Developing a Pan-European Technical Standard for a Comprehensive High-quality Lung Cancer CT Screening Program. An ERS Technical Standard.

Screening for lung cancer with low radiation dose computed tomography (LDCT) has a strong evidence base. The European Council adopted a recommendation in November 2022 that lung cancer screening be implemented using a stepwise approach. The imperative now is to ensure that implementation follows an evidence-based process that delivers clinical and cost effectiveness. This ERS Taskforce was formed to provide a technical standard for a high-quality lung cancer screening program. METHOD: A collaborative group was convened to include members of multiple European societies (see below). Topics were identified during a scoping review and a systematic review of the literature was conducted. Full text was provided to members of the group for each topic. The final document was approved by all members and the ERS Scientific Advisory Committee. RESULTS: Ten topics were identified representing key components of a screening program. The action on findings from the LDCT were not included as they are addressed by separate international guidelines (nodule management and clinical management of lung cancer) and by a linked taskforce (incidental findings). Other than smoking cessation, other interventions that are not part of the core screening process were not included (e.g. pulmonary function measurement). Fifty-three statements were produced and areas for further research identified. CONCLUSION: This European collaborative group has produced a technical standard that is a timely contribution to implementation of LCS. It will serve as a standard that can be used, as recommended by the European Council, to ensure a high quality and effective program.

Low diffusion capacity of the lung predicts pneumothorax and chest drainage after CT-guided lung biopsy.

OBJECTIVES: Complications after CT-guided lung biopsy is a burden both for the individual patient and for the overall healthcare. Pneumothorax is the most common complication. This study determined the association between lung function tests and pneumothorax and chest drainage following CT-guided lung biopsy in consecutive patients in a large university hospital. RESULTS: We prospectively registered 875 biopsy procedures from 786 patients in one institution from January 27th 2012 to March 1st 2017 and recorded complications including pneumothorax with or without chest drainage. Lung function data from 637 patients undergoing 710 of the procedures were available. The association of lung function measures with pneumothorax with or without chest drainage was assessed using multivariable logistic regression analyses. Diffusion capacity for carbon monoxide (DLCO) below 4.70 mmol/min/kPa was associated with increased occurrence of pneumothorax and chest drainage after CT guided lung biopsy. We found no association between FEV1, RV and occurrence of pneumothorax and chest drainage. We found low DLCO to be a risk factor of pneumothorax and chest drainage after CT-guided lung biopsy. This should be taken into account in planning and performing the procedure.

Diagnostic yield, complications, pathology and anatomical features in CT-guided percutaneous needle biopsy of mediastinal tumours.

OBJECTIVES: This study presents the experiences of percutaneous CT-guided needle biopsy at a university hospital in Norway. METHODS: A retrospective examination of all mediastinal biopsy procedures between April 2015 and August 2019 was performed at Akershus University Hospital in Norway. We registered patient and procedure characteristics, along with lesion pathology and characteristics including localization according to anatomical and Felson mediastinal compartments. RESULTS: The study included 48 procedures, conducted in 45 patients (29 men and 16 women) with a mean age of 60,5 years. Pneumothorax occurred in 12 procedures (60% of the transpulmonary procedures) and pneumomediastinum in 18 procedures (38%). Pneumothorax was only seen in procedures with transpulmonal access. Four of the pneumothorax cases required pleural drainage. Diagnostic yield was 96%. We found significant (p = 0,006), moderate to high association between anatomical compartment localization and histopathological diagnosis (Cramér's V = 0,49) for tumours selected for CT-guided percutaneous biopsy. Felson's compartment division on the other hand, did not show any significant associations. CONCLUSION: We found CT-guided percutaneous needle biopsy of mediastinal tumours to be an effective and safe procedure with a diagnostic yield of 96%. The main complications were pneumothorax and pnumomediastinum, with a relatively low chest drainage rate. Anatomical mediastinum compartment showed a significant, moderate to high association with the histopathological diagnosis for tumours selected for percutaneous CT-guided biopsies, where most malignancies were seen in the anterior compartment.

Predictors of pneumothorax and chest drainage after percutaneous CT-guided lung biopsy: A prospective study.

OBJECTIVES: We present an analysis of predictors of pneumothorax, and pneumothorax requiring chest drainage after CT-guided lung biopsy, in one of the largest Scandinavian dataset presented. METHODS: We prospectively registered 875 biopsy procedures from 786 patients in one institution from January 27, 2012, to March 1, 2017, and recorded complications including pneumothorax with or without chest drainage, and multiple variables we assumed could be associated with complications. We performed multivariable logistic regression analysis to identify predictors of pneumothorax and pneumothorax requiring chest drainage. RESULTS: Of the biopsied lesions, 65% were malignant, 29% benign, and 6% inconclusive. Pneumothorax occurred in 39% of the procedures and chest drainage was performed in 10%. In multivariable analysis, significant predictors of pneumothorax were emphysema (OR 1.92), smaller lesion size (OR 0.83, per 1 cm increase in lesion size), lateral body position during procedure (OR 2.00), longer needle time (OR 1.09, per minute), repositioning of coaxial needle with new insertion through pleura (OR 3.04), insertion through interlobar fissure (OR 5.21), and shorter distance to pleura (OR 0.79, per 1 cm increase in distance). Predictors of chest drainage were emphysema (OR 4.01), lateral body position (OR 2.61), and needle insertion through interlobar fissure (OR 4.17). CONCLUSION: Predictors of pneumothorax were emphysema, lateral body position, needle insertion through interlobar fissure, repositioning of coaxial needle with new insertion through pleura, and shorter distance to pleura. The finding of lateral body position as a predictor of pneumothorax is not earlier described. Emphysema, lateral body position, and needle insertion through interlobar fissure were also predictors of chest drainage. KEY POINTS: • Pneumothorax is a frequent complication to CT-guided lung biopsy; a smaller fraction of these complications needs chest drainage. • Predictors for pneumothorax are emphysema, smaller lesion size, lateral body position, longer needle time, repositioning of coaxial needle with new insertion through pleura, needle insertion through the interlobar fissure, and shorter distance to pleura. • Predictors for requirement for chest drainage post CT-guided lung biopsy are emphysema, lateral body position, and needle insertion through the interlobar fissure.

Increased respiratory morbidity in individuals with interstitial lung abnormalities.

BACKGROUND: Interstitial lung abnormalities (ILA) are common in participants of lung cancer screening trials and broad population-based cohorts. They are associated with increased mortality, but less is known about disease specific morbidity and healthcare utilisation in individuals with ILA. METHODS: We included all participants from the screening arm of the Danish Lung Cancer Screening Trial with available baseline CT scan data (n = 1990) in this cohort study. The baseline scan was scored for the presence of ILA and patients were followed for up to 12 years. Data about all hospital admissions, primary healthcare visits and medicine prescriptions were collected from the Danish National Health Registries and used to determine the participants' disease specific morbidity and healthcare utilisation using Cox proportional hazards models. RESULTS: The 332 (16.7%) participants with ILA were more likely to be diagnosed with one of several respiratory diseases, including interstitial lung disease (HR: 4.9, 95% CI: 1.8-13.3, p = 0.008), COPD (HR: 1.7, 95% CI: 1.2-2.3, p = 0.01), pneumonia (HR: 2.0, 95% CI: 1.4-2.7, p <  0.001), lung cancer (HR: 2.7, 95% CI: 1.8-4.0, p <  0.001) and respiratory failure (HR: 1.8, 95% CI: 1.1-3.0, p = 0.03) compared with participants without ILA. These findings were confirmed by increased hospital admission rates with these diagnoses and more frequent prescriptions for inhalation medicine and antibiotics in participants with ILA. CONCLUSIONS: Individuals with ILA are more likely to receive a diagnosis and treatment for several respiratory diseases, including interstitial lung disease, COPD, pneumonia, lung cancer and respiratory failure during long-term follow-up.

'Reduced' HUNT model outperforms NLST and NELSON study criteria in predicting lung cancer in the Danish screening trial.

Hypothesis: We hypothesise that the validated HUNT Lung Cancer Risk Model would perform better than the NLST (USA) and the NELSON (Dutch-Belgian) criteria in the Danish Lung Cancer Screening Trial (DLCST). Methods: The DLCST measured only five out of the seven variables included in validated HUNT Lung Cancer Model. Therefore a 'Reduced' model was retrained in the Norwegian HUNT2-cohort using the same statistical methodology as in the original HUNT model but based only on age, pack years, smoking intensity, quit time and body mass index (BMI), adjusted for sex. The model was applied on the DLCST-cohort and contrasted against the NLST and NELSON criteria. Results: Among the 4051 smokers in the DLCST with 10 years follow-up, median age was 57.6, BMI 24.75, pack years 33.8, cigarettes per day 20 and most were current smokers. For the same number of individuals selected for screening, the performance of the 'Reduced' HUNT was increased in all metrics compared with both the NLST and the NELSON criteria. In addition, to achieve the same sensitivity, one would need to screen fewer people by the 'Reduced' HUNT model versus using either the NLST or the NELSON criteria (709 vs 918, p=1.02e-11 and 1317 vs 1668, p=2.2e-16, respectively). Conclusions: The 'Reduced' HUNT model is superior in predicting lung cancer to both the NLST and NELSON criteria in a cost-effective way. This study supports the use of the HUNT Lung Cancer Model for selection based on risk ranking rather than age, pack year and quit time cut-off values. When we know how to rank personal risk, it will be up to the medical community and lawmakers to decide which risk threshold will be set for screening.

Interstitial lung abnormalities are associated with increased mortality in smokers.

OBJECTIVE: The aim of this study was to investigate whether smokers with incidental findings of interstitial lung abnormalities have an increased mortality during long-term follow-up, and review the contributing causes of death. METHODS: Baseline CT scans of 1990 participants from the Danish Lung Cancer Screening Trial were qualitatively assessed for predefined interstitial lung abnormalities of any severity. Inclusion criteria for this lung cancer screening trial included current or former smoking, > 20 pack-years, and age 50-70 years. Patients were followed up for up to 12 years. RESULTS: We found interstitial lung abnormalities in 332 participants (16.7%). Interstitial lung abnormalities were associated with increased all-cause mortality in the full cohort (HR: 2.0, 95% CI: 1.4-2.7, P < 0.001) and in lung cancer-free participants (HR: 1.6, 95% CI: 1.1-2.4, P = 0.007). The findings were associated with death from lung cancer (HR: 3.2, 95% CI: 1.7-6.2, P < 0.001) and non-pulmonary malignancies (HR: 2.1, 95% CI: 1.1-4.0, P = 0.02). Participants with fibrotic and non-fibrotic interstitial lung abnormalities had similar survival. CONCLUSION: Interstitial lung abnormalities were common in this lung cancer screening population of relatively healthy smokers and were associated with mortality regardless of the interstitial morphological phenotype. The increased mortality was partly due to an association with lung cancer and non-pulmonary malignancies.

Computer tomography guided lung biopsy using interactive breath-hold control: a randomized study.

BACKGROUND: Interactive breath-hold control (IBC) may improve the accuracy and decrease the complication rate of computed tomography (CT)-guided lung biopsy, but this presumption has not been proven in a randomized study. METHODS: Patients admitted for CT-guided lung biopsy were randomized to biopsy either with (N=201) or without (N=206) IBC. Biopsy accuracy, procedure time, radiation, and complications were compared in the two groups. Predictors for pneumothorax were analyzed. RESULTS: Procedures performed with the use of IBC (N=130) did not show higher biopsy accuracy (P=0.979) but were associated with a higher risk of pneumothorax (P=0.022) compared to procedures without the use of IBC (N=171). Overall, 50% of the biopsies were malignant, 13% were benign, and 33% were inconclusive (4% missing). Long needle time (P=0.037) and small nodule size (P=0.001) were predictors of pneumothorax. CONCLUSIONS: The use of IBC for CT-guided lung biopsy was not an advantage for unselected patients in our care, since it did not improve the biopsy accuracy and the risk of pneumothorax was increased.

Implementation of lung cancer CT screening in the Nordic countries.

INTRODUCTION: We review the current knowledge of CT screening for lung cancer and present an expert-based, joint protocol for the proper implementation of screening in the Nordic countries. MATERIALS AND METHODS: Experts representing all the Nordic countries performed literature review and concensus for a joint protocol for lung cancer screening. RESULTS AND DISCUSSION: Areas of concern and caution are presented and discussed. We suggest to perform CT screening pilot studies in the Nordic countries in order to gain experience and develop specific and safe protocols for the implementation of such a program.

Implementation and organization of lung cancer screening.

CT screening for lung cancer is now being implemented in the US and China on a widespread national scale but not in Europe so far. The review gives a status for the implementation process and the hurdles to overcome in the future. It also describes the guidelines and requirements for the structure and components of high quality CT screening programs. These are essential in order to achieve a successful program with the fewest possible harms and a possible mortality benefit like that documented in the American National Lung Screening Trial (NLST). In addition the importance of continued research in CT screening methods is described and discussed with focus on the great potential to further improve this method in the future for the benefit of patients and society.

Smoking cessation and lung cancer screening.

Smoking behavior may have a substantial influence on the overall effect of lung cancer screening. Non-randomized studies of smoking behavior during screening have indicated that computer tomography (CT) screening induces smoking cessation. Randomized studies have further elaborated that this effect has to do with participation in screening alone and not dependent on the CT scan. Participants in both CT and control arm in randomized screening trials had higher smoking abstinence rate compared to that of the general population. A positive screening test seems to further promote smoking cessation and decrease smoking relapse rate. Also low smoking dependency and high motivation to quit smoking at baseline predicted smoking abstinence in screening trials. Lung cancer screening therefore seems to be a teachable moment for smoking cessation. Targeted smoking cessation counselling should be an integrated part of future lung cancer screening trials.

Ground-Glass Opacity Lung Nodules in the Era of Lung Cancer CT Screening: Radiology, Pathology, and Clinical Management.

The advent of computed tomography screening for lung cancer will increase the incidence of ground-glass opacity (GGO) nodules detected and referred for diagnostic evaluation and management. GGO nodules remain a diagnostic challenge; therefore, a more systematic approach is necessary to ensure correct diagnosis and optimal management. Here we present the latest advances in the radiologic imaging and pathology of GGO nodules, demonstrating that radiologic features are increasingly predictive of the pathology of GGO nodules. We review the current guidelines from the Fleischner Society, the National Comprehensive Cancer Network, and the British Thoracic Society. In addition, we discuss the management and follow-up of GGO nodules in the light of experience from screening trials. Minimally invasive tissue biopsies and the marking of GGO nodules for surgery are new and rapidly developing fields that will yield improvements in both diagnosis and treatment. The standard-of-care surgical treatment of early lung cancer is still minimally invasive lobectomy with systematic lymph node dissection. However, recent research has shown that some GGO lesions may be treated with sublobar resections; these findings may expand the surgical treatment options available in the future.

Results of the Randomized Danish Lung Cancer Screening Trial with Focus on High-Risk Profiling.

RATIONALE: As of April 2015, participants in the Danish Lung Cancer Screening Trial had been followed for at least 5 years since their last screening. OBJECTIVES: Mortality, causes of death, and lung cancer findings are reported to explore the effect of computed tomography (CT) screening. METHODS: A total of 4,104 participants aged 50-70 years at the time of inclusion and with a minimum 20 pack-years of smoking were randomized to have five annual low-dose CT scans (study group) or no screening (control group). MEASUREMENTS AND MAIN RESULTS: Follow-up information regarding date and cause of death, lung cancer diagnosis, cancer stage, and histology was obtained from national registries. No differences between the two groups in lung cancer mortality (hazard ratio, 1.03; 95% confidence interval, 0.66-1.6; P = 0.888) or all-cause mortality (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27; P = 0.867) were observed. More cancers were found in the screening group than in the no-screening group (100 vs. 53, respectively; P < 0.001), particularly adenocarcinomas (58 vs. 18, respectively; P < 0.001). More early-stage cancers (stages I and II, 54 vs. 10, respectively; P < 0.001) and stage IIIa cancers (15 vs. 3, respectively; P = 0.009) were found in the screening group than in the control group. Stage IV cancers were nonsignificantly more frequent in the control group than in the screening group (32 vs. 23, respectively; P = 0.278). For the highest-stage cancers (T4N3M1, 21 vs. 8, respectively; P = 0.025), this difference was statistically significant, indicating an absolute stage shift. Older participants, those with chronic obstructive pulmonary disease, and those with more than 35 pack-years of smoking had a significantly increased risk of death due to lung cancer, with nonsignificantly fewer deaths in the screening group. CONCLUSIONS: No statistically significant effects of CT screening on lung cancer mortality were found, but the results of post hoc high-risk subgroup analyses showed nonsignificant trends that seem to be in good agreement with the results of the National Lung Screening Trial. Clinical trial registered with www.clinicaltrials.gov (NCT00496977).

[Lung cancer screening with low dose CT requires careful consideration].

Results from the American National Lung Screening Trial (NLST) show a significant reduction in lung cancer and all-cause mortality in a high risk population screened with annual low-dose CT. Handling of pulmonary nodules, false positive tests, overdiagnosis, psychosocial consequences and cost-efficiency etc. are all aspects that require careful consideration. This paper gives an overview of the current knowledge on these issues. Before a recommendation can be made, we need an overall evaluation of both the benefits and harms in CT screening for lung cancer.

[Lung cancer screening with low-dose CT - Danish and international results].

Lung cancer is the cancer type that causes the largest number of deaths in Denmark. With advances in medical imaging and widespread use of computed tomography (CT), it is possible to detect even small abnormalities in lung tissue. This has led to a great interest in lung cancer screening with low-dose CT and launching of randomised screening trials worldwide. This paper gives an overview of the current lung cancer screening trials in Denmark and internationally and focuses on main lung cancer findings and mortality results.

Smoking habits in the randomised Danish Lung Cancer Screening Trial with low-dose CT: final results after a 5-year screening programme.

BACKGROUND: We present the final results of the effect of lung cancer screening with low-dose CT on the smoking habits of participants in a 5-year screening trial. METHODS: The Danish Lung Cancer Screening Trial (DLCST) was a 5-year screening trial that enrolled 4104 subjects; 2052 were randomised to annual low-dose CT (CT group) and 2052 received no intervention (control group). Participants were current and ex-smokers (≥4 weeks abstinence from smoking) with a tobacco consumption of ≥20 pack years. Smoking habits were determined annually. Missing values for smoking status at the final screening round were handled using two different models. RESULTS: There were no statistically significant differences in annual smoking status between the CT group and control group. Overall the ex-smoker rates (CT + control group) significantly increased from 24% (baseline) to 37% at year 5 of screening (p<0.001). The annual point prevalence quit rate increased from 11% to 24% during the five screening rounds; the ex-smokers' relapse rate remained stable, around 11%, across the same period. CONCLUSIONS: Screening with low-dose CT had no extra effect on smoking status compared with the control group, but overall the screening programme probably promoted smoking cessation. CLINICAL TRIAL REGISTRATION: The DLCST is registered in Clinical Trials.gov Protocol Registration System (identification no. NCT00496977).

Relationship between chronic obstructive pulmonary disease and subclinical coronary artery disease in long-term smokers.

AIMS: Cardiovascular conditions are reported to be the most frequent cause of death in patients with chronic obstructive pulmonary disease (COPD). However, it remains unsettled whether severity of COPD per se is associated with coronary artery disease (CAD) independent of traditional cardiovascular risk factors. The aim of this study was to examine the relationship between the presence and severity of COPD and the amount of coronary artery calcium deposit, an indicator of CAD and cardiac risk, in a large population of current and former long-term smokers. METHODS AND RESULTS: In this cross-sectional study, long-term smokers without clinically manifested CAD were recruited from the Danish Lung Cancer Screening Trial and classified according to lung function by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Coronary artery calcium deposit as a measure of subclinical CAD and cardiac risk was evaluated with multi detector computed tomography and the Agatston coronary artery calcium score (CACS). Participants were categorized into five CACS risk classification groups according to the CACS. The population (n = 1535) consisted of 41% participants without COPD, 28% with mild, and 31% with moderate-to-severe COPD (n = 46 with severe COPD). In addition to age, male gender, hypertension, hypercholesterolaemia, and continued smoking, COPD according to GOLD classification were independent predictors of a higher CACS risk classification group in multivariable analysis [odds ratio (OR): 1.28 (1.01-1.63) and OR: 1.32 (1.05-1.67), for mild and moderate-to-severe COPD, respectively, compared with no COPD]. CONCLUSION: COPD in long-term smokers is independently correlated with the CACS, while COPD severity per se does not show a dose-response relationship.

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT.

BACKGROUND: The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. METHODS: 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. RESULTS: Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs. 24, p<0.001), and more were low stage (48 vs 21 stage I-IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA-IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). CONCLUSION: CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

Texture-based analysis of COPD: a data-driven approach.

This study presents a fully automatic, data-driven approach for texture-based quantitative analysis of chronic obstructive pulmonary disease (COPD) in pulmonary computed tomography (CT) images. The approach uses supervised learning where the class labels are, in contrast to previous work, based on measured lung function instead of on manually annotated regions of interest (ROIs). A quantitative measure of COPD is obtained by fusing COPD probabilities computed in ROIs within the lung fields where the individual ROI probabilities are computed using a k nearest neighbor (kNN ) classifier. The distance between two ROIs in the kNN classifier is computed as the textural dissimilarity between the ROIs, where the ROI texture is described by histograms of filter responses from a multi-scale, rotation invariant Gaussian filter bank. The method was trained on 400 images from a lung cancer screening trial and subsequently applied to classify 200 independent images from the same screening trial. The texture-based measure was significantly better at discriminating between subjects with and without COPD than were the two most common quantitative measures of COPD in the literature, which are based on density. The proposed measure achieved an area under the receiver operating characteristic curve (AUC) of 0.713 whereas the best performing density measure achieved an AUC of 0.598. Further, the proposed measure is as reproducible as the density measures, and there were indications that it correlates better with lung function and is less influenced by inspiration level.