Dutch-Belgian Lung Cancer Screening Trial Research Articles

OA05.04 A Comparison of Stage- and Histology-Specific CT Sensitivity in the NELSON Trial and the NLST

The Dutch-Belgian lung cancer screening trial (Nederlands-Leuvens Longkanker Screenings Onderzoek [NELSON]) demonstrated a reduction in lung cancer mortality of 24%1 for screening with low-dose computed tomography (CT), compared to the 20%2 found in the National Lung Screening Trial (NLST). The NELSON and NLST differed in study population and trial design. Specifically, in contrast to the NLST, the NELSON trial employed a nodule management protocol that incorporated nodule volume and growth3 as opposed to nodule diameter only.

Detection of pulmonary nodules with scoutless fixed-dose ultra-low-dose CT: a prospective study.

To determine the accuracy of scoutless, fixed-dose ultra-low-dose (ULD) CT compared to standard-dose (SD) CT for pulmonary nodule detection and semi-automated nodule measurement, across different patient sizes. Sixty-three patients underwent ULD and SD CT. Two readers examined all studies visually and with computer-aided detection (CAD). Nodules detected on SD CT were included in the reference standard by consensus and stratified into 4 categories (nodule category, NODCAT) from the Dutch-Belgian Lung Cancer Screening trial (NELSON). Effects of NODCAT and patient size on nodule detection were determined. For each nodule, volume and diameter were compared between both scans. The reference standard comprised 173 nodules. For both readers, detection rates on ULD versus SD CT were not significantly different for NODCAT 3 and 4 nodules > 50mm3 (reader 1: 93% versus 89% (p = 0.257); reader 2: 96% versus 98% (p = 0.317)). For NODCAT 1 and 2 nodules < 50mm3, detection rates on ULD versus SD CT dropped significantly (reader 1: 66% versus 80% (p = 0.023); reader 2: 77% versus 87% (p = 0.039)). Body mass index and chest circumference did not influence nodule detectability (p = 0.229 and p = 0.362, respectively). Calculated volumes and diameters were smaller on ULD CT (p < 0.0001), without altering NODCAT (84% agreement). Scoutless ULD CT reliably detects solid lung nodules with a clinically relevant volume (> 50mm3) in lung cancer screening, irrespective of patient size. Since detection rates were lower compared to SD CT for nodules < 50mm3, its use for lung metastasis detection should be considered on a case-by-case basis. • Detection rates of pulmonary nodules > 50mm3are not significantly different between scoutless ULD and SD CT (i.e. volumes clinically relevant in lung cancer screening based on the NELSON trial), but were different for the detection of nodules < 50mm3(i.e. volumes still potentially relevant in lung metastasis screening). • Calculated nodule volumes were on average 0.03mL or 9% smaller on ULD CT, which is below the 20-25% interscan variability previously reported with software-based volumetry. • Even though a scoutless, fixed-dose ULD CT protocol was used (CTDIvol0.15mGy), pulmonary nodule detection was not influenced by patient size.

Association between biomarkers of tobacco consumption and lung cancer risk among daily smokers

ABSTRACT Background Biomarkers of tobacco consumption may play a role in the lung cancer risk assessment. However, the role of salivary biomarkers has not been well studied. The aim of this study is to assess the use of salivary biomarkers of tobacco consumption as lung cancer screening criterion. Research design and methods Data came from the Determinants of cotinine phase 3 project (Barcelona, 2013–2014). We compared the concentrations of TSNAs, including NNAL, NNN and NNK, and cotinine, in saliva samples of 142 daily smokers from the general population according to their risk of lung cancer. High risk of lung cancer was defined as per the inclusion criteria in the US National Lung Screening Trial (NLST) and in the Dutch-Belgian lung cancer screening trial (NELSON). Results Among daily smokers accomplishing the age criterion for lung cancer screening, salivary concentrations of cotinine, NNAL and NNK adjusted for sex were significantly higher (p-value < 0.05) in daily smokers at high risk of lung cancer compared to smokers not at high risk according to both NELSON and NLST criteria. Conclusions Saliva concentrations of cotinine, NNAL and NNK may be used as additional criteria for lung cancer screening. Further research on this topic is guaranteed.

Managing of screening-detected sub-solid nodules-a European perspective.

Since the National Lung Screening Trial in 2011 showed a 20% reduction in lung cancer mortality using annual low-dose computed tomography (LDCT), several randomised controlled trials and studies have been started in Europe. These include the Italian lung study (ITALUNG), the Dutch-Belgian lung cancer screening trial (NELSON), the UK lung cancer screening trial (UKLS), the Detection and screening of early lung cancer with novel imaging technology (DANTE), the Danish lung cancer screening trial (DLCST), the German lung cancer screening intervention trial (LUSI), the Multicentric Italian lung detection trial (MILD) and the CT screening for lung cancer study (COSMOS). As a result of the increasing number of screening trials and the growing utilization of LDCT, the high detection of subsolid nodules is an increasingly important clinical problem. In the last few years, several guidelines have been published and providing guidance on the optimal management of subsolid nodules, but many controversies still exist. Follow-up imaging plays an important role in clinical assessment and subsequent management of this particular type of lung nodules, since they can be transient inflammatory lesions, and if persistent they can be both benign lesions or lung cancers of variable clinical behaviour. However, the vast majority of subsolid nodules retain an indolent course over many years. The aim of this review is to present a European perspective in management of screening detected subsolid nodules.

Abstract IA17: Lung cancer screening: a public health benefit that may deepen the divide

Abstract The National Lung Screening Trial (NLST) and most recently the Dutch–Belgian lung-cancer screening trial (NELSON) were transformative, demonstrating the efficacy of low-dose computed tomoagraphy (LDCT), and thus providing the evidence to support the implementation of screening for lung cancer, a cancer for which no efficacious screening strategy was previously available, into medical care. In a population at high risk for lung cancer as defined by age and smoking history, LDCT was associated with a 20-25% reduction on lung cancer mortality. In the absence of screening, only 16% of patients are diagnosed with a disease stage that has potential for cure by surgical resection. Lung cancer screening identifies cancer at an earlier, more treatable stage. Despite these results, a Grade B recommendation from the US Preventive Services Task Force and coverage by the Centers for Medicare and Medicaid Services, only 14.4% of those eligible underwent screening in 2017. The reasons for this reduction in access and utilization of lung cancer screening are multifactorial and include lack of provider time, limited patient and provider knowledge, and insufficient clinical and technological infrastructure. Further, there is an inverse relationship between the location of those at highest risk for lung cancer (e.g., individuals living in rural settings) and the access to lung cancer screening centers. While lung cancer screening has the potential to reduce mortality there is evidence to suggest that disparities in implementation will further widen existing gaps in lung cancer treatment and mortality among those of lower socioeconomic status, minorities, and un/underinsured populations. This presentation will highlight the challenges and suggest possible solutions. Citation Format: Nichole T. Tanner. Lung cancer screening: a public health benefit that may deepen the divide [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA17.

Variability in interpretation of low-dose chest CT using computerized assessment in a nationwide lung cancer screening program: comparison of prospective reading at individual institutions and retrospective central reading.

To evaluate the degree of variability in computer-assisted interpretation of low-dose chest CTs (LDCTs) among radiologists in a nationwide lung cancer screening (LCS) program, through comparison with a retrospective interpretation from a central laboratory. Consecutive baseline LDCTs (n = 3353) from a nationwide LCS program were investigated. In the institutional reading, 20 radiologists in 14 institutions interpreted LDCTs using computer-aided detection and semi-automated segmentation systems for lung nodules. In the retrospective central review, a single radiologist re-interpreted all LDCTs using the same system, recording any non-calcified nodules ≥ 3mm without arbitrary rejection of semi-automated segmentation to minimize the intervention of radiologist's discretion. Positive results (requiring additional follow-up LDCTs or diagnostic procedures) were initially classified by the lung CT screening reporting and data system (Lung-RADS) during the interpretation, while the classifications based on the volumetric criteria from the Dutch-Belgian lung cancer screening trial (NELSON) were retrospectively applied. Variabilities in positive rates were assessed with coefficients of variation (CVs). In the institutional reading, positive rates by the Lung-RADS ranged from 7.5 to 43.3%, and those by the NELSON ranged from 11.4 to 45.0% across radiologists. The central review exhibited higher positive rates by Lung-RADS (20.0% vs. 27.3%; p < .001) and the NELSON (23.1% vs. 37.0%; p < .001), and lower inter-institution variability (CV, 0.30 vs. 0.12, p = .003 by Lung-RADS; CV, 0.25 vs. 0.12, p = .014 by the NELSON) compared to the institutional reading. Considerable inter-institution variability in the interpretation of LCS results is caused by different usage of the computer-assisted system. • Considerable variability existed in the interpretation of screening LDCT among radiologists partly from the different usage of the computerized system. • A retrospective reading of low-dose chest CTs in the central laboratory resulted in reduced variability but an increased positive rate.

Relation between tobacco control policies and population at high risk of lung cancer in the European Union

IntroductionLung cancer accounts for nearly 2 million deaths per year worldwide, the majority of cases due to smoking as the main risk factor associated. The aim of this study was to assess the relation between the level of implementation of tobacco control policies and the population at high risk of lung cancer in the European Union (EU). MethodsThe Special Eurobarometer 458 “Attitudes of Europeans towards tobacco and electronic cigarettes”, conducted in 2017, and the Tobacco Control Scale (TCS) 2010, 2013, and 2016 were the sources of our data. High risk of lung cancer was defined by the inclusion criteria in the National Lung Screening Trial (NLST) and the Dutch-Belgian Lung Cancer Screening Trial (NELSON), the largest lung cancer screening trials carried out in the US and the EU. We calculated Spearman's rank correlation coefficients (rsp) and fitted multilevel generalized linear mixed models using the quasi-Poisson family to assess the correlation at the national level and analyze the association at the individual level, respectively, between the scores in the TCS (higher scores means better implementation of tobacco control policies) and the proportion of individuals at high risk of lung cancer in member states of the EU. ResultsThe scores in the TCS 2010 were statistically negatively correlated with the current proportion of ever and former smokers at high risk according to NELSON criteria (−0.41; 95%CI −0.68, −0.04 and −0.49; 95%CI −0.73, −0.13, respectively). We observed statistically significant inverse associations between the scores in the TCS 2010 for the highest quartiles and the proportion of individuals at high risk of lung cancer according to both criteria. Non-statistically significant negative correlations and inverse associations were observed with other TCS. ConclusionThere is a lag between the implementation of tobacco control policies and the reduction of the rates of high risk of lung cancer. Member states should reinforce comprehensive tobacco control policies to reduce the population at high risk of lung cancer in the EU.

Estimation of the adult population at high risk of developing lung cancer in the European Union

Background Lung cancer mortality accounts for over 266,000 deaths in the European Union (EU) every year, most of them attributed to smoking. The aim of this study was to estimate the prevalence of the adult population at high risk of developing lung cancer in the EU in 2014.Methods This is a cross-sectional study. We used data from the Special Eurobarometer 429 (n = 27,801). The fieldwork was conducted between November-December 2014. High risk of lung cancer was defined using the criteria of the National Lung Screening Trial (NLST) and the Dutch-Belgian Lung Cancer Screening Trial (NELSON).Results One out of ten smokers (11.6% of men and 9.6% of women) according to NLST criteria and one out of four smokers (24.6% of men and 22.4% of women) according to NELSON criteria are currently at high risk of lung cancer in the EU. According to both criteria, the prevalence of former smokers at high risk of lung cancer is under 10%.Conclusion Around 17 million citizens in the EU according to NLST criteria and 34 million according to NELSON criteria (around 4% and 8% of the adult population, respectively) are at high risk of developing lung cancer. Since the implementation of lung cancer screening programs still remains controversial, primary prevention activities should be encouraged.

Early lung cancer diagnosis among workers exposed to carcinogens.

«Early lung cancer diagnosis among workers exposed to carcinogens». Following the publication of results of NLST (National Lung Screening Trial, USA) and ELCAP (Early Lung Cancer Action Project, USA), lung cancer screening with low-dose computed tomography (LDCT) in high-risk subjects has been recommended in North-America. Conversely, the European Community has been waiting for further evidence. The recently concluded Dutch-Belgian Lung Cancer Screening trial (NELSON) confirmed the efficacy of LDCT screening in reducing lung cancer mortality. Two recent studies in the USA and Italy showed positive results in occupational settings among workers formerly exposed to asbestos. The available evidence seems to suggest the need to implement lung cancer screening programs among heavy smokers and workers substantively exposed to occupational carcinogens also in Europe, following common, standardized procedures, as indicated in a recent European position statement.

Uniform and blinded cause of death verification of the NELSON lung cancer screening participants

Primary outcome of the Dutch-Belgian lung cancer screening trial (NELSON) is lung cancer-specific mortality. Accurate assessment of the cause of death (CoD) is crucial. As death certificates regarding the CoD can be inaccurate, a clinical expert committee (CEC) was formed to assign the CoD. In this study, the medical files of deceased lung cancer patients were reviewed and the outcomes were compared with official death certificates. The first 266 completed medical files of Dutch deceased participants who were diagnosed with lung cancer during the study or of those with lung cancer on the death certificate were selected and blinded towards arms and patients identity. The end product of the review process consisted of six possible categories which defined the graduation of certainty that lung cancer was the primary CoD. The percentage agreement and the Cohen’s kappa statistics between the two CEC-memberswere calculated. The sensitivity and specificity of the official death certificates were determined. The results indicated that, the overall concordance and the Cohen’s kappa between the CEC-memberswere 86.1% and 0.57(0.45–0.69, p<0.001), respectively. This level increased with the numbers of cases evaluated. The sensitivity and the specificity of the official death certificate were 92.6% and 98.8%; 6.5% cases were reclassified to lung cancer specific death, which is lower than in the National Lung Screening trial(22.0%). Concluding, each death should be reviewed by at least two members. So far, in the NELSON trial, possible biases related to lung cancer death seem relatively small.

Risk stratification based on screening history: the NELSON lung cancer screening study

BackgroundDebate about the optimal lung cancer screening strategy is ongoing. In this study, previous screening history of the Dutch-Belgian Lung Cancer Screening trial (NELSON) is investigated on if it predicts...

Follow-up of CT-derived airway wall thickness: Correcting for changes in inspiration level improves reliability

ObjectivesAirway wall thickness (AWT) is affected by changes in lung volume. This study evaluated whether correcting AWT on computed tomography (CT) for differences in inspiration level improves measurement agreement, reliability, and power to detect changes over time. MethodsParticipants of the Dutch-Belgian lung cancer screening trial who underwent 3-month repeat CT for an indeterminate pulmonary nodule were included. AWT on CT was calculated by the square root of the wall area at a theoretical airway with an internal perimeter of 10mm (Pi10). The scan with the highest lung volume was labelled as the reference scan and the scan with the lowest lung volume was labelled as the comparison scan. Pi10 derived from the comparison scan was corrected by multiplying it with the ratio of CT lung volume of the comparison scan to CT lung volume on the reference scan. Agreement of uncorrected and corrected Pi10 was studied with the Bland-Altman method, reliability with intra-class correlation coefficients (ICC), and power to detect changes over time was calculated. Results315 male participants were included. Limit of agreement and reliability for Pi10 was −0.61 to 0.57mm (ICC=0.87), which improved to −0.38 to 0.37mm (ICC=0.94) after correction for inspiration level. To detect a 15% change over 3 months, 71 subjects are needed for Pi10 and 26 subjects for Pi10 adjusted for inspiration level. ConclusionsCorrecting Pi10 for differences in inspiration level improves reliability, agreement, and power to detect changes over time.

Final screening round of the NELSON lung cancer screening trial: the effect of a 2.5-year screening interval

BackgroundIn the USA annual lung cancer screening is recommended. However, the optimal screening strategy (eg, screening interval, screening rounds) is unknown. This study provides results of the fourth screening round...

Survivin Autoantibodies Are Not Elevated in Lung Cancer When Assayed Controlling for Specificity and Smoking Status.

The high mortality rate in lung cancer is largely attributable to late diagnosis. Case-control studies suggest that autoantibodies to the survivin protein are potential biomarkers for early diagnosis. We tested the hypothesis that sandwich ELISA can detect autoantibodies to survivin before radiologic diagnosis in patients with early-stage non-small cell lung cancer (NSCLC). Because previous studies assayed survivin autoantibodies with the direct antigen-coating ELISA (DAC-ELISA), we first compared that assay with the sandwich ELISA. Based on the more robust results from the sandwich ELISA, we used it to measure survivin autoantibodies in the serum of 100 individuals from a well-controlled population study [the Dutch-Belgian Lung Cancer Screening Trial (NELSON) trial] composed of current and former smokers (50 patients with NSCLC, both before and after diagnosis, and 50 matched, smoking-habit control subjects), and another 50 healthy nonsmoking control subjects. We found no difference in specific autoantibodies to survivin in NSCLC patients, although nonspecific median optical densities were 24% higher (P < 0.001) in both NSCLC patients and smokers, than in healthy nonsmokers. Finally, we confirmed the ELISA results with Western blot analysis of recombinant and endogenous survivin (HEK-293), which showed no anti-survivin reactivity in patient sera. We conclude that specific anti-survivin autoantibody reactivity is most likely not present in sera before or after diagnosis. Autoantibody studies benefit from a comparison to a well-controlled population, stratified for smoking habit.

Towards a close computed tomography monitoring approach for screen detected subsolid pulmonary nodules?

Pulmonary subsolid nodules (SSNs) have a high likelihood of malignancy, but are often indolent. A conservative treatment approach may therefore be suitable. The aim of the current study was to evaluate whether close follow-up of SSNs with computed tomography may be a safe approach. The study population consisted of participants of the Dutch-Belgian lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek; NELSON). All SSNs detected during the trial were included in this analysis. Retrospectively, all persistent SSNs and SSNs that were resected after first detection were segmented using dedicated software, and maximum diameter, volume and mass were measured. Mass doubling time (MDT) was calculated. In total 7135 volunteers were included in the current analysis. 264 (3.3%) SSNs in 234 participants were detected during the trial. 147 (63%) of these SSNs in 126 participants disappeared at follow-up, leaving 117 persistent or directly resected SSNs in 108 (1.5%) participants available for analysis. The median follow-up time was 95 months (range 20-110 months). 33 (28%) SSNs were resected and 28 of those were (pre-) invasive. None of the non-resected SSNs progressed into a clinically relevant malignancy. Persistent SSNs rarely developed into clinically manifest malignancies unexpectedly. Close follow-up with computed tomography may be a safe option to monitor changes.

Distribution of emphysema in heavy smokers: Impact on pulmonary function

To investigate impact of distribution of computed tomography (CT) emphysema on severity of airflow limitation and gas exchange impairment in current and former heavy smokers participating in a lung cancer screening trial. In total 875 current and former heavy smokers underwent baseline low-dose CT (30 mAs) in our center and spirometry and diffusion capacity testing on the same day as part of the Dutch-Belgian Lung Cancer Screening Trial (NELSON). Emphysema was quantified for 872 subjects as the number of voxels with an apparent lowered X-ray attenuation coefficient. Voxels attenuated <-950 HU were categorized as representing severe emphysema (ES950), while voxels attenuated between -910 HU and -950 HU represented moderate emphysema (ES910). Impact of distribution on severity of pulmonary function impairment was investigated with logistic regression, adjusted for total amount of emphysema. For ES910 an apical distribution was associated with more airflow obstruction and gas exchange impairment than a basal distribution (both p<0.01). The FEV(1)/FVC ratio was 1.6% (95% CI 0.42% to 2.8%) lower for apical predominance than for basal predominance, for Tlco/V(A) the difference was 0.12% (95% CI 0.076-0.15%). Distribution of ES950 had no impact on FEV(1)/FVC ratio, while an apical distribution was associated with a 0.076% (95% CI 0.038-0.11%) lower Tlco/V(A) (p<0.001). In a heavy smoking population, an apical distribution is associated with more severe gas exchange impairment than a basal distribution; for moderate emphysema it is also associated with a lower FEV(1)/FVC ratio. However, differences are small, and likely clinically irrelevant.

Pulmonary Nodules Detected at Lung Cancer Screening: Interobserver Variability of Semiautomated Volume Measurements

To retrospectively determine interobserver variability of semiautomated volume measurements of pulmonary nodules and the potential reasons for variability. The Dutch-Belgian lung cancer screening trial (NELSON) is a lung cancer screening study that includes men between the ages of 50 and 75 years who are current or former heavy smokers. The NELSON project was approved by the Dutch Ministry of Health and the ethics committee of each participating hospital. Informed consent was obtained from all participants. For this study, the authors evaluated 1200 consecutive low-dose computed tomographic (CT) scans of the chest obtained during the NELSON project and identified subjects who had at least one 50-500-mm(3) nodule. One local and one central observer independently evaluated the scans and measured the volume of any detected nodule by using semiautomated software. Noncalcified solid nodules with volumes of 15-500 mm(3) were included in this study if they were fully surrounded by air (intraparenchymal) and were detected by both observers. The mean volume and the difference between both measurements were calculated for all nodules. Intermeasurement agreement was assessed with the Spearman correlation coefficient. Potential reasons for discrepancies were assessed. There were 232 men (mean age, 60 years; age range, 52-73 years) with 430 eligible nodules (mean volume, 77.8 mm(3); range, 15.3-499.5 mm(3)). Interobserver correlation was high (r = 0.99). No difference in volume was seen for 383 nodules (89.1%). Discrepant results were obtained for 47 nodules (10.9%); in 16 cases (3.7%), the discrepancy was larger than 10%. The most frequent cause of variability was incomplete segmentation due to an irregular shape or irregular margins. In a minority (approximately 11%) of small solid intraparenchymal nodules, semiautomated measurements are not completely reproducible and, thus, may cause errors in the assessment of nodule growth. For small or irregularly shaped nodules, an observer should check the segmentation shown by the program.

P-280 Recruitment and first screening results of the Dutch-Belgian lung cancer screening trial (NELSON)

P-280 Recruitment and first screening results of the Dutch-Belgian lung cancer screening trial (NELSON)