Carlijn M. van der Aalst

Lung cancer screening and smoking abstinence: 2 year follow-up data from the Dutch–Belgian randomised controlled lung cancer screening trial

Background Lung cancer screening may provide a new opportunity for attempts to quit among smokers or might delay smoking cessation, but studies to date failed to provide evidence for this. This study investigated the effect of lung cancer screening on smoking abstinence in male smokers participating in the Dutch–Belgian randomised controlled lung cancer screening trial (NELSON trial). Methods In the NELSON trial, 50- to 75-year-old participants at high risk for developing lung cancer were randomised to either lung cancer screening or no screening. Smoking behaviour was evaluated in two random samples of male smokers in the screen (n=641) and control arm (n=643) before (T0) and 2 years after randomisation (T1). In addition, the data were also analysed by intention-to-treat (ITT) analysis, as recommended in smoking cessation intervention trials, although non-response in screening trials can also be due to reasons other than continued smoking. Results Almost 17% (16.6%) of the trial participants quit smoking, which is higher than the 3–7% found in the general adult population. However, screening was associated with a lower prolonged abstinence rate (14.5%) compared with no screening (19.1%) (OR 1.40, 95% CI 1.01 to 1.92; p<0.05). No stastistically significant difference was found after performing an ITT analysis. Conclusions This study showed that all trial participants were inclined to stop smoking more than average, which suggests that screening is a teachable moment to improve smoking behaviour. In those who underwent screening the smoking abstinence rate was significantly lower than for the control group, although the difference was modest. After ITT analysis this difference was no longer observed. Clinical trial number ISRCTN63545820.

Volumetric computed tomography screening for lung cancer: three rounds of the NELSON trial.

Several medical associations recommended lung cancer screening by low-dose computed tomography scanning for high-risk groups. Counselling of the candidates on the potential harms and benefits and their lung cancer risk is a prerequisite for screening. In the NELSON trial, screenings are considered positive for (part) solid lung nodules with a volume >500 mm3 and for (part) solid or nonsolid nodules with a volume-doubling time <400 days. For this study, the performance of the NELSON strategy in three screening rounds was evaluated and risk calculations were made for a follow-up period of 5.5 years. 458 (6%) of the 7582 participants screened had a positive screen result and 200 (2.6%) were diagnosed with lung cancer. The positive screenings had a predictive value of 40.6% and only 1.2% of all scan results were false-positive. In a period of 5.5 years, the risk of screen-detected lung cancer strongly depends on the result of the first scan: 1.0% after a negative baseline result, 5.7% after an indeterminate baseline and 48.3% after a positive baseline. The screening strategy yielded few positive and false-positive scans with a reasonable positive predictive value. The 5.5-year lung cancer risk calculations aid clinicians in counselling candidates for lung cancer screening with low-dose computed tomography. 5.5-year lung cancer risk calculations aid clinicians in counselling for lung cancer screening with low-dose CT http://ow.ly/p9J3q

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.

Characteristics of Lung Cancers Detected by Computer Tomography Screening in the Randomized NELSON Trial

RATIONALE The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial. OBJECTIVES To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials. METHODS All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials. MEASUREMENTS AND MAIN RESULTS In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB-IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB-IV. CONCLUSIONS Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy. Clinical trial registered with www.trialregister.nl (ISRCTN63545820).

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.

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

Background In 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 after a 2.5-year interval in the Dutch-Belgian Lung Cancer Screening trial (NELSON). Methods Europes largest, sufficiently powered randomised lung cancer screening trial was designed to determine whether low-dose CT screening reduces lung cancer mortality by ≥25% compared with no screening after 10 years of follow-up. The screening arm (n=7915) received screening at baseline, after 1 year, 2 years and 2.5 years. Performance of the NELSON screening strategy in the final fourth round was evaluated. Comparisons were made between lung cancers detected in the first three rounds, in the final round and during the 2.5-year interval. Results In round 4, 46 cancers were screen-detected and there were 28 interval cancers between the third and fourth screenings. Compared with the second round screening (1-year interval), in round 4 a higher proportion of stage IIIb/IV cancers (17.3% vs 6.8%, p=0.02) and higher proportions of squamous-cell, bronchoalveolar and small-cell carcinomas (p=0.001) were detected. Compared with a 2-year interval, the 2.5-year interval showed a higher non-significant stage distribution (stage IIIb/IV 17.3% vs 5.2%, p=0.10). Additionally, more interval cancers manifested in the 2.5-year interval than in the intervals of previous rounds (28 vs 5 and 28 vs 19). Conclusions A 2.5-year interval reduced the effect of screening: the interval cancer rate was higher compared with the 1-year and 2-year intervals, and proportion of advanced disease stage in the final round was higher compared with the previous rounds. Trial registration number ISRCTN63545820.

The effectiveness of a computer-tailored smoking cessation intervention for participants in lung cancer screening: A randomised controlled trial

BACKGROUND Lung cancer screening might be a teachable moment for smoking cessation intervention. The objective was to investigate whether a tailored self-help smoking cessation intervention is more effective in inducing smoking cessation compared to a standard brochure in male smokers who participate in the Dutch-Belgian randomised controlled lung cancer screening trial (NELSON trial). METHODS Two random samples of male smokers who had received either a standard brochure (n=642) or a tailoring questionnaire for computer-tailored smoking cessation information (n=642) were sent a questionnaire to measure smoking behaviour two years after randomisation. RESULTS Twenty-three percent of the male smokers in the tailored information group returned a completed tailoring questionnaire and thus received the tailored advice. The prolonged smoking abstinence was slightly, but not statistically significant, lower amongst those randomised in the tailored information group (12.5%) compared with the brochure group (15.6%) (OR=0.77 (95%-CI: 0.56-1.06). The level of education and intention to quit smoking significantly predicted smoking cessation at follow-up (p<0.05). The majority of the respondents did not recall whether and which smoking cessation intervention they had received at randomisation after 2-years of follow-up. CONCLUSION The current study showed no advantage of tailored smoking cessation information over standard self-help information amongst male smokers with a long term smoking history who participate in a lung cancer screening trial after two years of follow-up. However, the low percentage participants who actually received the tailored advice limited the ability to find an advantage.

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. Persistent subsolid pulmonary nodules may be safely monitored with follow-up computed tomography http://ow.ly/CqWN1

Contribution of CT Quantified Emphysema, Air Trapping and Airway Wall Thickness on Pulmonary Function in Male Smokers With and Without COPD

Abstract Emphysema, airway wall thickening and air trapping are associated with chronic obstructive pulmonary disease (COPD). All three can be quantified by computed tomography (CT) of the chest. The goal of the current study is to determine the relative contribution of CT derived parameters on spirometry, lung volume and lung diffusion testing. Emphysema, airway wall thickening and air trapping were quantified automatically on CT in 1,138 male smokers with and without COPD. Emphysema was quantified by the percentage of voxels below –950 Hounsfield Units (HU), airway wall thickness by the square root of wall area for a theoretical airway with 10 mm lumen perimeter (Pi10) and air trapping by the ratio of mean lung density at expiration and inspiration (E/I-ratio). Spirometry, residual volume to total lung capacity (RV/TLC) and diffusion capacity (Kco) were obtained. Standardized regression coefficients (β) were used to analyze the relative contribution of CT changes to pulmonary function measures. The independent contribution of the three CT measures differed per lung function parameter. For the FEV1 airway wall thickness was the most contributing structural lung change (β = –0.46), while for the FEV1/FVC this was emphysema (β = –0.55). For the residual volume (RV) air trapping was most contributing (β = –0.35). Lung diffusion capacity was most influenced by emphysema (β = –0.42). In a cohort of smokers with and without COPD the effect of different CT changes varies per lung function measure and therefore emphysema, airway wall thickness and air trapping need to be taken in account.

Diagnosis of chronic obstructive pulmonary disease in lung cancer screening Computed Tomography scans: independent contribution of emphysema, air trapping and bronchial wall thickening

BackgroundBeyond lung cancer, screening CT contains additional information on other smoking related diseases (e.g. chronic obstructive pulmonary disease, COPD). Since pulmonary function testing is not regularly incorporated in lung cancer screening, imaging biomarkers for COPD are likely to provide important surrogate measures for disease evaluation. Therefore, this study aims to determine the independent diagnostic value of CT emphysema, CT air trapping and CT bronchial wall thickness for COPD in low-dose screening CT scans.MethodsPrebronchodilator spirometry and volumetric inspiratory and expiratory chest CT were obtained on the same day in 1140 male lung cancer screening participants. Emphysema, air trapping and bronchial wall thickness were automatically quantified in the CT scans. Logistic regression analysis was performed to derivate a model to diagnose COPD. The model was internally validated using bootstrapping techniques.ResultsEach of the three CT biomarkers independently contributed diagnostic value for COPD, additional to age, body mass index, smoking history and smoking status. The diagnostic model that included all three CT biomarkers had a sensitivity and specificity of 73.2% and 88.%, respectively. The positive and negative predictive value were 80.2% and 84.2%, respectively. Of all participants, 82.8% was assigned the correct status. The C-statistic was 0.87, and the Net Reclassification Index compared to a model without any CT biomarkers was 44.4%. However, the added value of the expiratory CT data was limited, with an increase in Net Reclassification Index of 4.5% compared to a model with only inspiratory CT data.ConclusionQuantitatively assessed CT emphysema, air trapping and bronchial wall thickness each contain independent diagnostic information for COPD, and these imaging biomarkers might prove useful in the absence of lung function testing and may influence lung cancer screening strategy. Inspiratory CT biomarkers alone may be sufficient to identify patients with COPD in lung cancer screening setting.