Performance of Lung-RADS in different target populations: a systematic review and meta-analysis.

OBJECTIVES: Multiple lung cancer screening studies reported the performance of Lung CT Screening Reporting and Data System (Lung-RADS), but none systematically evaluated its performance across different populations. This systematic review and meta-analysis aimed to evaluate the performance of Lung-RADS (versions 1.0 and 1.1) for detecting lung cancer in different populations. METHODS: We performed literature searches in PubMed, Web of Science, Cochrane Library, and Embase databases on October 21, 2022, for studies that evaluated the accuracy of Lung-RADS in lung cancer screening. A bivariate random-effects model was used to estimate pooled sensitivity and specificity, and heterogeneity was explored in stratified and meta-regression analyses. RESULTS: A total of 31 studies with 104,224 participants were included. For version 1.0 (27 studies, 95,413 individuals), pooled sensitivity was 0.96 (95% confidence interval [CI]: 0.90-0.99) and pooled specificity was 0.90 (95% CI: 0.87-0.92). Studies in high-risk populations showed higher sensitivity (0.98 [95% CI: 0.92-0.99] vs. 0.84 [95% CI: 0.50-0.96]) and lower specificity (0.87 [95% CI: 0.85-0.88] vs. 0.95 (95% CI: 0.92-0.97]) than studies in general populations. Non-Asian studies tended toward higher sensitivity (0.97 [95% CI: 0.91-0.99] vs. 0.91 [95% CI: 0.67-0.98]) and lower specificity (0.88 [95% CI: 0.85-0.90] vs. 0.93 [95% CI: 0.88-0.96]) than Asian studies. For version 1.1 (4 studies, 8811 individuals), pooled sensitivity was 0.91 (95% CI: 0.83-0.96) and specificity was 0.81 (95% CI: 0.67-0.90). CONCLUSION: Among studies using Lung-RADS version 1.0, considerable heterogeneity in sensitivity and specificity was noted, explained by population type (high risk vs. general), population area (Asia vs. non-Asia), and cancer prevalence. CLINICAL RELEVANCE STATEMENT: Meta-regression of lung cancer screening studies using Lung-RADS version 1.0 showed considerable heterogeneity in sensitivity and specificity, explained by the different target populations, including high-risk versus general populations, Asian versus non-Asian populations, and populations with different lung cancer prevalence. KEY POINTS: • High-risk population studies showed higher sensitivity and lower specificity compared with studies performed in general populations by using Lung-RADS version 1.0. • In non-Asian studies, the diagnostic performance of Lung-RADS version 1.0 tended to be better than in Asian studies. • There are limited studies on the performance of Lung-RADS version 1.1, and evidence is lacking for Asian populations.

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.).

Contextualizing the Role of Volumetric Analysis in Pulmonary Nodule Assessment: AJR Expert Panel Narrative Review.

Pulmonary nodules are managed on the basis of their size and morphologic characteristics. Radiologists are familiar with assessing nodule size by measuring diameter using manually deployed electronic calipers. Size may also be assessed with 3D volumetric measurements (referred to as volumetry) obtained with software. Nodule size and growth are more accurately assessed with volumetry than on the basis of diameter, and the evidence supporting clinical use of volumetry has expanded, driven by its use in lung cancer screening nodule management algorithms in Europe. The application of volumetry has the potential to reduce recommendations for imaging follow-up of indeterminate solid nodules without impacting cancer detection. Although changes in scanning conditions and volumetry software packages can lead to variation in volumetry results, ongoing technical advances have improved the reliability of calculated volumes. Volumetry is now the primary method for determining size of solid nodules in the European lung cancer screening position statement and British Thoracic Society recommendations. The purposes of this article are to review technical aspects, advantages, and limitations of volumetry and, by considering specific scenarios, to contextualize the use of volumetry with respect to its importance in morphologic evaluation, its role in predicting malignancy in risk models, and its practical impact on nodule management. Implementation challenges and areas requiring further evidence are also highlighted.

Multi-source data approach for personalized outcome prediction in lung cancer screening: update from the NELSON trial.

Trials show that low-dose computed tomography (CT) lung cancer screening in long-term (ex-)smokers reduces lung cancer mortality. However, many individuals were exposed to unnecessary diagnostic procedures. This project aims to improve the efficiency of lung cancer screening by identifying high-risk participants, and improving risk discrimination for nodules. This study is an extension of the Dutch-Belgian Randomized Lung Cancer Screening Trial, with a focus on personalized outcome prediction (NELSON-POP). New data will be added on genetics, air pollution, malignancy risk for lung nodules, and CT biomarkers beyond lung nodules (emphysema, coronary calcification, bone density, vertebral height and body composition). The roles of polygenic risk scores and air pollution in screen-detected lung cancer diagnosis and survival will be established. The association between the AI-based nodule malignancy score and lung cancer will be evaluated at baseline and incident screening rounds. The association of chest CT imaging biomarkers with outcomes will be established. Based on these results, multisource prediction models for pre-screening and post-baseline-screening participant selection and nodule management will be developed. The new models will be externally validated. We hypothesize that we can identify 15-20% participants with low-risk of lung cancer or short life expectancy and thus prevent ~140,000 Dutch individuals from being screened unnecessarily. We hypothesize that our models will improve the specificity of nodule management by 10% without loss of sensitivity as compared to assessment of nodule size/growth alone, and reduce unnecessary work-up by 40-50%.

Association between Chest CT-defined Emphysema and Lung Cancer: A Systematic Review and Meta-Analysis.

Background Given the different methods of assessing emphysema, controversy exists as to whether it is associated with lung cancer. Purpose To perform a systematic review and meta-analysis of the association between chest CT-defined emphysema and the presence of lung cancer. Materials and Methods The PubMed, Embase, and Cochrane databases were searched up to July 15, 2021, to identify studies on the association between emphysema assessed visually or quantitatively with CT and lung cancer. Associations were determined by emphysema severity (trace, mild, or moderate to severe, assessed visually and quantitatively) and subtype (centrilobular and paraseptal, assessed visually). Overall and stratified pooled odds ratios (ORs) with their 95% CIs were obtained. Results Of the 3343 screened studies, 21 studies (107 082 patients) with 26 subsets were included. The overall pooled ORs for lung cancer given the presence of emphysema were 2.3 (95% CI: 2.0, 2.6; I2 = 35%; 19 subsets) and 1.02 (95% CI: 1.01, 1.02; six subsets) per 1% increase in low attenuation area. Studies with visual (pooled OR, 2.3; 95% CI: 1.9, 2.6; I2 = 48%; 12 subsets) and quantitative (pooled OR, 2.2; 95% CI: 1.8, 2.8; I2 = 3.7%; eight subsets) assessments yielded comparable results for the dichotomous assessment. Based on six studies (1716 patients), the pooled ORs for lung cancer increased with emphysema severity and were higher for visual assessment (2.5, 3.7, and 4.5 for trace, mild, and moderate to severe, respectively) than for quantitative assessment (1.9, 2.2, and 2.5) based on point estimates. Compared with no emphysema, only centrilobular emphysema (three studies) was associated with lung cancer (pooled OR, 2.2; 95% CI: 1.5, 3.2; P < .001). Conclusion Both visual and quantitative CT assessments of emphysema were associated with a higher odds of lung cancer, which also increased with emphysema severity. Regarding subtype, only centrilobular emphysema was significantly associated with lung cancer. Clinical trial registration no. CRD42021262163 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Hunsaker in this issue.

Low-dose computed tomography lung cancer screening: Clinical evidence and implementation research.

Lung cancer causes more deaths than breast, cervical, and colorectal cancer combined. Nevertheless, population-based lung cancer screening is still not considered standard practice in most countries worldwide. Early lung cancer detection leads to better survival outcomes: patients diagnosed with stage 1A lung cancer have a >75% 5-year survival rate, compared to <5% at stage 4. Low-dose computed tomography (LDCT) thorax imaging for the secondary prevention of lung cancer has been studied at length, and has been shown to significantly reduce lung cancer mortality in high-risk populations. The US National Lung Screening Trial reported a 20% overall reduction in lung cancer mortality when comparing LDCT to chest X-ray, and the Nederlands-Leuvens Longkanker Screenings Onderzoek (NELSON) trial more recently reported a 24% reduction when comparing LDCT to no screening. Hence, the focus has now shifted to implementation research. Consequently, the 4-IN-THE-LUNG-RUN consortium based in five European countries, has set up a large-scale multicenter implementation trial. Successful implementation of and accessibility to LDCT lung cancer screening are dependent on many factors, not limited to population selection, recruitment strategy, computed tomography screening frequency, lung-nodule management, participant compliance, and cost effectiveness. This review provides an overview of current evidence for LDCT lung cancer screening, and draws attention to major factors that need to be addressed to successfully implement standardized, effective, and accessible screening throughout Europe. Evidence shows that through the appropriate use of risk-prediction models and a more personalized approach to screening, efficacy could be improved. Furthermore, extending the screening interval for low-risk individuals to reduce costs and associated harms is a possibility, and through the use of volumetric-based measurement and follow-up, false positive results can be greatly reduced. Finally, smoking cessation programs could be a valuable addition to screening programs and artificial intelligence could offer a solution to the added workload pressures radiologists are facing.

Association between visual emphysema and lung nodules on low-dose CT scan in a Chinese Lung Cancer Screening Program (Nelcin-B3).

OBJECTIVES: This study aimed to evaluate the association between visual emphysema and the presence of lung nodules, and Lung-RADS category with low-dose CT (LDCT). METHODS: Baseline LDCT scans of 1162 participants from a lung cancer screening study (Nelcin-B3) performed in a Chinese general population were included. The presence, subtypes, and severity of emphysema (at least trace) were visually assessed by one radiologist. The presence, size, and classification of non-calcified lung nodules (≥ 30 mm3) and Lung-RADS category were independently assessed by another two radiologists. Multivariable logistic regression and stratified analyses were performed to estimate the association between emphysema and lung nodules, Lung-RADS category, after adjusting for age, sex, BMI, smoking status, pack-years, and passive smoking. RESULTS: Emphysema and lung nodules were observed in 674 (58.0%) and 424 (36.5%) participants, respectively. Participants with emphysema had a 71% increased risk of having lung nodules (adjusted odds ratios, aOR: 1.71, 95% CI: 1.26-2.31) and 70% increased risk of positive Lung-RADS category (aOR: 1.70, 95% CI: 1.09-2.66) than those without emphysema. Participants with paraseptal emphysema (n = 47, 4.0%) were at a higher risk for lung nodules than those with centrilobular emphysema (CLE) (aOR: 2.43, 95% CI: 1.32-4.50 and aOR: 1.60, 95% CI: 1.23-2.09, respectively). Only CLE was associated with positive Lung-RADS category (p = 0.02). CLE severity was related to a higher risk of lung nodules (ranges aOR: 1.44-2.61, overall p < 0.01). CONCLUSION: In a Chinese general population, visual emphysema based on LDCT is independently related to the presence of lung nodules (≥ 30 mm3) and specifically CLE subtype is related to positive Lung-RADS category. The risk of lung nodules increases with CLE severity. KEY POINTS: • Participants with emphysema had an increased risk of having lung nodules, especially smokers. • Participants with PSE were at a higher risk for lung nodules than those with CLE, but nodules in participants with CLE had a higher risk of positive Lung-RADS category. • The risk of lung nodules increases with CLE severity.

Early imaging biomarkers of lung cancer, COPD and coronary artery disease in the general population: rationale and design of the ImaLife (Imaging in Lifelines) Study.

Lung cancer, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD) are expected to cause most deaths by 2050. State-of-the-art computed tomography (CT) allows early detection of lung cancer and simultaneous evaluation of imaging biomarkers for the early stages of COPD, based on pulmonary density and bronchial wall thickness, and of CAD, based on the coronary artery calcium score (CACS), at low radiation dose. To determine cut-off values for positive tests for elevated risk and presence of disease is one of the major tasks before considering implementation of CT screening in a general population. The ImaLife (Imaging in Lifelines) study, embedded in the Lifelines study, is designed to establish the reference values of the imaging biomarkers for the big three diseases in a well-defined general population aged 45 years and older. In total, 12,000 participants will undergo CACS and chest acquisitions with latest CT technology. The estimated percentage of individuals with lung nodules needing further workup is around 1-2%. Given the around 10% prevalence of COPD and CAD in the general population, the expected number of COPD and CAD is around 1000 each. So far, nearly 4000 participants have been included. The ImaLife study will allow differentiation between normal aging of the pulmonary and cardiovascular system and early stages of the big three diseases based on low-dose CT imaging. This information can be finally integrated into personalized precision health strategies in the general population.

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.

Disagreement of diameter and volume measurements for pulmonary nodule size estimation in CT lung cancer screening.

We studied 2240 indeterminate solid nodules (volume 50-500mm3) to determine the correlation of diameter and semi-automated volume measurements for pulmonary nodule size estimation. Intra-nodular diameter variation, defined as maximum minus minimum diameter through the nodule's center, varied by 2.8 mm (median, IQR:2.2-3.7 mm), so above the 1.5 mm cutoff for nodule growth used in Lung CT Screening Reporting and Data System (Lung-RADS). Using mean or maximum axial diameter to assess nodule volume led to a substantial mean overestimation of nodule volume of 47.2% and 85.1%, respectively, compared to semi-automated volume. Thus, size of indeterminate nodules is poorly represented by diameter. TRIAL REGISTRATION NUMBER: Pre-results, ISRCTN63545820.

Characteristics of new solid nodules detected in incidence screening rounds of low-dose CT lung cancer screening: the NELSON study.

PURPOSE: New nodules after baseline are regularly found in low-dose CT lung cancer screening and have a high lung cancer probability. It is unknown whether morphological and location characteristics can improve new nodule risk stratification by size. METHODS: Solid non-calcified nodules detected during incidence screening rounds of the randomised controlled Dutch-Belgian lung cancer screening (NELSON) trial and registered as new or previously below detection limit (15 mm3) were included. A multivariate logistic regression analysis with lung cancer as outcome was performed, including previously established volume cut-offs (<30 mm3, 30-<200 mm3 and ≥200 mm3) and nodule characteristics (location, distribution, shape, margin and visibility <15 mm3 in retrospect). RESULTS: Overall, 1280 new nodules were included with 73 (6%) being lung cancer. Of nodules ≥30 mm3 at detection and visible <15 mm3 in retrospect, 22% (6/27) were lung cancer. Discrimination based on volume cut-offs (area under the receiver operating characteristic curve (AUC): 0.80, 95% CI 0.75 to 0.84) and continuous volume (AUC: 0.82, 95% CI 0.77 to 0.87) was similar. After adjustment for volume cut-offs, only location in the right upper lobe (OR 2.0, P=0.012), central distribution (OR 2.4, P=0.001) and visibility <15 mm3 in retrospect (OR 4.7, P=0.003) remained significant predictors for lung cancer. The Hosmer-Lemeshow test (P=0.75) and assessment of bootstrap calibration curves indicated adequate model fit. Discrimination based on the continuous model probability (AUC: 0.85, 95% CI 0.81 to 0.89) was superior to volume cut-offs alone, but when stratified into three risk groups (AUC: 0.82, 95% CI 0.78 to 0.86), discrimination was similar. CONCLUSION: Contrary to morphological nodule characteristics, growth-independent characteristics may further improve volume-based new nodule lung cancer prediction, but in a three-category stratification approach, this is limited. TRIAL REGISTRATION NUMBER: ISRCTN63545820; pre-results.

European position statement on lung cancer screening.

Lung cancer screening with low-dose CT can save lives. This European Union (EU) position statement presents the available evidence and the major issues that need to be addressed to ensure the successful implementation of low-dose CT lung cancer screening in Europe. This statement identified specific actions required by the European lung cancer screening community to adopt before the implementation of low-dose CT lung cancer screening. This position statement recommends the following actions: a risk stratification approach should be used for future lung cancer low-dose CT programmes; that individuals who enter screening programmes should be provided with information on the benefits and harms of screening, and smoking cessation should be offered to all current smokers; that management of detected solid nodules should use semi-automatically measured volume and volume-doubling time; that national quality assurance boards should be set up to oversee technical standards; that a lung nodule management pathway should be established and incorporated into clinical practice with a tailored screening approach; that non-calcified baseline lung nodules greater than 300 mm3, and new lung nodules greater than 200 mm3, should be managed in multidisciplinary teams according to this EU position statement recommendations to ensure that patients receive the most appropriate treatment; and planning for implementation of low-dose CT screening should start throughout Europe as soon as possible. European countries need to set a timeline for implementing lung cancer screening.

Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial.

BACKGROUND: US guidelines now recommend lung cancer screening with low-dose CT for high-risk individuals. Reports of new nodules after baseline screening have been scarce and are inconsistent because of differences in definitions used. We aimed to identify the occurrence of new solid nodules and their probability of being lung cancer at incidence screening rounds in the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). METHODS: In the ongoing, multicentre, randomised controlled NELSON trial, between Dec 23, 2003, and July 6, 2006, 15 822 participants who had smoked at least 15 cigarettes a day for more than 25 years or ten cigarettes a day for more than 30 years and were current smokers, or had quit smoking less than 10 years ago, were enrolled and randomly assigned to receive either screening with low-dose CT (n=7915) or no screening (n=7907). From Jan 28, 2004, to Dec 18, 2006, 7557 individuals underwent baseline screening with low-dose CT; 7295 participants underwent second and third screening rounds. We included all participants with solid non-calcified nodules, registered by the NELSON radiologists as new or smaller than 15 mm(3) (study detection limit) at previous screens. Nodule volume was generated semiautomatically by software. We calculated the maximum volume doubling time for nodules with an estimated percentage volume change of 25% or more, representing the minimum growth rate for the time since the previous scan. Lung cancer diagnosis was based on histology, and benignity was based on histology or stable size for at least 2 years. The NELSON trial is registered at trialregister.nl, number ISRCTN63545820. FINDINGS: We analysed data for participants with at least one solid non-calcified nodule at the second or third screening round. In the two incidence screening rounds, the NELSON radiologists registered 1222 new solid nodules in 787 (11%) participants. A new solid nodule was lung cancer in 49 (6%) participants with new solid nodules and, in total, 50 lung cancers were found, representing 4% of all new solid nodules. 34 (68%) lung cancers were diagnosed at stage I. Nodule volume had a high discriminatory power (area under the receiver operating curve 0·795 [95% CI 0·728-0·862]; p<0·0001). Nodules smaller than 27 mm(3) had a low probability of lung cancer (two [0·5%] of 417 nodules; lung cancer probability 0·5% [95% CI 0·0-1·9]), nodules with a volume of 27 mm(3) up to 206 mm(3) had an intermediate probability (17 [3·1%] of 542 nodules; lung cancer probability 3·1% [1·9-5·0]), and nodules of 206 mm(3) or greater had a high probability (29 [16·9%] of 172 nodules; lung cancer probability 16·9% [12·0-23·2]). A volume cutoff value of 27 mm(3) or greater had more than 95% sensitivity for lung cancer. INTERPRETATION: Our study shows that new solid nodules are detected at each screening round in 5-7% of individuals who undergo screening for lung cancer with low-dose CT. These new nodules have a high probability of malignancy even at a small size. These findings should be considered in future screening guidelines, and new solid nodules should be followed up more aggressively than nodules detected at baseline screening. FUNDING: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds Kankerbestrijding.

The impact of radiologists' expertise on screen results decisions in a CT lung cancer screening trial.

OBJECTIVE: To evaluate the impact of radiological expertise on screen result decisions in a CT lung cancer screening trial. METHODS: In the NELSON lung cancer screening trial, the baseline CT result was based on the largest lung nodule's volume. The protocol allowed radiologists to manually adjust screen results in cases of high suspicion of benign or malignant nodule nature. Participants whose baseline CT result was based on a solid or part-solid nodule were included in this study. Adjustments by radiologists at baseline were evaluated. Histology was the reference for diagnosis or to confirm benignity and stability on subsequent CT examinations. RESULTS: A total of 3,318 participants (2,796 male, median age 58.0 years) were included. In 195 participants (5.9 %) the initial baseline screen result was adjusted by the radiologist. Adjustment was downwards from positive or indeterminate to negative in two and 119 participants, respectively, and from positive to indeterminate in 65 participants. None of these nodules turned out to be malignant. In 9/195 participants (4.6 %) the screen result was adjusted upwards from negative to indeterminate or indeterminate to positive; two nodules were malignant. CONCLUSION: In one in 20 cases of baseline lung cancer screening, nodules were reclassified by the radiologist, leading to a reduction of false-positive screen results.

Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers.

BACKGROUND: Low-dose CT screening is recommended for individuals at high risk of developing lung cancer. However, CT screening does not detect all lung cancers: some might be missed at screening, and others can develop in the interval between screens. The NELSON trial is a randomised trial to assess the effect of screening with increasing screening intervals on lung cancer mortality. In this prespecified analysis, we aimed to assess screening test performance, and the epidemiological, radiological, and clinical characteristics of interval cancers in NELSON trial participants assigned to the screening group. METHODS: Eligible participants in the NELSON trial were those aged 50-75 years, who had smoked 15 or more cigarettes per day for more than 25 years or ten or more cigarettes for more than 30 years, and were still smoking or had quit less than 10 years ago. We included all participants assigned to the screening group who had attended at least one round of screening. Screening test results were based on volumetry using a two-step approach. Initially, screening test results were classified as negative, indeterminate, or positive based on nodule presence and volume. Subsequently, participants with an initial indeterminate result underwent follow-up screening to classify their final screening test result as negative or positive, based on nodule volume doubling time. We obtained information about all lung cancer diagnoses made during the first three rounds of screening, plus an additional 2 years of follow-up from the national cancer registry. We determined epidemiological, radiological, participant, and tumour characteristics by reassessing medical files, screening CTs, and clinical CTs. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. FINDINGS: 15,822 participants were enrolled in the NELSON trial, of whom 7915 were assigned to low-dose CT screening with increasing interval between screens, and 7907 to no screening. We included 7155 participants in our study, with median follow-up of 8·16 years (IQR 7·56-8·56). 187 (3%) of 7155 screened participants were diagnosed with 196 screen-detected lung cancers, and another 34 (<1%; 19 [56%] in the first year after screening, and 15 [44%] in the second year after screening) were diagnosed with 35 interval cancers. For the three screening rounds combined, with a 2-year follow-up, sensitivity was 84·6% (95% CI 79·6-89·2), specificity was 98·6% (95% CI 98·5-98·8), positive predictive value was 40·4% (95% CI 35·9-44·7), and negative predictive value was 99·8% (95% CI 99·8-99·9). Retrospective assessment of the last screening CT and clinical CT in 34 patients with interval cancer showed that interval cancers were not visible in 12 (35%) cases. In the remaining cases, cancers were visible when retrospectively assessed, but were not diagnosed because of radiological detection and interpretation errors (17 [50%]), misclassification by the protocol (two [6%]), participant non-compliance (two [6%]), and non-adherence to protocol (one [3%]). Compared with screen-detected cancers, interval cancers were diagnosed at more advanced stages (29 [83%] of 35 interval cancers vs 44 [22%] of 196 screen-detected cancers diagnosed in stage III or IV; p<0·0001), were more often small-cell carcinomas (seven [20%] vs eight [4%]; p=0·003) and less often adenocarcinomas (nine [26%] vs 102 [52%]; p=0·005). INTERPRETATION: Lung cancer screening in the NELSON trial yielded high specificity and sensitivity, with only a small number of interval cancers. The results of this study could be used to improve screening algorithms, and reduce the number of missed cancers. FUNDING: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening.

BACKGROUND: The main challenge in CT screening for lung cancer is the high prevalence of pulmonary nodules and the relatively low incidence of lung cancer. Management protocols use thresholds for nodule size and growth rate to determine which nodules require additional diagnostic procedures, but these should be based on individuals' probabilities of developing lung cancer. In this prespecified analysis, using data from the NELSON CT screening trial, we aimed to quantify how nodule diameter, volume, and volume doubling time affect the probability of developing lung cancer within 2 years of a CT scan, and to propose and evaluate thresholds for management protocols. METHODS: Eligible participants in the NELSON trial were those aged 50-75 years, who have smoked 15 cigarettes or more per day for more than 25 years, or ten cigarettes or more for more than 30 years and were still smoking, or had stopped smoking less than 10 years ago. Participants were randomly assigned to low-dose CT screening at increasing intervals, or no screening. We included all participants assigned to the screening group who had attended at least one round of screening, and whose results were available from the national cancer registry database. We calculated lung cancer probabilities, stratified by nodule diameter, volume, and volume doubling time and did logistic regression analysis using diameter, volume, volume doubling time, and multinodularity as potential predictor variables. We assessed management strategies based on nodule threshold characteristics for specificity and sensitivity, and compared them to the American College of Chest Physicians (ACCP) guidelines. The NELSON trial is registered at www.trialregister.nl, number ISRCTN63545820. FINDINGS: Volume, volume doubling time, and volumetry-based diameter of 9681 non-calcified nodules detected by CT screening in 7155 participants in the screening group of NELSON were used to quantify lung cancer probability. Lung cancer probability was low in participants with a nodule volume of 100 mm(3) or smaller (0·6% [95% CI 0·4-0·8]) or maximum transverse diameter smaller than 5 mm (0·4% [0·2-0·7]), and not significantly different from participants without nodules (0·4% [0·3-0·6], p=0·17 and p=1·00, respectively). Lung cancer probability was intermediate (requiring follow-up CT) if nodules had a volume of 100-300 mm(3) (2·4% [95% CI 1·7-3·5]) or a diameter 5-10 mm (1·3% [1·0-1·8]). Volume doubling time further stratified the probabilities: 0·8% (95% CI 0·4-1·7) for volume doubling times 600 days or more, 4·0% (1·8-8·3) for volume doubling times 400-600 days, and 9·9% (6·9-14·1) for volume doubling times of 400 days or fewer. Lung cancer probability was high for participants with nodule volumes 300 mm(3) or bigger (16·9% [95% CI 14·1-20·0]) or diameters 10 mm or bigger (15·2% [12·7-18·1]). The simulated ACCP management protocol yielded a sensitivity and specificity of 90·9% (95% CI 81·2-96·1), and 87·2% (86·4-87·9), respectively. A diameter-based protocol with volumetry-based nodule diameter yielded a higher sensitivity (92·4% [95% CI 83·1-97·1]), and a higher specificity (90·0% [89·3-90·7). A volume-based protocol (with thresholds based on lung cancer probability) yielded the same sensitivity as the ACCP protocol (90·9% [95% CI 81·2-96·1]), and a higher specificity (94·9% [94·4-95·4]). INTERPRETATION: Small nodules (those with a volume <100 mm(3) or diameter <5 mm) are not predictive for lung cancer. Immediate diagnostic evaluation is necessary for large nodules (≥300 mm(3) or ≥10 mm). Volume doubling time assessment is advocated only for intermediate-sized nodules (with a volume ranging between 100-300 mm(3) or diameter of 5-10 mm). Nodule management protocols based on these thresholds performed better than the simulated ACCP nodule protocol. FUNDING: Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds.

Features of resolving and nonresolving indeterminate pulmonary nodules at follow-up CT: the NELSON study.

PURPOSE: To retrospectively identify features that allow prediction of the disappearance of solid, indeterminate, intraparenchymal nodules detected at baseline computed tomographic (CT) screening of individuals at high risk for lung cancer. MATERIALS AND METHODS: The study was institutional review board approved. Participants gave informed consent. Participants with at least one noncalcified, solid, indeterminate, intraparenchymal nodule (volume range, 50-500 mm(3)) at baseline were included (964 nodules in 750 participants). According to protocol, indeterminate nodules were re-examined at a 3-month follow-up CT examination. Repeat screening was performed at years 2 and 4. A nodule was defined as resolving if it did not appear at a subsequent CT examination. Nodule resolution was regarded as spontaneous, not the effect of treatment. CT features of resolving and nonresolving (stable and malignant) nodules were compared by means of generalized estimating equations analysis. RESULTS: At subsequent screening, 10.1% (97 of 964) of the nodules had disappeared, 77.3% (n = 75) of these at the 3-month follow-up CT and 94.8% (n = 92) at the second round of screening. Nonperipheral nodules were more likely to resolve than were peripheral nodules (odds ratio: 3.16; 95% confidence interval: 1.76, 5.70). Compared with smooth nodules, nodules with spiculated margins showed the highest probability of disappearance (odds ratio: 4.36; 95% confidence interval: 2.24, 8.49). CONCLUSION: Approximately 10% of solid, intermediate-sized, intraparenchymal pulmonary nodules found at baseline screening for lung cancer resolved during follow-up, three-quarters of which had disappeared at the 3-month follow-up CT examination. Resolving pulmonary nodules share CT features with malignant nodules.

Ct-defined emphysema prevalence in a Chinese and Dutch general population.

PURPOSE: We determine and compare the prevalence, subtypes, severity, and risk factors for emphysema assessed by low-dose CT(LDCT) in Chinese and Dutch general populations. METHODS: This cross-sectional study included LDCT scans of 1143 participants between May and October 2017 from a Chinese Cohort study and 1200 participants with same age range and different smoking status between May and October 2019 from a Dutch population-based study. An experienced radiologist visually assessed the scans for emphysema presence (≥trace), subtype, and severity. Logistic regression analyses, overall and stratified by smoking status, were performed and adjusted for fume exposure, demographic and smoking data. RESULTS: The Chinese population had a comparable proportion of women to the Dutch population (54.9 % vs 58.9 %), was older (61.7 ± 6.3 vs 59.8 ± 8.1), included more never smokers (66.4 % vs 38.3 %), had a higher emphysema prevalence ([58.8 % vs 39.7 %], adjusted odds ratio, aOR = 2.06, 95 %CI = 1.68-2.53), and more often had centrilobular emphysema (54.8 % vs 32.8 %, p < 0.001), but no differences in emphysema severity. After stratification, only in never smokers an increased odds of emphysema was observed in the Chinese compared to the Dutch (aOR = 2.55, 95 %CI = 1.95-3.35). Never smokers in both populations shared older age (aOR = 1.59, 95 %CI = 1.25-2.02 vs 1.26, 95 %CI = 0.97-1.64) and male sex (aOR = 1.50, 95 %CI = 1.02-2.22 vs 1.93, 95 %CI = 1.26-2.96) as risk factors for emphysema. CONCLUSIONS: Only never smokers had a higher prevalence of mainly centrilobular emphysema in the Chinese general population compared to the Dutch after adjusting for confounders, indicating that factors other than smoking, age and sex contribute to presence of CT-defined emphysema.