Population-Based Newborn Screening for Germline TP53 Variants: Clinical Benefits, Cost-Effectiveness, and Value of Further Research.

BACKGROUND: Identification of children and infants with Li-Fraumeni syndrome prompts tumor surveillance and allows potential early cancer detection. We assessed the clinical benefits and cost-effectiveness of population-wide newborn screening for TP53 variants (TP53-NBS). METHODS: We simulated the impact of TP53-NBS using data regarding TP53-associated pediatric cancers and pathogenic or likely pathogenic (P/LP) TP53 variants from Surveillance, Epidemiology, and End Results; ClinVar and gnomAD; and clinical studies. We simulated an annual US birth cohort under usual care and TP53-NBS and estimated clinical benefits, life-years, and costs associated with usual care and TP53-NBS. RESULTS: Under usual care, of 4 million newborns, 608 (uncertainty interval [UI] = 581-636) individuals would develop TP53-associated cancers before age 20 years. Under TP53-NBS, 894 individuals would have P/LP TP53 variants detected. These individuals would undergo routine surveillance after detection of P/LP TP53 variants decreasing the number of cancer-related deaths by 7.2% (UI = 4.0%-12.1%) overall via early malignancy detection. Compared with usual care, TP53-NBS had an incremental cost-effectiveness ratio of $106 009 per life-year gained. Probabilistic analysis estimated a 40% probability that TP53-NBS would be cost-effective given a $100 000 per life-year gained willingness-to-pay threshold. Using this threshold, a value of information analysis found that additional research on the prevalence of TP53 variants among rhabdomyosarcoma cases would resolve most of the decision uncertainty, resulting in an expected benefit of 349 life-years gained (or $36.6 million). CONCLUSIONS: We found that TP53-NBS could be cost-effective; however, our findings suggest that further research is needed to reduce the uncertainty in the potential health outcomes and costs associated with TP53-NBS.

Characteristics of new adult users of mepolizumab with asthma in the USA.

BACKGROUND: In the USA, over 25 million people have asthma; 5%-10% of cases are severe. Mepolizumab (Nucala) is an interleukin-5 antagonist monoclonal antibody; it was approved by the FDA in 2015 as add-on maintenance treatment of severe asthma for patients aged ≥12 years with an eosinophilic phenotype. OBJECTIVES: (1) Describe baseline demographic and clinical characteristics of new US adult mepolizumab users 2015-2019, (2) describe asthma medication use in the 12 months preceding initiation of and concomitant with mepolizumab and (3) assess mepolizumab adherence, persistence and discontinuation patterns in 12 months postinitiation. METHODS: We conducted a new-user observational cohort study using data from Aetna, a CVS Health Company, HealthCore (Anthem), Harvard Pilgrim Healthcare, and IBM MarketScan Research Databases. Curated administrative claims data in the FDA Sentinel System common data model format and publicly available Sentinel analytical tools were used to query the databases. We included adults who initiated mepolizumab in 2015-2019 with an asthma diagnosis in the preceding 12 months and no evidence of cystic fibrosis. We examined age, sex, comorbid conditions, asthma medication use and severe asthma exacerbations. RESULTS: We identified 3496 adults (mean age 54.2 years, SD 12.5 years) who initiated mepolizumab. In the 12 months before mepolizumab initiation, 22% had received inhaled corticosteroids, 46% had inhaled corticosteroid/long-acting beta agonists, 72.6% had leukotriene antagonists, 38% had long-acting muscarinic antagonist, 18% had omalizumab,<1% had reslizumab, dupilumab or benralizumab. In the previous 12 months, 70% had a diagnosis of allergic rhinitis, 32% had chronic obstructive pulmonary disease, 17% eosinophilia and 3% eosinophilic granulomatosis with polyangiitis. Further, 56% had an asthma-related ambulatory visit, 73%≥1 course of oral corticosteroids lasting 3-27 days, 10% an asthma-related emergency department visit and 22% an asthma-related hospitalisation. In the 12 months following initiation, the mean proportion of days covered was 70%, and reductions in the average mean dispensings of rescue oral corticosteriods (35%) and omalizumab (61%) were observed. CONCLUSIONS: Adults with asthma treated with mepolizumab had varying levels of healthcare utilisation and we observed evidence of mepolizumab use in patients without severe asthma.

Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights.

PURPOSE: Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs. METHODS: We developed a simulation model to evaluate universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence. RESULTS: Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained. CONCLUSION: Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.

The impact of overdiagnosis on the selection of efficient lung cancer screening strategies.

The U.S. Preventive Services Task Force (USPSTF) recently updated their national lung screening guidelines and recommended low-dose computed tomography (LDCT) for lung cancer (LC) screening through age 80. However, the risk of overdiagnosis among older populations is a concern. Using four comparative models from the Cancer Intervention and Surveillance Modeling Network, we evaluate the overdiagnosis of the screening program recommended by USPSTF in the U.S. 1950 birth cohort. We estimate the number of LC deaths averted by screening (D) per overdiagnosed case (O), yielding the ratio D/O, to quantify the trade-off between the harms and benefits of LDCT. We analyze 576 hypothetical screening strategies that vary by age, smoking, and screening frequency and evaluate efficient screening strategies that maximize the D/O ratio and other metrics including D and life-years gained (LYG) per overdiagnosed case. The estimated D/O ratio for the USPSTF screening program is 2.85 (model range: 1.5-4.5) in the 1950 birth cohort, implying LDCT can prevent ∼3 LC deaths per overdiagnosed case. This D/O ratio increases by 22% when the program stops screening at an earlier age 75 instead of 80. Efficiency frontier analysis shows that while the most efficient screening strategies that maximize the mortality reduction (D) irrespective of overdiagnosis screen through age 80, screening strategies that stop at age 75 versus 80 produce greater efficiency in increasing life-years gained per overdiagnosed case. Given the risk of overdiagnosis with LC screening, the stopping age of screening merits further consideration when balancing benefits and harms.

Cost Analysis of a Randomized Trial of Early Palliative Care in Patients with Metastatic Nonsmall-Cell Lung Cancer.

BACKGROUND: Several trials have shown that integrated palliative and oncology care improves quality of life and mood in patients with advanced cancers. However, the degree to which early involvement of palliative care (PC) in the outpatient setting impacts the cost of care remains unknown. METHODS: Data for this secondary analysis came from a trial of 151 patients with metastatic nonsmall-cell lung cancer (NSCLC) who were randomized to early PC integrated with standard oncology care (SC) or SC alone. We abstracted costs for hospital and outpatient care, including intravenous chemotherapy, from the hospital accounting system. Oral chemotherapy costs were estimated based on actual drug costs. To estimate hospice costs, we used Medicare reimbursement rates. We examined between-group differences in costs of care throughout the entire study period and during the last 30 days before death using the bootstrap-t method. RESULTS: The analytic sample includes the 138/151 patients who died by July 15, 2013. Early PC was associated with a lower mean total cost per day of $117 (p = 0.13) compared to SC. In the final 30 days of life, patients in the early PC group incurred higher hospice care costs (mean difference = $1,053; p = 0.07), while expenses for chemotherapy were less (mean difference = $757; p = 0.03). Costs for emergency department visits and hospitalizations did not differ significantly between groups over the course of the study or at the end of life. CONCLUSIONS: The delivery of early PC does not appear to increase overall medical care expenses for patients with metastatic NSCLC. Larger, sufficiently powered cost studies of early PC are needed.

Evaluating the impacts of screening and smoking cessation programmes on lung cancer in a high-burden region of the USA: a simulation modelling study.

OBJECTIVE: While the US Preventive Services Task Force has issued recommendations for lung cancer screening, its effectiveness at reducing lung cancer burden may vary at local levels due to regional variations in smoking behaviour. Our objective was to use an existing model to determine the impacts of lung cancer screening alone or in addition to increased smoking cessation in a US region with a relatively high smoking prevalence and lung cancer incidence. SETTING: Computer-based simulation model. PARTICIPANTS: Simulated population of individuals 55 and older based on smoking prevalence and census data from Northeast Pennsylvania. INTERVENTIONS: Hypothetical lung cancer control from 2014 to 2050 through (1) screening with CT, (2) intensified smoking cessation or (3) a combination strategy. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were lung cancer mortality rates. Secondary outcomes included number of people eligible for screening and number of radiation-induced lung cancers. RESULTS: Combining lung cancer screening with increased smoking cessation would yield an estimated 8.1% reduction in cumulative lung cancer mortality by 2050. Our model estimated that the number of screening-eligible individuals would progressively decrease over time, indicating declining benefit of a screening-only programme. Lung cancer screening achieved a greater mortality reduction in earlier years, but was later surpassed by smoking cessation. CONCLUSIONS: Combining smoking cessation programmes with lung cancer screening would provide the most benefit to a population, especially considering the growing proportion of patients ineligible for screening based on current recommendations.

Combined Biomarker and Computed Tomography Screening Strategies for Lung Cancer: Projections of Health and Economic Tradeoffs in the US Population.

BACKGROUND: Lung cancer screening with computed tomography (CT) of individuals who meet certain age and smoking history criteria is the current standard-of-care. METHODS: Using a published simulation model, we compared outcomes associated with seven biomarker+CT screening strategies to CT screening alone using CMS eligibility criteria. We assumed that the biomarker: had conditionally independent performance; was used for first-line screening in some, or all, individuals screened; and could be extended to CMS-ineligible smokers. Strategies differed by inclusion criteria (e.g. pack-years) and proportion of individuals for whom CT remained the first-line test. Each model run simulated a combined cohort of one million men and one million women born in 1950. Primary outcomes were cancer-specific mortality reduction and screening costs; biomarker costs were measured relative to CT. Efficiency frontiers identified optimal health and economic trade-offs. Sensitivity analysis evaluated the stability of results. RESULTS: Standard-of-care screening yielded an 8.3% cancer-specific mortality reduction in the simulated U.S. population (screened+unscreened individuals). For a biomarker test with 75% sensitivity and 95% specificity, mortality reductions across biomarker+CT strategies ranged from 7.0% to 23.9%. If the biomarker's cost was >0.86× that of CT, standard-of-care screening remained on the efficiency frontier, indicating that health and economic trade-offs were equally (or more) efficient relative to all biomarker+CT strategies. Biomarker+CT strategy costs were principally driven by biomarker specificity; mortality reduction was driven by sensitivity. CONCLUSION: Combined biomarker+CT strategies have the potential to improve future lung cancer screening effectiveness in the U.S. and achieve economic efficiency that is greater than the current standard-of-care.

Protocol to Clear Cervical Spine Injuries in Pediatric Trauma Patients.

In order to minimize the amount of ionizing radiation to which young trauma patients are subjected, a cervical spine clearance project was implemented. The aim was to increase the number of pediatric trauma patients clinically cleared and decrease the number of such patients undergoing cervical spine CT imaging when they met clinical clearance criteria. To accomplish the goals, a brief education program about the epidemiology of pediatric cervical spine injuries, radiation exposure risks, and safe and effective means available for cervical spine clearance to pediatric trauma providers was delivered. This was made possible through funds awarded by the AHRA & Toshiba Putting Patients First grant. Mean knowledge scores after the program increased significantly for all groups of providers. This study showed that after implementation of the cervical spine clinical clearance protocol, there was an increase of 35.7% in the number of patients who were clinically cleared based on the protocol's criteria. Additionally, a 24%. decrease was seen in the number of pediatric patients undergoing CT scans of the cervical spine when they met criteria for clinical clearance of the cervical spine.

Personalizing annual lung cancer screening for patients with chronic obstructive pulmonary disease: A decision analysis.

BACKGROUND: Lung cancer screening with annual chest computed tomography (CT) is recommended for current and former smokers with a ≥30-pack-year smoking history. Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lung cancer and may benefit from screening at lower pack-year thresholds. METHODS: We used a previously validated simulation model to compare the health benefits of lung cancer screening in current and former smokers ages 55-80 with ≥30 pack-years with hypothetical programs using lower pack-year thresholds for individuals with COPD (≥20, ≥10, and ≥1 pack-years). Calibration targets for COPD prevalence and associated lung cancer risk were derived using the Framingham Offspring Study limited data set. We performed sensitivity analyses to evaluate the stability of results across different rates of adherence to screening, increased competing mortality risk from COPD, and increased surgical ineligibility in individuals with COPD. The primary outcome was projected life expectancy. RESULTS: Programs using lower pack-year thresholds for individuals with COPD yielded the highest life expectancy gains for a given number of screens. Highest life expectancy was achieved when lowering the pack-year threshold to ≥1 pack-year for individuals with COPD, which dominated all other screening strategies. These results were stable across different adherence rates to screening and increases in competing mortality risk for COPD and surgical ineligibility. CONCLUSIONS: Current and former smokers with COPD may disproportionately benefit from lung cancer screening. A lower pack-year threshold for screening eligibility may benefit this high-risk patient population.

Catalog and comparison of societal preferences (utilities) for lung cancer health states: results from the Cancer Care Outcomes Research and Surveillance (CanCORS) study.

BACKGROUND: The EQ-5D and SF-6D are 2 health-related quality-of-life indexes that provide preference-weighted measures for use in cost-effectiveness analyses. METHODS: The National Cancer Institute's Cancer Care Outcomes Research and Surveillance (CanCORS) Consortium included the EQ-5D and SF-12v2 in their survey of newly diagnosed lung cancer patients. Utilities were calculated from patient-provided scores for each domain of the EQ-5D or the SF-6D. Utilities were calculated for categories of cancer type, stage, and treatment. RESULTS: There were 5015 enrolled lung cancer patients with a baseline survey in CanCORS; 2396 (47.8%) completed the EQ-5D, and 2344 (46.7%) also completed the SF-12v2. The mean (standard deviation) utility from the EQ-5D was 0.78 (0.18), and from the SF-6D (derived from SF-12v2) was 0.68 (0.14). The EQ-5D demonstrated a ceiling effect, with 20% of patients reporting perfect scores, translating to a utility of 1.0. No substantial SF-6D floor effects were noted. Utilities increased with age and decreased with stage and comorbidities. Patient-reported (EQ-5D) visual analog scale scores for health status had a moderate (r = 0.48, p < 0.0001) positive correlation with utilities. A subset (n = 1474) completed follow-up EQ-5D questionnaires 11-13 months after diagnosis. Among these patients, there was a nonsignificant decrease in mean utility for stage IV and an increase in mean utility for stages I, II, and III. CONCLUSION: This study generated a catalog of community-weighted utilities applicable to societal-perspective cost-effectiveness analyses of lung cancer interventions and compared utilities based on the EQ-5D and SF-6D. Potential users of these scores should be aware of the limitations and think carefully about their use in specific studies.

Comparing benefits from many possible computed tomography lung cancer screening programs: extrapolating from the National Lung Screening Trial using comparative modeling.

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that in current and former smokers aged 55 to 74 years, with at least 30 pack-years of cigarette smoking history and who had quit smoking no more than 15 years ago, 3 annual computed tomography (CT) screens reduced lung cancer-specific mortality by 20% relative to 3 annual chest X-ray screens. We compared the benefits achievable with 576 lung cancer screening programs that varied CT screen number and frequency, ages of screening, and eligibility based on smoking. METHODS AND FINDINGS: We used five independent microsimulation models with lung cancer natural history parameters previously calibrated to the NLST to simulate life histories of the US cohort born in 1950 under all 576 programs. 'Efficient' (within model) programs prevented the greatest number of lung cancer deaths, compared to no screening, for a given number of CT screens. Among 120 'consensus efficient' (identified as efficient across models) programs, the average starting age was 55 years, the stopping age was 80 or 85 years, the average minimum pack-years was 27, and the maximum years since quitting was 20. Among consensus efficient programs, 11% to 40% of the cohort was screened, and 153 to 846 lung cancer deaths were averted per 100,000 people. In all models, annual screening based on age and smoking eligibility in NLST was not efficient; continuing screening to age 80 or 85 years was more efficient. CONCLUSIONS: Consensus results from five models identified a set of efficient screening programs that include annual CT lung cancer screening using criteria like NLST eligibility but extended to older ages. Guidelines for screening should also consider harms of screening and individual patient characteristics.

Cost-effectiveness of follow-up of pulmonary nodules incidentally detected on cardiac computed tomographic angiography in patients with suspected coronary artery disease.

BACKGROUND: Pulmonary nodules (PNs) are often detected incidentally during coronary computed tomographic (CT) angiography, which is increasingly being used to evaluate patients with chest pain symptoms. However, the efficiency of following up on incidentally detected PN is unknown. METHODS AND RESULTS: We determined demographic and clinical characteristics of stable symptomatic patients referred for coronary CT angiography in whom incidentally detected PNs warranted follow-up. A validated lung cancer simulation model was populated with data from these patients, and clinical and economic consequences of follow-up per Fleischner guidelines versus no follow-up were simulated. Of the 3665 patients referred for coronary CT angiography, 591 (16%) had PNs requiring follow-up. The mean age of patients with PNs was 59±10 years; 66% were male; 67% had ever smoked; and 21% had obstructive coronary artery disease. The projected overall lung cancer incidence was 5.8% in these patients, but the majority died of coronary artery disease (38%) and other causes (57%). Follow-up of PNs was associated with a 4.6% relative reduction in cumulative lung cancer mortality (absolute mortality: follow-up, 4.33% versus non-follow-up, 4.54%), more downstream testing (follow-up, 2.34 CTs per patient versus non-follow-up, 1.01 CTs per patient), and an average increase in quality-adjusted life of 7 days. Costs per quality-adjusted life-year gained were $154 700 to follow up the entire cohort and $129 800 per quality-adjusted life-year when only smokers were included. CONCLUSIONS: Follow-up of PNs incidentally detected in patients undergoing coronary CT angiography for chest pain evaluation is associated with a small reduction in lung cancer mortality. However, significant downstream testing contributes to limited efficiency, as demonstrated by a high cost per quality-adjusted life-year, especially in nonsmokers.

Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.

BACKGROUND: The National Lung Screening Trial (NLST) demonstrated that low-dose computed tomography screening is an effective way of reducing lung cancer (LC) mortality. However, optimal screening strategies have not been determined to date and it is uncertain whether lighter smokers than those examined in the NLST may also benefit from screening. To address these questions, it is necessary to first develop LC natural history models that can reproduce NLST outcomes and simulate screening programs at the population level. METHODS: Five independent LC screening models were developed using common inputs and calibration targets derived from the NLST and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Imputation of missing information regarding smoking, histology, and stage of disease for a small percentage of individuals and diagnosed LCs in both trials was performed. Models were calibrated to LC incidence, mortality, or both outcomes simultaneously. RESULTS: Initially, all models were calibrated to the NLST and validated against PLCO. Models were found to validate well against individuals in PLCO who would have been eligible for the NLST. However, all models required further calibration to PLCO to adequately capture LC outcomes in PLCO never-smokers and light smokers. Final versions of all models produced incidence and mortality outcomes in the presence and absence of screening that were consistent with both trials. CONCLUSIONS: The authors developed 5 distinct LC screening simulation models based on the evidence in the NLST and PLCO. The results of their analyses demonstrated that the NLST and PLCO have produced consistent results. The resulting models can be important tools to generate additional evidence to determine the effectiveness of lung cancer screening strategies using low-dose computed tomography.

Annual financial impact of well-differentiated thyroid cancer care in the United States.

BACKGROUND: Well-differentiated thyroid cancer (WDTC) is a prevalent disease, which is increasing in incidence faster than any other cancer. Substantial direct medical care costs are related to the diagnosis and treatment of newly diagnosed patients as well as the ongoing surveillance of patients who have a long life expectancy. Prior analyses of the aggregate health care costs attributable to WDTC in the United States have not been reported. METHODS: A stacked cohort cost analysis was performed on the US population from 1985 to 2013 to estimate the number of WDTC survivors in 2013. Incidence rates, and cancer-specific and overall survival were based on Surveillance, Epidemiology, and End Results (SEER) data. Current and projected direct medical care costs attributable to the care of patients with WDTC were then estimated. Health care-related costs and event probabilities were based on Medicare reimbursement schedules and the literature. RESULTS: Estimated overall societal cost of WDTC care in 2013 for all US patients diagnosed after 1985 is $1.6 billion. Diagnosis, surgery, and adjuvant therapy for newly diagnosed patients (41%) constitutes the greatest proportion of costs, followed by surveillance of survivors (37%), and nonoperative death costs attributable to thyroid cancer care (22%). Projected 2030 costs (in 2013 US dollars) based on current incidence trends exceed $3.5 billion. CONCLUSIONS: Health care costs of WDTC are substantial. Unlike other cancers, the majority of the cost is incurred in the initial and continuing phases of care. With the projected increasing incidence, population, and survival trends, costs will continue to escalate.

Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force.

BACKGROUND: The optimum screening policy for lung cancer is unknown. OBJECTIVE: To identify efficient computed tomography (CT) screening scenarios in which relatively more lung cancer deaths are averted for fewer CT screening examinations. DESIGN: Comparative modeling study using 5 independent models. DATA SOURCES: The National Lung Screening Trial; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial; the Surveillance, Epidemiology, and End Results program; and the U.S. Smoking History Generator. TARGET POPULATION: U.S. cohort born in 1950. TIME HORIZON: Cohort followed from ages 45 to 90 years. PERSPECTIVE: Societal. INTERVENTION: 576 scenarios with varying eligibility criteria (age, pack-years of smoking, years since quitting) and screening intervals. OUTCOME MEASURES: Benefits included lung cancer deaths averted or life-years gained. Harms included CT examinations, false-positive results (including those obtained from biopsy/surgery), overdiagnosed cases, and radiation-related deaths. RESULTS OF BEST-CASE SCENARIO: The most advantageous strategy was annual screening from ages 55 through 80 years for ever-smokers with a smoking history of at least 30 pack-years and ex-smokers with less than 15 years since quitting. It would lead to 50% (model ranges, 45% to 54%) of cases of cancer being detected at an early stage (stage I/II), 575 screening examinations per lung cancer death averted, a 14% (range, 8.2% to 23.5%) reduction in lung cancer mortality, 497 lung cancer deaths averted, and 5250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive test results, 910 biopsies or surgeries for benign lesions, and 190 overdiagnosed cases of cancer (3.7% of all cases of lung cancer [model ranges, 1.4% to 8.3%]). RESULTS OF SENSITIVITY ANALYSIS: The number of cancer deaths averted for the scenario varied across models between 177 and 862; the number of overdiagnosed cases of cancer varied between 72 and 426. LIMITATIONS: Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to lifetime follow-up. CONCLUSION: Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-years' exposure to smoking. PRIMARY FUNDING SOURCE: National Cancer Institute.

Observation versus initial treatment for men with localized, low-risk prostate cancer: a cost-effectiveness analysis.

BACKGROUND: Observation is underutilized among men with localized, low-risk prostate cancer. OBJECTIVE: To assess the costs and benefits of observation versus initial treatment. DESIGN: Decision analysis simulating treatment or observation. DATA SOURCES: Medicare schedules, published literature. TARGET POPULATION: Men aged 65 and 75 years who had newly diagnosed low-risk prostate cancer (prostate-specific antigen level <10 µg/L, stage ≤T2a, Gleason score ≤3 + 3). TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Treatment (brachytherapy, intensity-modulated radiation therapy, or radical prostatectomy) or observation (active surveillance [AS] or watchful waiting [WW]). OUTCOME MEASURES: Quality-adjusted life expectancy and costs. RESULTS OF BASE-CASE ANALYSIS: Observation was more effective and less costly than initial treatment. Compared with AS, WW provided 2 additional months of quality-adjusted life expectancy (9.02 vs. 8.85 years) at a savings of $15,374 ($24,520 vs. $39,894) in men aged 65 years and 2 additional months (6.14 vs. 5.98 years) at a savings of $11,746 ($18,302 vs. $30,048) in men aged 75 years. Brachytherapy was the most effective and least expensive initial treatment. RESULTS OF SENSITIVITY ANALYSIS: Treatment became more effective than observation when it led to more dramatic reductions in prostate cancer death (hazard ratio, 0.47 vs. WW and 0.64 vs. AS). Active surveillance became as effective as WW in men aged 65 years when the probability of progressing to treatment on AS decreased below 63% or when the quality of life with AS versus WW was 4% higher in men aged 65 years or 1% higher in men aged 75 years. Watchful waiting remained least expensive in all analyses. LIMITATION: Results depend on outcomes reported in the published literature, which is limited. CONCLUSION: Among these men, observation is more effective and costs less than initial treatment, and WW is most effective and least expensive under a wide range of clinical scenarios. PRIMARY FUNDING SOURCE: National Cancer Institute, U.S. Department of Defense, Prostate Cancer Foundation, and Institute for Clinical and Economic Review.

Microsimulation model predicts survival benefit of radiofrequency ablation and stereotactic body radiotherapy versus radiotherapy for treating inoperable stage I non-small cell lung cancer.

OBJECTIVE: A subset of patients with stage IA and IB non-small cell lung cancer (NSCLC) is ineligible for surgical resection and undergoes radiation therapy. Radiofrequency ablation (RFA) and stereotactic body radiotherapy are newer potentially attractive alternative therapies. MATERIALS AND METHODS: We added RFA and stereotactic body radiotherapy treatment modules to a microsimulation model that simulates lung cancer's natural history, detection, and treatment. Natural history parameters were previously estimated via calibration against tumor registry data and cohort studies; the model was validated with screening study and cohort data. RFA model parameters were calibrated against 2-year survival from the Radiofrequency Ablation of Pulmonary Tumor Response Evaluation (RAPTURE) study, and stereotactic body radiotherapy model parameters were calibrated against 3-year survival from a phase 2 prospective trial. We simulated lifetime histories of identical patients with early-stage NSCLC who were ineligible for resection, who were treated with radiation therapy, RFA, or stereotactic body radiotherapy under a range of scenarios. From 5,000,000 simulated individuals, we selected a cohort of patients with stage I medically inoperable cancer for analysis (n = 2056 per treatment scenario). Main outcomes were life expectancy gains. RESULTS: RFA or stereotactic body radiotherapy treatment in patients with peripheral stage IA or IB NSCLC who were nonoperative candidates resulted in life expectancy gains of 1.71 and 1.46 life-years, respectively, compared with universal radiation therapy. A strategy where patients with central tumors underwent stereotactic body radiotherapy and those with peripheral tumors underwent RFA resulted in a gain of 2.02 life-years compared with universal radiation therapy. Findings were robust with respect to changes in model parameters. CONCLUSION: Microsimulation modeling results suggest that RFA and stereotactic body radiotherapy could provide life expectancy gains to patients with stage IA or IB NSCLC who are ineligible for resection.

Cost-effectiveness of alternating magnetic resonance imaging and digital mammography screening in BRCA1 and BRCA2 gene mutation carriers.

BACKGROUND: Current clinical guidelines recommend earlier, more intensive breast cancer screening with both magnetic resonance imaging (MRI) and mammography for women with breast cancer susceptibility gene (BRCA) mutations. Unspecified details of screening schedules are a challenge for implementing guidelines. METHODS: A Markov Monte Carlo computer model was used to simulate screening in asymptomatic women who were BRCA1 and BRCA2 mutation carriers. Three dual-modality strategies were compared with digital mammography (DM) alone: 1) DM and MRI alternating at 6-month intervals beginning at age 25 years (Alt25), 2) annual MRI beginning at age 25 years with alternating DM added at age 30 years (MRI25/Alt30), and 3) DM and MRI alternating at 6-month intervals beginning at age 30 years (Alt30). Primary outcomes were quality-adjusted life years (QALYs), lifetime costs (in 2010 US dollars), and incremental cost-effectiveness (dollars per QALY gained). Additional outcomes included potential harms of screening, and lifetime costs stratified into component categories (screening and diagnosis, treatment, mortality, and patient time costs). RESULTS: All 3 dual-modality screening strategies increased QALYs and costs. Alt30 screening had the lowest incremental costs per additional QALY gained (BRCA1, $74,200 per QALY; BRCA2, $215,700 per QALY). False-positive test results increased substantially with dual-modality screening and occurred more frequently in BRCA2 carriers. Downstream savings in both breast cancer treatment and mortality costs were outweighed by increases in up-front screening and diagnosis costs. The results were influenced most by estimates of breast cancer risk and MRI costs. CONCLUSIONS: Alternating MRI and DM screening at 6-month intervals beginning at age 30 years was identified as a clinically effective approach to applying current guidelines, and was more cost-effective in BRCA1 gene mutation carriers compared with BRCA2 gene mutation carriers.

Chapter 9: The MGH-HMS lung cancer policy model: tobacco control versus screening.

The natural history model underlying the MGH Lung Cancer Policy Model (LCPM) does not include the two-stage clonal expansion model employed in other CISNET lung models. We used the LCPM to predict numbers of U.S. lung cancer deaths for ages 30-84 between 1975 and 2000 under four scenarios as part of the comparative modeling analysis described in this issue. The LCPM is a comprehensive microsimulation model of lung cancer development, progression, detection, treatment, and survival. Individual-level patient histories are aggregated to estimate cohort or population-level outcomes. Lung cancer states are defined according to underlying disease variables, test results, and clinical events. By simulating detailed clinical procedures, the LCPM can predict benefits and harms attributable to a variety of patient management practices, including annual screening programs. Under the scenario of observed smoking patterns, predicted numbers of deaths from the calibrated LCPM were within 2% of observed over all years (1975-2000). The LCPM estimated that historical tobacco control policies achieved 28.6% (25.2% in men, 30.5% in women) of the potential reduction in U.S. lung cancer deaths had smoking had been eliminated entirely. The hypothetical adoption in 1975 of annual helical CT screening of all persons aged 55-74 with at least 30 pack-years of cigarette exposure to historical tobacco control would have yielded a proportion realized of 39.0% (42.0% in men, 33.3% in women). The adoption of annual screening would have prevented less than half as many lung cancer deaths as the elimination of cigarette smoking.