately $50,000 per life-year gained. RESULTS: The optimal screening strategy for individuals with 1 first-degree relative diagnosed after age 50 years was 6 colonoscopies every 5 years starting at age 50 years, compared with 4 colonoscopies every 7 years starting at age 50 years for average risk individuals. The optimal strategy had 10 colonoscopies every 4 years for individuals with 1 first-degree relative diagnosed before age 50 years, 13 colonoscopies every 3 years for individuals with 2 or more first-degree relatives diagnosed after age 50 years, and 15 colonoscopies every 3 years for individuals with 2 or more first-degree relatives of whom at least 1 was diagnosed before age 50 years. CONCLUSIONS: The optimal screening strategy varies considerably with the number of affected first-degree relatives and their age of diagnosis. Shorter screening intervals than the currently recommended 5 years may be appropriate for the highest risk individuals.

Stool DNA testing to screen for colorectal cancer in the Medicare population: a cost-effectiveness analysis.

BACKGROUND: The Centers for Medicare & Medicaid Services considered whether to reimburse stool DNA testing for colorectal cancer screening among Medicare enrollees. OBJECTIVE: To evaluate the conditions under which stool DNA testing could be cost-effective compared with the colorectal cancer screening tests currently reimbursed by the Centers for Medicare & Medicaid Services. DESIGN: Comparative microsimulation modeling study using 2 independently developed models. DATA SOURCES: Derived from literature. TARGET POPULATION: A cohort of persons aged 65 years. A sensitivity analysis was also conducted, in which a cohort of persons aged 50 years was studied. TIME HORIZON: Lifetime. PERSPECTIVE: Third-party payer. INTERVENTION: Stool DNA test every 3 or 5 years in comparison with currently recommended colorectal cancer screening strategies. OUTCOME MEASURES: Life expectancy, lifetime costs, incremental cost-effectiveness ratios, and threshold costs. RESULTS OF BASE-CASE ANALYSIS: Assuming a cost of $350 per test, strategies of stool DNA testing every 3 or 5 years yielded fewer life-years and higher costs than the currently recommended colorectal cancer screening strategies. Screening with the stool DNA test would be cost-effective at a per-test cost of $40 to $60 for stool DNA testing every 3 years, depending on the simulation model used. There were no levels of sensitivity and specificity for which stool DNA testing would be cost-effective at its current cost of $350 per test. Stool DNA testing every 3 years would be cost-effective at a cost of $350 per test if the relative adherence to stool DNA testing were at least 50% better than that with other screening tests. RESULTS OF SENSITIVITY ANALYSIS: None of the results changed substantially when a cohort of persons aged 50 years was considered. LIMITATION: No pathways other than the traditional adenoma-carcinoma sequence were modeled. CONCLUSION: Stool DNA testing could be a cost-effective alternative for colorectal cancer screening if the cost of the test substantially decreased or if its availability would entice a large fraction of otherwise unscreened persons to receive screening.

A decision-analytic evaluation of the cost-effectiveness of family history-based colorectal cancer screening programs.

OBJECTIVES: The aim of this study was to determine the cost-effectiveness of family history screening (FHS) for colorectal cancer (CRC) susceptibility at age 40 with early screening of those with increased risk. METHODS: The cost-effectiveness of several family history-based screening programs was estimated with a validated microsimulation model, using data from the SEER cancer registry, life tables, medicare records, and published data. Familial cancer syndromes were excluded. Screening programs evaluated included (i) colonoscopy screening every 10 years starting at age 50 (no family history assessment); (ii) colonoscopy every 10 years from age 40 for persons with a family history; (iii) colonoscopy every 5 years from age 50 for those with a family history; and (iv) colonoscopy every 5 years from age 40 for persons with a family history. In each FHS scenario, persons without a family history are screened with colonoscopy at age 50, then every 10 years to age 80. RESULTS: Compared with colonoscopy screening of all persons from age 50, the cost-effectiveness of the family history-based screening programs varied from $18,000-$51,000 per life year (LY) gained. Screening family history cases every 5 years from age 40 is more cost-effective than screening every 10 years from age 40. Reducing screening frequency for those without a family history lowers program expenditures substantially at a modest loss of LYs. The results are sensitive to the CRC risk difference between positive and negative family histories. CONCLUSIONS: The cost-effectiveness of CRC FHS guidelines varies widely. Economic issues should be considered before implementing family history-directed screening programs.

Individualizing colonoscopy screening by sex and race.

BACKGROUND: There is increasing discussion whether colorectal cancer (CRC) screening guidelines should be individualized by sex and race. OBJECTIVES: To determine individualized colonoscopic screening guidelines by sex and race for the average-risk population and to compare the cost-effectiveness of this approach with that of uniform guidelines for all. DESIGN: We used the MISCAN-Colon microsimulation model to estimate life expectancy and lifetime CRC screening and treatment costs in a U.S. cohort of black and white men and women at average risk for CRC. We compared the base-case strategy of no screening and 3 competing colonoscopy strategies: (1) the currently recommended "uniform 10-yearly colonoscopy from age 50 years," (2) a shorter interval "uniform 8-yearly colonoscopy from age 51 years," and (3) "individualized screening according to sex and race." RESULTS: The base-case strategy of no screening was the least expensive, yet least effective. The uniform 10-yearly colonoscopy strategy was dominated. The uniform 8-yearly colonoscopy and individualized strategies both increased life expectancy by 0.0433 to 0.0435 years per individual, at a cost of $15,565 to $15,837 per life-year gained. In the individualized strategy, blacks began screening 6 years earlier, with a 1-year shorter interval compared with whites. The individualized policies were essentially the same for men and women, because the higher CRC risk in men was offset by their shorter life expectancy. The results were robust for changes in model assumptions. CONCLUSIONS: The improvements in costs and effects of individualizing CRC screening on a population level were only marginal. Individualized guidelines, however, could contribute to decreasing disparities between blacks and whites. The acceptability and feasibility of individualized guidelines, therefore, should be explored.

At what costs will screening with CT colonography be competitive? A cost-effectiveness approach.

The costs of computed tomographic colonography (CTC) are not yet established for screening use. In our study, we estimated the threshold costs for which CTC screening would be a cost-effective alternative to colonoscopy for colorectal cancer (CRC) screening in the general population. We used the MISCAN-colon microsimulation model to estimate the costs and life-years gained of screening persons aged 50-80 years for 4 screening strategies: (i) optical colonoscopy; and CTC with referral to optical colonoscopy of (ii) any suspected polyp; (iii) a suspected polyp >or=6 mm and (iv) a suspected polyp >or=10 mm. For each of the 4 strategies, screen intervals of 5, 10, 15 and 20 years were considered. Subsequently, for each CTC strategy and interval, the threshold costs of CTC were calculated. We performed a sensitivity analysis to assess the effect of uncertain model parameters on the threshold costs. With equal costs ($662), optical colonoscopy dominated CTC screening. For CTC to gain similar life-years as colonoscopy screening every 10 years, it should be offered every 5 years with referral of polyps >or=6 mm. For this strategy to be as cost-effective as colonoscopy screening, the costs must not exceed $285 or 43% of colonoscopy costs (range in sensitivity analysis: 39-47%). With 25% higher adherence than colonoscopy, CTC threshold costs could be 71% of colonoscopy costs. Our estimate of 43% is considerably lower than previous estimates in literature, because previous studies only compared CTC screening to 10-yearly colonoscopy, where we compared to different intervals of colonoscopy screening.

Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force.

BACKGROUND: The U.S. Preventive Services Task Force requested a decision analysis to inform their update of recommendations for colorectal cancer screening. OBJECTIVE: To assess life-years gained and colonoscopy requirements for colorectal cancer screening strategies and identify a set of recommendable screening strategies. DESIGN: Decision analysis using 2 colorectal cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network. DATA SOURCES: Derived from the literature. TARGET POPULATION: U.S. average-risk 40-year-old population. PERSPECTIVE: Societal. TIME HORIZON: Lifetime. INTERVENTIONS: Fecal occult blood tests (FOBTs), flexible sigmoidoscopy, or colonoscopy screening beginning at age 40, 50, or 60 years and stopping at age 75 or 85 years, with screening intervals of 1, 2, or 3 years for FOBT and 5, 10, or 20 years for sigmoidoscopy and colonoscopy. OUTCOME MEASURES: Number of life-years gained compared with no screening and number of colonoscopies and noncolonoscopy tests required. RESULTS OF BASE-CASE ANALYSIS: Beginning screening at age 50 years was consistently better than at age 60. Decreasing the stop age from 85 to 75 years decreased life-years gained by 1% to 4%, whereas colonoscopy use decreased by 4% to 15%. Assuming equally high adherence, 4 strategies provided similar life-years gained: colonoscopy every 10 years, annual Hemoccult SENSA (Beckman Coulter, Fullerton, California) testing or fecal immunochemical testing, and sigmoidoscopy every 5 years with midinterval Hemoccult SENSA testing. Annual Hemoccult II and flexible sigmoidoscopy every 5 years alone were less effective. RESULTS OF SENSITIVITY ANALYSIS: The results were most sensitive to beginning screening at age 40 years. LIMITATION: The stop age for screening was based only on chronologic age. CONCLUSION: The findings support colorectal cancer screening with the following: colonoscopy every 10 years, annual screening with a sensitive FOBT, or flexible sigmoidoscopy every 5 years with a midinterval sensitive FOBT from age 50 to 75 years.