Multi-Modality Imaging for Prevention of Coronary Artery Disease and Myocardial Infarction in the General Population: Ready for Prime Time?

Cardiovascular disease (CVD) remains a leading cause of death and disability worldwide. Acute myocardial infarction (AMI) causes irreversible myocardial damage, heart failure, life-threatening arrythmias and sudden cardiac death (SCD), and is a main driver of CVD mortality and morbidity. To control the forecasted increase in CVD burden for both the individual and society, improved strategies for the prevention of AMI and SCD are required. Current prevention of AMI and SCD is directed towards risk-modifying interventions, guided by risk assessment using clinical risk prediction scores (CRPSs) and the coronary artery calcium score (CACS). Early detection of more advanced coronary artery disease (CAD), beyond risk assessment by CRPSs or CACS, is a promising strategy to allow personalized treatment for the improved prevention of AMI and SCD in the general population. We review evidence for further testing, beyond CRPSs and CACS, and therapies focusing on promising targets, including subclinical obstructive CAD, high-risk plaques, and silent myocardial ischemia. We also evaluate the potential of multi-modality imaging to enhance the conduction of adequately powered trials to provide high-quality evidence on the impact of add-on tests and therapies in the prevention of AMI and SCD in asymptomatic individuals. To conclude, we discuss the occurrence of AMI and SCD in individuals currently estimated to be at "low-risk" by the current strategy based on CRPSs, and methods to improve prevention of AMI and SCD in this "low-risk" population.

Early detection of obstructive coronary artery disease in the asymptomatic high-risk population: objectives and study design of the EARLY-SYNERGY trial.

BACKGROUND: Coronary artery disease (CAD) burden for society is expected to steeply increase over the next decade. Improved feasibility and efficiency of preventive strategies is necessary to flatten the curve. Acute myocardial infarction (AMI) is the main determinant of CAD-related mortality and morbidity, and predominantly occurs in individuals with more advanced stages of CAD causing subclinical myocardial ischemia (obstructive CAD; OCAD). Unfortunately, OCAD can remain subclinical until its destructive presentation with AMI or sudden death. Current primary preventive strategies are not designed to differentiate between non-OCAD and OCAD and the opportunity is missed to treat individuals with OCAD more aggressively. METHODS: EARLY-SYNERGY is a multicenter, randomized-controlled clinical trial in individuals with coronary artery calcium (CAC) presence to study (1.) the yield of cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) for early OCAD diagnosis and (2) whether early OCAD diagnosis improves outcomes. Individuals with CAC score ≥300 objectified in 2 population-based trials (ROBINSCA; ImaLife) are recruited for study participation. Eligible candidates are randomized 1:1 to cardiac magnetic resonance stress myocardial perfusion imaging (CMR-MPI) or no additional functional imaging. In the CMR-MPI arm, feedback on imaging results is provided to primary care provider and participant in case of guideline-based actionable findings. Participants are followed-up for clinical events, healthcare utilization and quality of life. CONCLUSIONS: EARLY-SYNERGY is the first randomized-controlled clinical trial designed to test the hypothesis that subclinical OCAD is widely present in the general at-risk population and that early differentiation of OCAD from non-OCAD followed by guideline-recommended treatment improves outcomes.

Personalising lung cancer screening: An overview of risk-stratification opportunities and challenges.

Randomised clinical trials have shown the efficacy of computed tomography lung cancer screening, initiating discussions on whether and how to implement population-based screening programs. Due to smoking behaviour being the primary risk-factor for lung cancer and part of the criteria for determining screening eligibility, lung cancer screening is inherently risk-based. In fact, the selection of high-risk individuals has been shown to be essential in implementing lung cancer screening in a cost-effective manner. Furthermore, studies have shown that further risk-stratification may improve screening efficiency, allow personalisation of the screening interval and reduce health disparities. However, implementing risk-based lung cancer screening programs also requires overcoming a number of challenges. There are indications that risk-based approaches can negatively influence the trade-off between individual benefits and harms if not applied thoughtfully. Large-scale implementation of targeted, risk-based screening programs has been limited thus far. Consequently, questions remain on how to efficiently identify and invite high-risk individuals from the general population. Finally, while risk-based approaches may increase screening program efficiency, efficiency should be balanced with the overall impact of the screening program. In this review, we will address the opportunities and challenges in applying risk-stratification in different aspects of lung cancer screening programs, as well as the balance between screening program efficiency and impact.

Implementation of lung cancer screening: what are the main issues?

Two large-scale RCTs have shown computed tomography (CT) lung cancer screening to be efficacious in reducing lung cancer mortality (8-24% in men, 26-59% in women). However, lung cancer screening implicitly means personalised and risk-based approaches. Health care systems' implementation of personalised screening and prevention is still sparse, and likely to be of variable quality, because of important remaining uncertainties, which have been incompletely addressed or not at all so far. Further optimisation of lung cancer screening programs is expected to reduce harms and maintain or enhance benefit for eligible European citizens, whilst significantly reducing health care costs. Some main uncertainties (e.g., Risk-based eligibility, Risk-based screening intervals, Volume CT screening, Smoking Cessation, Gender and Sex differences, Cost-Effectiveness) are discussed in this review. 4-IN-THE-LUNG-RUN (acronym for: Towards INdividually tailored INvitations, screening INtervals and INtegrated co-morbidity reducing strategies in lung cancer screening) is the first multi-centred implementation trial on volume CT lung cancer screening amongst 24,000 males and females, at high risk for developing lung cancer, across five European countries, started in January 2020. Through providing answers to the remaining questions with this trial, many EU citizens will swiftly benefit from this high-quality screening technology, others will face less harms than previously anticipated, and health care costs will be substantially reduced. Implementing a new cancer screening programme is a major task, with many stakeholders and many possible facilitators but also barriers and obstacle.

Lung cancer screening and smoking cessation efforts.

Randomized-controlled trials have confirmed substantial reductions in lung cancer mortality with low-dose computed tomography (LDCT) screening. Evidence on how to integrate smoking cessation support in lung cancer screening is however scarce. This represents a significant gap in the literature, as a combined strategy of lung cancer screening and smoking cessation greatly reduces the mortality risk due to lung cancer and other related comorbidities. In this review, a literature search in MEDLINE, Embase, Web of Science, the Cochrane Central Register of Controlled Trials and Google Scholar was performed to identify randomized-controlled and observational studies investigating the effect of lung cancer screening trials and integrated cessation interventions on smoking cessation. Of the 236 identified records, we included 32 original publications. Smoking cessation rates in lung cancer screening trials are promising. Especially findings suspicious for lung cancer and referral to a physician might function as a teachable moment to motivate smoking abstinence in current smokers or recent quitters. More intensive, personalized and multi-modality smoking cessation interventions delivered by a clinician appear to be the most successful in influencing smoking behavior. While it is evident that smoking cessation should be incorporated in lung cancer screening, further research is required to ascertain the optimal treatment type, modality, timing, and content of communication including the incorporation of CT results to motivate health behavior change.

Screening for cardiovascular disease risk using traditional risk factor assessment or coronary artery calcium scoring: the ROBINSCA trial.

AIMS: Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or coronary artery calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial. METHODS AND RESULTS: Individuals at expected elevated CVD risk were randomized into screening arm A (n = 14 478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n = 14 450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. A total of 12 185 participants (84.2%) in arm A and 12 950 (89.6%) in arm B were screened. In total, 48.7% were women, and median age was 62 (interquartile range 10) years. SCORE screening identified 45.1% at low risk (SCORE < 10%), 26.5% at intermediate risk (SCORE 10-20%), and 28.4% at high risk (SCORE ≥ 20%). According to CAC screening, 76.0% were at low risk (Agatston < 100), 15.1% at high risk (Agatston 100-399), and 8.9% at very high risk (Agatston ≥ 400). CAC scoring significantly reduced the number of individuals indicated for preventive treatment compared to SCORE (relative reduction women: 37.2%; men: 28.8%). CONCLUSION: We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. TRIAL REGISTRATION NUMBER: NTR6471.

Coronary artery calcium scoring in individuals at risk for coronary artery disease: current status and future perspectives.

The aim of this review is to provide clinicians with an overview of the role of coronary artery calcium (CAC) scoring across the spectrum ranging from asymptomatic individuals to chronic chest pain patients. We will briefly introduce the technical background of CAC scoring, summarize the major guidelines per type of patient at risk and discuss latest research with respect to CAC. Finally, the reader should be able to determine when CAC scoring is indicated or may be of added value.

Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.

BACKGROUND: There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers. METHODS: A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants. RESULTS: Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9. CONCLUSIONS: In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

New Fissure-Attached Nodules in Lung Cancer Screening: A Brief Report From The NELSON Study.

INTRODUCTION: In incidence lung cancer screening rounds, new pulmonary nodules are regular findings. They have a higher lung cancer probability than baseline nodules. Previous studies have shown that baseline perifissural nodules (PFNs) represent benign lesions. Whether this is also the case for incident PFNs is unknown. This study evaluated newly detected nodules in the Dutch-Belgian randomized-controlled NELSON study with respect to incidence of fissure-attached nodules, their classification, and lung cancer probability. METHODS: Within the NELSON trial, 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new nodules detected after baseline were included. Nodules were classified based on location and attachment. Fissure-attached nodules were re-evaluated to be classified as typical, atypical, or non-PFN by two radiologists without knowledge of participant lung cancer status. RESULTS: One thousand four hundred eighty-four new nodules were detected in 949 participants (77.4% male, median age 59 years [interquartile range: 55-63 years]) in the second, third, and final NELSON screening round. Based on 2-year follow-up or pathology, 1393 nodules (93.8%) were benign. In total, 97 (6.5%) were fissure-attached, including 10 malignant nodules. None of the new fissure-attached malignant nodules was classified as typical or atypical PFN. CONCLUSIONS: In the NELSON study, 6.5% of incident lung nodules were fissure-attached. None of the lung cancers that originated from a new fissure-attached nodule in the incidence lung cancer screening rounds was classified as a typical or atypical PFN. Our results suggest that also in the case of a new PFN, it is highly unlikely that these PFNs will be diagnosed as lung cancer.

Impact of a cardiovascular disease risk screening result on preventive behaviour in asymptomatic participants of the ROBINSCA trial.

INTRODUCTION: A teachable moment for preventive behavioural change can occur when asymptomatic individuals receive their cardiovascular disease screening result. This study investigated prevention-seeking behaviour and compliance with preventive treatment of participants of the population-based Risk Or Benefit IN Screening for CArdiovascular disease (ROBINSCA) trial after receiving a screening result. METHODS: Asymptomatic Dutch individuals (n = 43,447) were randomly assigned (1:1:1) to screening for cardiovascular disease by either traditional risk assessment (intervention arm A), or determining the amount of coronary artery calcification (intervention arm B), or to usual care (control arm). A random sample (n = 600) of ROBINSCA participants with a screening result (arms A and B) received an online questionnaire (in 2017) to measure the impact of a cardiovascular disease screening result in low and increased (arm A: risk > 10%; arm B: Agatston ≥ 100) risk groups. RESULTS: Of all respondents (438/600; 73%) 63.5% were men and the mean age ( ± standard deviation) was 63.8 ± 6.9 years. Individuals with an increased coronary artery calcification score consulted their general practitioner more often compared to increased risk individuals from arm A: 140/149 (94%) and 86/137 (62.8%), respectively (P < 0.001). Current use of blood pressure and cholesterol-lowering drugs was significantly higher in the increased coronary artery calcification score group (108/140; 77.1%), compared to the group with an increased traditional risk (35/80, 43.8%; P < 0.001). Self-reported compliance was high (98.1-100%). CONCLUSION: Receiving the screening result might be a teachable moment that can enhance cardiovascular disease prevention-seeking behaviour through consulting a general practitioner and high compliance with preventive treatment. The impact of the screening result was more profound in the increased coronary artery calcification score group. Trial registration number: NTR6471.

Persisting new nodules in incidence rounds of the NELSON CT lung cancer screening study.

BACKGROUND: The US guidelines recommend low-dose CT (LDCT) lung cancer screening for high-risk individuals. New solid nodules after baseline screening are common and have a high lung cancer probability. Currently, no evidence exists concerning the risk stratification of non-resolving new solid nodules at first LDCT screening after initial detection. METHODS: In the Dutch-Belgian Randomized Lung Cancer Screening (NELSON) trial, 7295 participants underwent the second and 6922 participants the third screening round. We included participants with solid nodules that were registered as new or <15 mm³ (study detection limit) at previous screens and received additional screening after initial detection, thereby excluding high-risk nodules according to the NELSON management protocol (nodules ≥500 mm3). RESULTS: Overall, 680 participants with 1020 low-risk and intermediate-risk new solid nodules were included. A total of 562 (55%) new solid nodules were resolving, leaving 356 (52%) participants with a non-resolving new solid nodule, of whom 25 (7%) were diagnosed with lung cancer. At first screening after initial detection, volume doubling time (VDT), volume, and VDT combined with a predefined ≥200 mm3 volume cut-off had high discrimination for lung cancer (VDT, area under the curve (AUC): 0.913; volume, AUC: 0.875; VDT and ≥200 mm3 combination, AUC: 0.939). Classifying a new solid nodule with either ≤590 days VDT or ≥200 mm3 volume positive provided 100% sensitivity, 84% specificity and 27% positive predictive value for lung cancer. CONCLUSIONS: More than half of new low-risk and intermediate-risk solid nodules in LDCT lung cancer screening resolve. At follow-up, growth assessment potentially combined with a volume limit can be used for risk stratification. TRIAL REGISTRATION NUMBER: ISRCTN63545820; pre-results.

Relationship between the number of new nodules and lung cancer probability in incidence screening rounds of CT lung cancer screening: The NELSON study.

BACKGROUND: New nodules are regularly found after the baseline round of low-dose computed tomography (LDCT) lung cancer screening. The relationship between a participant's number of new nodules and lung cancer probability is unknown. METHODS: Participants of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial with (sub)solid nodules detected after baseline and registered as new by the NELSON radiologists were included. The correlation between a participant's new nodule count and the largest new nodule size was assessed using Spearman's rank correlation. To evaluate the new nodule count as predictor for new nodule lung cancer together with largest new nodule size, a multivariable logistic regression analysis was performed. RESULTS: In total, 705 participants with 964 new nodules were included. In 48% (336/705) of participants no nodule had been found previously during baseline screening and in 22% (154/705) of participants >1 new nodule was detected (range 1-12 new nodules). Eventually, 9% (65/705) of the participants had lung cancer in a new nodule. In 100% (65/65) of participants with new nodule lung cancer, the lung cancer was the largest or only new nodule at initial detection. The new nodule lung cancer probability did not differ significantly between participants with 1 (10% [56/551], 95%CI 8-13%) or >1 new nodule (6% [9/154], 95%CI 3-11%, P = .116). An increased number of new nodules positively correlated with a participant's largest nodule size (P < 0.001, Spearman's rho 0.177). When adjusted for largest new nodule size, the new nodule count had a significant negative association with lung cancer (odds ratio 0.59, 0.37-0.95, P = .03). CONCLUSION: A participant's new nodule count alone only has limited association with lung cancer. However, a higher new nodule count correlates with an increased largest new nodule size, while the lung cancer probability remains equivalent, and may improve lung cancer risk prediction by size only.

New Subsolid Pulmonary Nodules in Lung Cancer Screening: The NELSON Trial.

INTRODUCTION: Low-dose computed tomography (LDCT) lung cancer screening is recommended in the United States. While new solid nodules after baseline screening have a high lung cancer probability at small size and require lower size cutoff values than baseline nodules, there only is limited evidence on management of new subsolid nodules. METHODS: Within the Dutch-Belgian randomized controlled LDCT lung cancer screening trial (NELSON), 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new subsolid nodules detected after the baseline screening round were included. RESULTS: In the three incidence screening rounds, 60 new subsolid nodules (43 [72%] part-solid, 17 [28%] nonsolid) not visible in retrospect were detected in 51 participants, representing 0.7% (51 of 7295) of participants with at least one incidence screening. Eventually, 6% (3 of 51) of participants with a new subsolid nodule were diagnosed with (pre-)malignancy in such a nodule. All (pre-)malignancies were adenocarcinoma (in situ) and diagnostic workup (referral 950, 364, and 366 days after first detection, respectively) showed favorable staging (stage I). Overall, 67% (33 of 49) of subsolid nodules with an additional follow-up screening were resolving. CONCLUSIONS: Less than 1% of participants in LDCT lung cancer screening presents with a new subsolid nodule after baseline. Contrary to new solid nodules, data suggest that new subsolid nodules may not require a more aggressive follow-up.

High-pitch versus sequential mode for coronary calcium in individuals with a high heart rate: Potential for dose reduction.

BACKGROUND: To determine the impact of high-pitch spiral acquisition on radiation dose and cardiovascular disease (CVD) risk stratification by coronary artery calcium (CAC) assessment with computed tomography in individuals with a high heart rate. METHODS: Of the ROBINSCA trial, 1990 participants with regular rhythm and heart rates >65 beats per minute (bpm) were included. As reference, 390 participants with regular heart rates ≤65 bpm were used. All participants underwent prospectively electrocardiographically(ECG)-triggered imaging of the coronary arteries using dual source CT at 120 kVp, 80 ref mAs using both high-pitch spiral mode and sequential mode. Radiation dose, Agatston score, number of positive scores, as well as median absolute difference of the Agatston score were determined and participants were stratified into CVD risk categories. RESULTS: A similar percentage of participants with low heart rates and high heart rates had a positive CAC score in data sets acquired in high-pitch spiral (low heart rate: 57.7%, high heart rate: 55.8%) and sequential mode (58.0%, 54.7%, p = n.s.). The median absolute difference in Agatston scores between acquisition modes was 14.2% and 9.2%, for the high and low heart rate groups, respectively. Excellent agreement for risk categorization between the two data acquisition modes was found for the high (κ = 0.927) and low (κ = 0.946) heart rate groups. Radiation dose was 48% lower for high-pitch spiral versus sequential acquisitions. CONCLUSION: Radiation dose for the quantification of coronary calcium can be reduced by 48% when using the high-pitch spiral acquisition mode compared to the sequential mode in participants with a regular high heart rate. CVD risk stratification agreement between the two modes of data acquisition is excellent.

Coronary Artery Calcium Imaging in the ROBINSCA Trial: Rationale, Design, and Technical Background.

RATIONALE AND OBJECTIVES: To describe the rationale, design, and technical background of coronary artery calcium (CAC) imaging in the large-scale population-based cardiovascular disease screening trial (Risk Or Benefit IN Screening for CArdiovascular Diseases [ROBINSCA]). MATERIALS AND METHODS: First, literature search was performed to review the logistics, setup, and settings of previously performed CAC imaging studies, and current clinical CAC imaging protocols of participating centers in the ROBINSCA trial were evaluated. A second literature search was performed to evaluate the impact of computed tomography parameter settings on CAC score. RESULTS: Based on literature reviews and experts opinion an imaging protocol accompanied by data management protocol was created for ROBINSCA. The imaging protocol should consist of a fixed tube voltage, individually tailored tube current setting, mid-diastolic electrocardiography-triggering, fixed field-of-view, fixed reconstruction kernel, fixed slice thickness, overlapping reconstruction and without iterative reconstruction. The analysis of scans is performed with one type and version of CAC scoring software, by two dedicated and experienced researchers. The data management protocol describes the organization of data handling between the coordinating center, participating centers, and core analysis center. CONCLUSION: In this paper we describe the rationale and technical considerations to be taken in developing CAC imaging protocol, and we present a detailed protocol that can be implemented for CAC screening purposes.

Performance and Cost-Effectiveness of Computed Tomography Lung Cancer Screening Scenarios in a Population-Based Setting: A Microsimulation Modeling Analysis in Ontario, Canada.

BACKGROUND: The National Lung Screening Trial (NLST) results indicate that computed tomography (CT) lung cancer screening for current and former smokers with three annual screens can be cost-effective in a trial setting. However, the cost-effectiveness in a population-based setting with >3 screening rounds is uncertain. Therefore, the objective of this study was to estimate the cost-effectiveness of lung cancer screening in a population-based setting in Ontario, Canada, and evaluate the effects of screening eligibility criteria. METHODS AND FINDINGS: This study used microsimulation modeling informed by various data sources, including the Ontario Health Insurance Plan (OHIP), Ontario Cancer Registry, smoking behavior surveys, and the NLST. Persons, born between 1940 and 1969, were examined from a third-party health care payer perspective across a lifetime horizon. Starting in 2015, 576 CT screening scenarios were examined, varying by age to start and end screening, smoking eligibility criteria, and screening interval. Among the examined outcome measures were lung cancer deaths averted, life-years gained, percentage ever screened, costs (in 2015 Canadian dollars), and overdiagnosis. The results of the base-case analysis indicated that annual screening was more cost-effective than biennial screening. Scenarios with eligibility criteria that required as few as 20 pack-years were dominated by scenarios that required higher numbers of accumulated pack-years. In general, scenarios that applied stringent smoking eligibility criteria (i.e., requiring higher levels of accumulated smoking exposure) were more cost-effective than scenarios with less stringent smoking eligibility criteria, with modest differences in life-years gained. Annual screening between ages 55-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago yielded an incremental cost-effectiveness ratio of $41,136 Canadian dollars ($33,825 in May 1, 2015, United States dollars) per life-year gained (compared to annual screening between ages 60-75 for persons who smoked ≥40 pack-years and who currently smoke or quit ≤10 y ago), which was considered optimal at a cost-effectiveness threshold of $50,000 Canadian dollars ($41,114 May 1, 2015, US dollars). If 50% lower or higher attributable costs were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $38,240 ($31,444 May 1, 2015, US dollars) or $48,525 ($39,901 May 1, 2015, US dollars), respectively. If 50% lower or higher costs for CT examinations were assumed, the incremental cost-effectiveness ratio of this scenario was estimated to be $28,630 ($23,542 May 1, 2015, US dollars) or $73,507 ($60,443 May 1, 2015, US dollars), respectively. This scenario would screen 9.56% (499,261 individuals) of the total population (ever- and never-smokers) at least once, which would require 4,788,523 CT examinations, and reduce lung cancer mortality in the total population by 9.05% (preventing 13,108 lung cancer deaths), while 12.53% of screen-detected cancers would be overdiagnosed (4,282 overdiagnosed cases). Sensitivity analyses indicated that the overall results were most sensitive to variations in CT examination costs. Quality of life was not incorporated in the analyses, and assumptions for follow-up procedures were based on data from the NLST, which may not be generalizable to a population-based setting. CONCLUSIONS: Lung cancer screening with stringent smoking eligibility criteria can be cost-effective in a population-based setting.