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H. De Koning



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    MS 15 - Current Screening Trials, Current Evidence and Screening Algorithms (ID 33)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 1
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      MS15.02 - NELSON Emerging Data (ID 1913)

      14:15 - 15:45  |  Author(s): H. De Koning

      • Abstract
      • Presentation

      Abstract:
      Background: lung cancer mortality is still the leading cause of cancer death worldwide[(][1][)]. The majority of patients present with advanced disease and the current 5-year survival is only 15%. Despite treatment advances, there is little improvement of prognosis. As the American National Lung cancer Screening trial (NLST) showed that low-dose CT-scan (LDCT) screening can reduce lung cancer mortality in high risk subjects[(][2][)], the United States Preventive Task Force (USPTFS) recommends annual LDCT screening in adults who have a smoking history of at least 30 pack-years, and smoke now or have quit within the past 15 years and are between 55 and 80 years old[(][3][)]. However, there are still some important challenges, f.e. high prevalence of false-positives, overdiagnosis and the optimal screening strategy . In Europe, the sufficiently powered Dutch-Belgian lung cancer screening trial (NELSON) is still ongoing. This trial is currently in the final phase of follow-up prior to definitive analysis and reporting. Results: the NELSON trial has been setup in 2003, in which subjects at high risk for lung cancer were selected from the general population[(][4][)]. After informed consent, 15,791 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,891) (Figure 1). The screen arm participants received LDCT screening at four times: at baseline, after one year, after two years and after two and a half years, whereas the control arm participants received usual care (no screening). According to size and volume doubling time (VDT) of the nodules, three screen results were possible: negative (invitation for the next screening round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Main results of the first three screening rounds showed a favorable cancer stage distribution of the screen-detected lung cancers detected in the NELSON trial compared to the other trials and was more favorable (p<0.001) than in the NLST[(][5][)]. More than half of the screen-detected lung cancers were adenocarcinomas (51.2%) and a large proportion was localized in the right upper lobe (45.0%). Women diagnosed with lung cancer were significantly younger (58.0 vs. 62.0 years; p=0.03), had a lower BMI (23.8 vs 25.9;p=0.003) and were diagnosed at a more favorable cancer stage (p=0.028) than the men diagnosed with lung cancer. From the first screening round up to two years of follow-up after the third round scan, 34 participants were diagnosed with an interval lung cancer[(][6][, ][7][)]. Retrospectively, two-thirds of these interval cancers were visible on the last screening CT; detection errors, interpretation errors, and human errors were identified as the main causes of the failure in half of the interval cancers. Interval cancers were diagnosed at more advanced stages (p<0.001 ), and were more often small cell carcinoma (p=0.003) and less often adenocarcinomas (p=0.005) than screen-detected lung cancers. For the first three rounds combined, sensitivity was 84.6% (95% CI 79.6-89.2%), specificity was 98.6% (95% 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%)[(][6][)]. For the first screening round, the sensitivity was the same, but the specificity was higher in the NELSON trial relative to the NLST: 98.3% vs. 73.4%. The positive predictive value was in our trial (40.4%) substantially higher than in other trials: f.e. 3.8% in the NLST[(][2][)]. Furthermore, our findings showed that the 2 year-probability of developing lung cancer for all included participants was 1.3% (1.2-1.5)[(][8][)]. For screened participants without any nodules this probability (more than half of the included participants) was 0.4%, which suggests that a screening interval of at least two years might be safe to apply in these individuals. In all participants with CT-detected nodules, lung cancer probability was 2.5% (2.1-2.9) but individuals’ probabilities depended strongly on nodule volume, diameter and VDT. New data: the last screening round, which took place 2.5 years after the third round, showed 46 screen-detected lung cancers, of which 58.7% were diagnosed at stage I and 23.8% at stage III/IV. More squamous-cell carcinomas (21.7% vs. 16.3%), small cell carcinomas (6.5% vs. 3.8%) and bronchioalveolar carcinomas (8.7% vs. 5.3%) were detected compared to the first three screening rounds. However, relative to the first three rounds the lung cancer detection rate was lower (0.80 vs 0.80-1.1) and lung cancer was detected at a more advanced stage (stage III/IV; 23.8% vs 8.1). Currently, we are working on the review of blinded medical files of the deceased participants to determine the cause of death, and we are collecting medical data of control arm participants. Figure 1 References 1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014 Jan-Feb;64(1):9-29. 2. National Lung Screening Trial Research T, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. 3. Moyer VA, Force USPST. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014 Mar 4;160(5):330-8. 4. van Klaveren RJ, Oudkerk M, Prokop M, Scholten ET, Nackaerts K, Vernhout R, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med. 2009 Dec 3;361(23):2221-9. 5. Horeweg N, van der Aalst CM, Thunnissen E, Nackaerts K, Weenink C, Groen HJ, et al. Characteristics of lung cancers detected by computer tomography screening in the randomized NELSON trial. Am J Respir Crit Care Med. 2013 Apr 15;187(8):848-54. 6. Horeweg N, Scholten ET, de Jong PA, van der Aalst CM, Weenink C, Lammers JW, et al. Detection of lung cancer through low-dose CT screening (NELSON): a prespecified analysis of screening test performance and interval cancers. Lancet Oncol. 2014 Nov;15(12):1342-50. 7. Scholten ET, Horeweg N, de Koning HJ, Vliegenthart R, Oudkerk M, Mali WP, et al. Computed tomographic characteristics of interval and post screen carcinomas in lung cancer screening. Eur Radiol. 2015 Jan;25(1):81-8. 8. Horeweg N, van Rosmalen J, Heuvelmans MA, van der Aalst CM, Vliegenthart R, Scholten ET, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014 Nov;15(12):1332-41.



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    ORAL 09 - CT Screening - New Data and Risk Assessment (ID 95)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
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      ORAL09.02 - Results of the Fourth Screening Round of the NELSON Lung Cancer Screening Study (ID 1354)

      10:45 - 12:15  |  Author(s): H. De Koning

      • Abstract
      • Presentation
      • Slides

      Background:
      Although screening can reduce lung cancer (LC) mortality, the optimal screening strategy (e.g. numbers of screening rounds, screening interval) is unclear. The use of different screening intervals in the NELSON study is unique and makes it possible to investigate how the screening test performances (e.g. lung cancer detection rate, false positive rate) and characteristics of screen-detected lung cancers might change. This study describes the results of a fourth screening round that took place 2.5 years after the third round.

      Methods:
      The Dutch-Belgian randomized-controlled Lung Cancer Screening Trial (NELSON) aims to investigate whether low-dose CT screening would reduce LC mortality by at least 25% relative to no screening after ten years of follow-up. Therefore, screen group participants were screened four times: at baseline and year 1, 3, and 5.5. Screening test results were classified as negative, indeterminate, or positive based on nodule presence, volume (in case of new nodules) and volume doubling time (in case of previous existing nodules). Participants with an indeterminate test result underwent follow-up screening to classify their final screening test result as positive or negative. Participants with a positive scan result were referred to a pulmonologist for a diagnostic work-up. For this study, we included only participants who had attended all four screening rounds (n=5279). Epidemiological, radiological and clinical characteristics of lung cancers detected in the fourth round were compared with those of the lung cancers detected in the first three rounds. In addition, the risk for lung cancer detection in the fourth round (5.5 year risk) was quantified for subgroups.

      Results:
      In round four, 46 lung cancers were detected; 58.7% were diagnosed at stage I, 15.2% at stage II and 23.8% at stage III/IV. Adenocarcinomas were correlated with better cancer stage distribution, while small-cell carcinomas (SCLC) were associated with higher stage distribution (p=0.064). False positive rate after positive screening was 59.04% (62/105) and the overall false positive rate of the fourth round was 1.15% (62/5383). Relative to the results of the first three rounds, the LC detection rate was lower (0.80 vs 0.80-1.1) and LC was detected at a more advanced stage (23.8% vs 8.1%). In the fourth round more squamous-cell carcinomas (21.7% vs. 16.3%), SCLC (6.5% vs 3.8%) and bronchioloalveolar carcinomas (8.7% vs 5.3%) were detected. No large-cell carcinomas, large-cell neuroendocrine carcinomas or carcinoids were found in the fourth round. Screening results of the first three rounds led to formation of subgroups with significantly different probability of screening result in the fourth round: participants with previous exclusively negative results had a probability of 97.2% of negative screen compared to participants with ≥1 indeterminate or positive screen (94.6% and 87.1%) in the first three rounds. The risk of detecting LC in the fourth round also differed between these subgroups: exclusively negative results (<1.0%) and any time ≥1 indeterminate or positive result (1.5-1.7%).

      Conclusion:
      The LC detection rate after the third screening round was slightly lower and the stage distribution of screen-detected lung cancers in the fourth round was slightly less favorable. However, the differences seem limited.

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