Benefits, harms, and costs of newborn genetic screening for hypertrophic cardiomyopathy: Estimates from the PreEMPT model.

PURPOSE: Population newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain. METHODS: We developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns. Those identified with pathogenic/likely pathogenic variants associated with increased risk of HCM underwent surveillance and recommended treatment, whereas in usual care, individuals with family histories of HCM underwent surveillance. RESULTS: In a cohort of 3.7 million newborns, newborn genetic screening would reduce HCM-related deaths through age 20 years by 44 (95% uncertainty interval [UI] = 10-103) however increase the numbers of children undergoing surveillance by 8127 (95% UI = 6308-9664). Compared with usual care, newborn genetic screening costs $267,000 per life year saved (95% UI, $106,000 to $919,000 per life year saved). CONCLUSION: Newborn genetic screening for HCM could prevent deaths but at a high cost and would require many healthy children to undergo surveillance. This study shows how modeling can provide insights into the tradeoffs between benefits and costs that will need to be considered as newborn genetic screening is more widely adopted.

The association of varying treatment thresholds of mepolizumab on asthma exacerbations in adults.

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited.Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use.Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period.Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

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-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.

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.

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.

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.

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.

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.

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.

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.

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.

Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis.

BACKGROUND: Although breast cancer screening with mammography and magnetic resonance imaging (MRI) is recommended for breast cancer-susceptibility gene (BRCA) mutation carriers, there is no current consensus on the optimal screening regimen. METHODS: The authors used a computer simulation model to compare 6 annual screening strategies (film mammography [FM], digital mammography [DM], FM and magnetic resonance imaging [MRI] or DM and MRI contemporaneously, and alternating FM/MRI or DM/MRI at 6-month intervals) beginning at ages 25 years, 30 years, 35 years, and 40 years, and 2 strategies of annual MRI with delayed alternating DM/FM versus clinical surveillance alone. Strategies were evaluated without and with mammography-induced breast cancer risk using 2 models of excess relative risk. Input parameters were obtained from the medical literature, publicly available databases, and calibration. RESULTS: Without radiation risk effects, alternating DM/MRI starting at age 25 years provided the highest life expectancy (BRCA1, 72.52 years, BRCA2, 77.63 years). When radiation risk was included, a small proportion of diagnosed cancers was attributable to radiation exposure (BRCA1, <2%; BRCA2, <4%). With radiation risk, alternating DM/MRI at age 25 years or annual MRI at age 25 years/delayed alternating DM at age 30 years was the most effective, depending on the radiation risk model used. Alternating DM/MRI starting at age 25 years also produced the highest number of false-positive screens per woman (BRCA1, 4.5 BRCA2, 8.1). CONCLUSIONS: Annual MRI at age 25 years/delayed alternating DM at age 30 years is probably the most effective screening strategy in BRCA mutation carriers. Screening benefits, associated risks, and personal acceptance of false-positive results should be considered in choosing the optimal screening strategy for individual women.

Using radiation risk models in cancer screening simulations: important assumptions and effects on outcome projections.

PURPOSE: To evaluate the effect of incorporating radiation risk into microsimulation (first-order Monte Carlo) models for breast and lung cancer screening to illustrate effects of including radiation risk on patient outcome projections. MATERIALS AND METHODS: All data used in this study were derived from publicly available or deidentified human subject data. Institutional review board approval was not required. The challenges of incorporating radiation risk into simulation models are illustrated with two cancer screening models (Breast Cancer Model and Lung Cancer Policy Model) adapted to include radiation exposure effects from mammography and chest computed tomography (CT), respectively. The primary outcome projected by the breast model was life expectancy (LE) for BRCA1 mutation carriers. Digital mammographic screening beginning at ages 25, 30, 35, and 40 years was evaluated in the context of screenings with false-positive results and radiation exposure effects. The primary outcome of the lung model was lung cancer-specific mortality reduction due to annual screening, comparing two diagnostic CT protocols for lung nodule evaluation. The Metropolis-Hastings algorithm was used to estimate the mean values of the results with 95% uncertainty intervals (UIs). RESULTS: Without radiation exposure effects, the breast model indicated that annual digital mammography starting at age 25 years maximized LE (72.03 years; 95% UI: 72.01 years, 72.05 years) and had the highest number of screenings with false-positive results (2.0 per woman). When radiation effects were included, annual digital mammography beginning at age 30 years maximized LE (71.90 years; 95% UI: 71.87 years, 71.94 years) with a lower number of screenings with false-positive results (1.4 per woman). For annual chest CT screening of 50-year-old females with no follow-up for nodules smaller than 4 mm in diameter, the lung model predicted lung cancer-specific mortality reduction of 21.50% (95% UI: 20.90%, 22.10%) without radiation risk and 17.75% (95% UI: 16.97%, 18.41%) with radiation risk. CONCLUSION: Because including radiation exposure risk can influence long-term projections from simulation models, it is important to include these risks when conducting modeling-based assessments of diagnostic imaging.

Chapter 13: CISNET lung models: comparison of model assumptions and model structures.

Sophisticated modeling techniques can be powerful tools to help us understand the effects of cancer control interventions on population trends in cancer incidence and mortality. Readers of journal articles are, however, rarely supplied with modeling details. Six modeling groups collaborated as part of the National Cancer Institute's Cancer Intervention and Surveillance Modeling Network (CISNET) to investigate the contribution of U.S. tobacco-control efforts toward reducing lung cancer deaths over the period 1975-2000. The six models included in this monograph were developed independently and use distinct, complementary approaches toward modeling the natural history of lung cancer. The models used the same data for inputs, and agreed on the design of the analysis and the outcome measures. This article highlights aspects of the models that are most relevant to similarities of or differences between the results. Structured comparisons can increase the transparency of these complex models.

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.

Chapter 3: Cohort life tables by smoking status, removing lung cancer as a cause of death.

The purpose of this study was to develop life tables by smoking status removing lung cancer as a cause of death. These life tables are inputs to studies that compare the effectiveness of lung cancer treatments or interventions, and provide a way to quantify time until death from causes other than lung cancer. The study combined actuarial and statistical smoothing methods, as well as data from multiple sources, to develop separate life tables by smoking status, birth cohort, by single year of age, and by sex. For current smokers, separate life tables by smoking quintiles were developed based on the average number of cigarettes smoked per day by birth cohort. The end product is the creation of six non-lung-cancer life tables for males and six tables for females: five current smoker quintiles and one for never smokers. Tables for former smokers are linear combinations of the appropriate table based on the current smoker quintile before quitting smoking and the never smoker probabilities, plus added covariates for the smoking quit age and time since quitting.

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.

Lung cancer treatment costs, including patient responsibility, by disease stage and treatment modality, 1992 to 2003.

OBJECTIVES: The objective of this analysis was to estimate costs for lung cancer care and evaluate trends in the share of treatment costs that are the responsibility of Medicare beneficiaries. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 1991-2003 for 60,231 patients with lung cancer were used to estimate monthly and patient-liability costs for clinical phases of lung cancer (prediagnosis, staging, initial, continuing, and terminal), stratified by treatment, stage, and non-small- versus small-cell lung cancer. Lung cancer-attributable costs were estimated by subtracting each patient's own prediagnosis costs. Costs were estimated as the sum of Medicare reimbursements (payments from Medicare to the service provider), co-insurance reimbursements, and patient-liability costs (deductibles and "co-payments" that are the patient's responsibility). Costs and patient-liability costs were fit with regression models to compare trends by calendar year, adjusting for age at diagnosis. RESULTS: The monthly treatment costs for a 72-year-old patient, diagnosed with lung cancer in 2000, in the first 6 months ranged from $2687 (no active treatment) to $9360 (chemo-radiotherapy); costs varied by stage at diagnosis and histologic type. Patient liability represented up to 21.6% of care costs and increased over the period 1992-2003 for most stage and treatment categories, even when care costs decreased or remained unchanged. The greatest monthly patient liability was incurred by chemo-radiotherapy patients, which ranged from $1617 to $2004 per month across cancer stages. CONCLUSIONS: Costs for lung cancer care are substantial, and Medicare is paying a smaller proportion of the total cost over time.