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Harry J De Koning



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    ES 02 - Diagnostic and Interventional Radiology in Lung Cancer: Update 2017 (ID 511)

    • Event: WCLC 2017
    • Type: Educational Session
    • Track: Radiology/Staging/Screening
    • Presentations: 1
    • Now Available
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      ES 02.01 - The Dutch-Belgian Lung Cancer Screening Trial (NELSON) (Now Available) (ID 7587)

      11:00 - 11:15  |  Presenting Author(s): Harry J De Koning

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Background Lung cancer is the most important tobacco-related health problem worldwide, accounting for an estimated 1.3 million deaths each year, representing 28% of all deaths from cancer. Lung cancer screening aims to reduce lung cancer-related mortality with relatively limited harm through early detection and treatment. The US National Lung Screening Trial showed that individuals randomly assigned to screening with low-dose CT scans had 20% lower lung cancer mortality than did those screened with conventional chest radiography. On the basis of a review of the literature and a modelling study, the US Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer for high-risk individuals. However, the balance between benefits and harms of lung cancer screening is still greatly debated. Some investigators suggest the ratio between benefits and harms could be improved through various means. Nevertheless, many questions remain with regard to the implementation of lung cancer screening. Whether nationally implemented programmes can provide similar levels of quality as achieved in these trials remains unclear. The NELSON trial is Europe’s largest running lung cancer screening trial. The main purposes of this trial are; (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. The NELSON trial was set up in 2003 in which subjects with high risk for lung cancer were selected from the general population. After informed consent, 15,792 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,892). Screen arm participants received CT-screening at baseline, after 1 year, after 2 years and after 2,5 years. Control arm participants received usual care (no screening). In the NELSON trial a unique nodule management protocol was used. According to the size and volume doubling time of the nodules, initially three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Those with an indeterminate scan result received a follow-up scan in order to classify the final result as positive or negative. All scans were accomplished at the end of 2012. The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. The cumulative lung cancer detection rate is 3.2% which is comparable with the Danish Lung Cancer Screening Trial (DLCST). Relative to the National Lung Screening Trial (NLST), more lung cancers were found in the NELSON: 3.2% vs. 2.4%. However, the NLST had less screening rounds and a different nodule management protocol and a different study population. False-positive rate after a positive screen result of the NELSON is 59.4%. The overall false-positive (over four rounds) is 1.2% in the NELSON study, which is lower compared to other lung cancer screening studies. A 2-year interval did not lead to significantly more advanced stage lung cancers compared with a 1-year interval (p=0.09). However, a 2.5-year interval led to a stage shift in screening-detected cancers that was significantly less favourable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). It also led to significantly higher proportions of squamous-cell carcinoma, boncho-alveolar carcinoma, and small-cell carcinoma (p<0.001). Compared with a 2-year screening interval, there was a similar tendency towards unfavourable change in stage distribution for a 2.5-year screening interval although this did not reach statistical significance. Also, the interval cancer rate was 1.47(28/19) times higher in the 2.5-year interval compared with the 2-year interval. Moreover, in the last six months before the final fourth screening round the interval rate was 1.3(16/12) times higher than in the first 24 months after the third round, suggesting that a 2.5-year interval may be too long. On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. This cumulative stage distribution of the screening-detected lung cancers in the NELSON trial appears to be favourable compared to those of the DLCST and the NLST (68.1% and 61.6% of cancers at stage I, and 15.9% and 20.0% at stage IIIb/IV, respectively).However, this finding should be interpreted with caution because 1) the NLST used the 6th edition of the TNM staging system, while the NELSON trial used the 7th edition, 2) the NLST and DLCST applied different eligibility criteria than the NELSON trial, and 3) the proportion of over-diagnosed lung cancers in the screening group is yet unknown. The lung cancers found in the NELSON control group have yet to be investigated.

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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    OA 15 - Diagnostic Radiology, Staging and Screening for Lung Cancer II (ID 684)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Radiology/Staging/Screening
    • Presentations: 2
    • Now Available
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      OA 15.06 - Management of Nonresolving New Solid Nodules after Initial Detection in Incidence Rounds of CT Lung Cancer Screening (Now Available) (ID 8922)

      15:25 - 15:35  |  Author(s): Harry J De Koning

      • Abstract
      • Presentation
      • Slides

      Background:
      Low-dose computed tomography (LDCT) lung cancer screening is recommended by US guidelines for high-risk individuals. New solid nodules are regularly found in incidence screening rounds and have a higher lung cancer probability at smaller size than do baseline nodules, leading to the proposal of lower size cutoffs at initial new solid nodule detection. However, currently there is no evidence concerning the risk-stratification of new solid nodules at first LDCT screening after initial detection.

      Method:
      In the ongoing, multicenter, randomized controlled Dutch-Belgian Lung Cancer Screening (NELSON) Trial, 7,295 participants underwent the second and 6,922 participants the third screening round. We included participants with solid non-calcified nodules, that were registered by the NELSON radiologists as new or smaller than 15mm[3] (study detection limit) at previous screens and received a follow-up or regular LDCT screening after initial detection; thereby excluding high-risk nodules according to the NELSON management protocol (nodules ≥500mm[3]). Nodule volume was generated semiautomatically. For assessment of the predictive performance, the area under the receiver operating characteristics curve (AUC) of nodule volume, volume doubling time (VDT), and VDT combined with a predefined 200mm[3] volume cutoff were evaluated with eventual lung cancer diagnosis as outcome.

      Result:
      Overall, 680 participants with 1,020 low and intermediate risk new solid nodules were included. A total of 562 (55%) new solid nodules were resolving, leaving 356 (52%) participants with a nonresolving new solid nodule of whom 25 (7%) were eventually diagnosed with lung cancer in such a nodule. At first follow-up or regular LDCT screening after initial new solid nodule detection, VDT, volume, and VDT combined with the predefined ≥200mm[3] volume cutoff had a high discriminative performance for lung cancer (VDT, AUC: 0.91; volume, AUC: 0.88; VDT and ≥200mm[3] combination, AUC: 0.94). A cutoff combination of ≤590 days VDT or ≥200mm[3] at first LDCT after initial new solid nodule detection, classifying a nodule positive when at least one criterion was fulfilled, provided 100% (95% confidence interval [CI] 84-100%) sensitivity and 84% (95%CI 80-87%) specificity for discriminating lung cancer, with positively classified nodules having a lung cancer probability of 27% (95%CI 19-37%).

      Conclusion:
      More than half of new solid nodules identified in LDCT lung cancer screening are resolving nodules. At first follow-up, a cutoff combination of ≤590 days VDT or ≥200mm[3] volume can be used for risk stratification.

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      OA 15.07 - Value of Nodule Characteristics in Risk-Stratification of New Incident Nodules Detected in CT Lung Cancer Screening (Now Available) (ID 9067)

      15:35 - 15:45  |  Author(s): Harry J De Koning

      • Abstract
      • Presentation
      • Slides

      Background:
      New solid nodules detected in low-dose computed tomography (LDCT) lung cancer screening have a higher lung cancer probability at a smaller size than baseline nodules and lower size cutoff values for risk stratification at initial detection have been proposed. So far, it is unknown whether nodule characteristics, such as morphology or location, could improve risk stratification by size in new solid nodules.

      Method:
      This study forms part of the ongoing, randomized controlled Dutch-Belgian Lung Cancer Screening (NELSON) trial. This analysis included solid non-calcified nodules detected during the three incidence screening rounds and registered by the NELSON radiologists as new or previously below detection limit (15mm[3]). Nodule volume was generated semiautomatically. The predictive performance of nodule characteristics (location, distribution [peripheral, nonperipheral], shape [round, polygonal, irregular], margin [smooth, lobulated, spiculated, irregular], visibility <15mm[3] in retrospect) combined with previously established volume cutoffs (<30mm[3], low risk; 30-<200mm[3], intermediate risk; ≥200mm[3] high risk) was evaluated by multivariable logistic regression analysis with eventual lung cancer diagnosis as outcome. Discrimination of lung cancer based on volume, the final parsimonious model, and the model stratified into three risk groups (low, intermediate, high) was assessed through the area under the receiver operating characteristics curve (AUC) and compared using DeLong's Method.

      Result:
      Overall, 1,280 new nodules were included with 73 (6%) being diagnosed as lung cancer eventually. Of the new nodules visible <15mm[3] in retrospect and now ≥30mm[3], 22% (6/27) were lung cancer. Discrimination based on volume cutoffs (AUC: 0.80, 95% confidence interval [CI] 0.75-0.84) and continuous volume (AUC: 0.82, 95%CI 0.77-0.87) was comparable (P=0.14). After adjustment for volume cutoffs, only location in the right upper lobe (odds ratio [OR] 2.0, 95%CI 1.2-3.4), nonperipheral distribution (OR 2.4, 95%CI 1.4-4.2), and visibility <15mm[3] in retrospect (OR 4.7, 95%CI 1.7-12.8) remained significant predictors. Discrimination based on the model (AUC: 0.85, 95%CI 0.81-0.89) was superior to the volume cutoffs alone (P=0.0002), but when stratified into three risk groups (AUC: 0.82, 95%CI 0.78-0.86) discrimination was comparable (P=0.2).

      Conclusion:
      At initial detection, nodule volume is the strongest predictor for lung cancer in new nodules. Nodule characteristics may further improve lung cancer prediction, but only have limited incremental discriminatory value additional to volume cutoffs in a three-category stratification approach.

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    P2.13 - Radiology/Staging/Screening (ID 714)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Radiology/Staging/Screening
    • Presentations: 2
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      P2.13-007 - Relationship of Nodule Count and Lung Cancer Probability in New Nodules Detected after Baseline in CT Lung Cancer Screening (ID 9065)

      09:30 - 09:30  |  Author(s): Harry J De Koning

      • Abstract

      Background:
      In low-dose computed tomography (LDCT) lung cancer screening new nodules are frequently found after baseline. Currently, there is no evidence concerning the relationship between a participant’s number of nodules and the lung cancer probability of new nodules.

      Method:
      This study is part of the ongoing Dutch-Belgian Randomized Lung Cancer Screening (NELSON) Trial. Participants with solid and sub-solid nodules detected after baseline and registered as new by the NELSON radiologists were included. Three nodule counts were calculated: The participant’s total number of new nodules present at new nodule detection, the participant’s overall number of nodules detected before new nodule detection, and the participants overall number of calcified nodules detected until new nodule detection. The discriminative performance of the nodule counts for prediction of lung cancer was assessed through the area under the receiver operating characteristic curve (AUC). On participant level, a multivariable logistic regression analysis with eventual lung cancer diagnosis in a detected new nodule as outcome was performed, including the nodule count and participant’s largest new nodule size (categorized as <50mm[3], 50-<500mm[3], ≥500mm[3]). On nodule level, the equivalent analysis was performed, including the nodule count and nodule size while adjusting for clustering of data within participants using Huber-White robust estimators.

      Result:
      A total of 706 participants with 964 new nodules (median 1, range 1-12) were included. Eventually, 9% (65/706) of the participants had lung cancer in one of the new nodules. The lung cancer probability was 10% (56/552) for participants with 1 new nodule, 7% (7/100) with 2 new nodules, and 4% (2/54) with ≥3 new nodules (P=0.21). On nodule level, the number of new nodules provided moderate discrimination for lung cancer (AUC: 0.67, P<0.001) and remained a significant predictor after adjusting for nodule size (odds ratio [OR] 0.42, 95% confidence interval [CI] 0.26-0.68, per additional new nodule present). On participant level, the number of new nodules provided poor discrimination for eventual lung cancer diagnosis in a detected new nodule (AUC: 0.55, P=0.22), but was significantly associated with lung cancer when corrected for largest new nodule size (OR 0.61, 95%CI 0.39-0.98 per additional new nodule present). The participant’s overall number of nodules before new nodule detection and the number of calcified nodules were not associated with lung cancer.

      Conclusion:
      While an increased number of detected new nodules signifies a reduced lung cancer probability of each individual new nodule, the impact on the participant’s overall lung cancer probability in the new nodules is limited.

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      P2.13-025 - Selecting the Risk Cut off for the LLP Model (ID 9519)

      09:30 - 09:30  |  Author(s): Harry J De Koning

      • Abstract

      Background:
      The application of risk prediction models for the selection of individuals for lung cancer (LC) screening requires risk thresholds to distinguish between individuals eligible and ineligible for screening. However, little is known about the performance of risk prediction models across different risk thresholds. The UKLS trial utilised the Liverpool Lung Project risk model (LLP~v2~) with a risk threshold of 5% for 5-year LC incidence as the selection criteria in the trial. The UKLS yielded a 1.7% LC detection rate at baseline, which was higher than the NLST or NELSON trials. This study evaluates the performance of different risk thresholds for the selection of individuals for lung cancer screening utilising the LLP~v2~ model.

      Method:
      The performance of the LLP~v2~ risk model to predict 5-year LC incidence was evaluated in ever-smokers from the PLCO. The sensitivity (the proportion of LC in the total population that occur within those selected for screening), specificity (the proportion of individuals excluded from screening which do not develop LC), and proportion of individuals eligible for screening was assessed across a wide range of risk thresholds. In addition, the trade-off between the sensitivity and the proportion of individuals eligible for screening was assessed.

      Result:
      Applying low risk thresholds yielded high sensitivities, at the cost of low specificities and higher ratios of persons eligible per LC included within the eligible population. For example, a LLP~v2~ risk threshold of 1.0% would yield a sensitivity of 91.5% at the cost of a specificity of 37.2% and a ratio of 39 eligible individuals per LC. In contrast, a LLP~v2~ risk threshold of 5.0% would only yield a sensitivity of 36.5%, but had a specificity of 88.8% and a ratio of 18 eligible individuals per LC. A LLP~v2~ risk threshold of 2.03% yielded a similar sensitivity, but higher specificity and a more favourable ratio of eligible individuals per LC compared to the NLST criteria. LLP~v2~ risk thresholds between 2.0-3.0% may provide an advantageous balance between sensitivity and the ratio of eligible individuals per LC.

      Conclusion:
      The level of the risk threshold applied to select individuals for screening has an inverse relationship between the efficacy and efficiency of LC screening. Implementing LC screening programs which use risk prediction models to determine screening eligibility require further assessment of the trade-off between these aspects with regards to the long-term benefits, harms and cost-effectiveness to ascertain the optimal risk threshold.

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    WS 01 - IASLC Supporting the Implementation of Quality Assured Global CT Screening Workshop (By Invitation Only) (ID 632)

    • Event: WCLC 2017
    • Type: Workshop
    • Track: Radiology/Staging/Screening
    • Presentations: 2
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      WS 01.02 - Session 1 (ID 10640)

      08:40 - 08:40  |  Presenting Author(s): Harry J De Koning

      • Abstract
      • Slides

      Abstract not provided

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      WS 01.36 - NELSON – Update (ID 10681)

      15:50 - 16:00  |  Presenting Author(s): Harry J De Koning

      • Abstract

      Abstract:
      Background Lung cancer is the most important tobacco-related health problem worldwide, accounting for an estimated 1.3 million deaths each year, representing 28% of all deaths from cancer. Lung cancer screening aims to reduce lung cancer-related mortality with relatively limited harm through early detection and treatment. The US National Lung Screening Trial showed that individuals randomly assigned to screening with low-dose CT scans had 20% lower lung cancer mortality than did those screened with conventional chest radiography. On the basis of a review of the literature and a modelling study, the US Preventive Services Task Force (USPSTF) recommends annual screening for lung cancer for high-risk individuals. However, the balance between benefits and harms of lung cancer screening is still greatly debated. Some investigators suggest the ratio between benefits and harms could be improved through various means. Nevertheless, many questions remain with regard to the implementation of lung cancer screening. Whether nationally implemented programmes can provide similar levels of quality as achieved in these trials remains unclear. The NELSON trial is Europe’s largest running lung cancer screening trial. The main purposes of this trial are; (1) to see if screening for lung cancer by multi-slice low-dose CT in high risk subjects will lead to a 25% decrease in lung cancer mortality or more; (2) to estimate the impact of lung cancer screening on health related quality of life and smoking cessation; (3) to estimate cost-effectiveness of lung cancer screening. The NELSON trial was set up in 2003 in which subjects with high risk for lung cancer were selected from the general population. After informed consent, 15,792 participants were randomised (1:1) to the screen arm (n=7,900) or the control arm (n=7,892). Screen arm participants received CT-screening at baseline, after 1 year, after 2 years and after 2,5 years. Control arm participants received usual care (no screening). In the NELSON trial a unique nodule management protocol was used. According to the size and volume doubling time of the nodules, initially three screen results were possible: negative (an invitation for the next round), indeterminate (an invitation for a follow-up scan) or positive (referred to the pulmonologist because of suspected lung cancer). Those with an indeterminate scan result received a follow-up scan in order to classify the final result as positive or negative. All scans were accomplished at the end of 2012. The lung cancer detection rate across the four rounds were, respectively: 0.9%, 0.8%, 1.1% and 0.8%. The cumulative lung cancer detection rate is 3.2% which is comparable with the Danish Lung Cancer Screening Trial (DLCST). Relative to the National Lung Screening Trial (NLST), more lung cancers were found in the NELSON: 3.2% vs. 2.4%. However, the NLST had less screening rounds and a different nodule management protocol and a different study population. False-positive rate after a positive screen result of the NELSON is 59.4%. The overall false-positive (over four rounds) is 1.2% in the NELSON study, which is lower compared to other lung cancer screening studies. A 2-year interval did not lead to significantly more advanced stage lung cancers compared with a 1-year interval (p=0.09). However, a 2.5-year interval led to a stage shift in screening-detected cancers that was significantly less favourable than after a 1-year screening interval (e.g. more stage IIIb/IV cancers). It also led to significantly higher proportions of squamous-cell carcinoma, boncho-alveolar carcinoma, and small-cell carcinoma (p<0.001). Compared with a 2-year screening interval, there was a similar tendency towards unfavourable change in stage distribution for a 2.5-year screening interval although this did not reach statistical significance. Also, the interval cancer rate was 1.47(28/19) times higher in the 2.5-year interval compared with the 2-year interval. Moreover, in the last six months before the final fourth screening round the interval rate was 1.3(16/12) times higher than in the first 24 months after the third round, suggesting that a 2.5-year interval may be too long. On average, 69.4% of the screening-detected lung cancers across the four screening rounds in the NELSON trial were diagnosed in stage I and 9.8% in stage IIIb/IV. This cumulative stage distribution of the screening-detected lung cancers in the NELSON trial appears to be favourable compared to those of the DLCST and the NLST (68.1% and 61.6% of cancers at stage I, and 15.9% and 20.0% at stage IIIb/IV, respectively).However, this finding should be interpreted with caution because 1) the NLST used the 6th edition of the TNM staging system, while the NELSON trial used the 7th edition, 2) the NLST and DLCST applied different eligibility criteria than the NELSON trial, and 3) the proportion of over-diagnosed lung cancers in the screening group is yet unknown. The lung cancers found in the NELSON control group have yet to be investigated.