IASLC | International Association for the Study of Lung Cancer

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ES 02.01 - The Dutch-Belgian Lung Cancer Screening Trial (NELSON) (ID 7587)

11:00 - 12:30 | Presenting Author(s): Harry J De Koning

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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.

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ES 02.02 - The Fleischner Guideline / Lung-RADs (ID 7588)

11:00 - 12:30 | Presenting Author(s): Matthew Eric Callister

Abstract
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Abstract:
The Fleischner Society guidelines (most recently revised in 2017) [1,2] are the most referenced guidelines for management of pulmonary nodules detected incidentally on CT images. In 2014, the American College of Radiology produced the Lung-RADS assessment categories specifically to guide management of nodules detected by Low Dose CT screening for lung cancer [3]. Nodule management guidelines have also been published by the American College of Chest Physicians (ACCP) in 2013 [4] and the British Thoracic Society (BTS) in 2015 [5]. Whilst the Fleisher guidelines and Lung-RADS predominantly offer specific recommendations for interpretation of CT images and guidance for surveillance imaging, the ACCP and BTS guidelines in addition offer more proscriptive recommendations for ongoing investigation or treatment of larger nodules with PET-CT, biopsy techniques, and surgical/non-surgical treatment. There is much common ground between the four proposals. Most of the high quality evidence for nodule management comes from screening studies that only included patients at high risk of lung cancer, and there is an acknowledged paucity of evidence for guiding nodule management in patients with a lower background risk of cancer. There is agreement about the need to minimise radiation dose for CT surveillance for nodules, and an acknowledgement of the low likelihood of malignancy in small nodules detected through any route. All guidelines recognise that sub-solid nodules require a different management algorithm which incorporates a less interventional approach (acknowledging the more indolent nature of the tumours that these may represent) but by implication the need for longer follow-up before nodules can be deemed benign or harmless. Differences between the recommendations are summarised in Table 1. The size below which nodules can be ignored differs slightly between the guidelines. Lung-RADS recommends no intervention for nodules <6mm (or <4mm for new nodules) on the assumption that the patient continues with annual LDCT screening. Determining a threshold for discharge of small nodules detected out a screening program is of potentially greater significance, as a patient with a small malignant nodule discharged in this context is likely to have a poor outcome if that nodule subsequently presents as a symptomatic lung cancer. The Fleischner Society guidelines select a threshold of 1% lung cancer risk (roughly equating to 6mm diameter) below which surveillance is not routinely recommended (although is an option if the patient is high risk). The BTS guidelines base their discharge threshold of 80mm[3] (5mm) on data from the NELSON screening trial which demonstrated this to be the threshold below which the presence of a nodule did not appear to increase the likelihood of subsequently diagnosed lung cancer above that seen in screening participants with no nodules [6]. More recent data from NELSON has suggested a different size threshold for nodules newly appearing during the screening process. New incident nodules above 27mm[3] appeared to confer an increased risk of cancer [7], and this is reflected in the Lung-RADS category 3 which suggests a 6 month surveillance scan for new incident nodules ≥4mm. When an incidentally detected nodule can be shown to be new compared to recent CT imaging, a lower threshold for ongoing surveillance is probably merited, although not currently recommended in the three relevant guidelines. The use of composite risk-prediction scores in guiding nodule management differs between the various guidelines. The Fleischner guidelines highlight the various risk factors to be considered when deciding management but do not recommend use of a risk prediction score. The ACCP guidelines recommend either qualitative assessment of the probability of malignancy, or quantitative assessment using a validated model (referencing the Mayo model [8]). The BTS guideline recommend use of the Pancan lung cancer risk calculator [9] to decide which nodules should be evaluated with PET-CT on the basis of a validation study in a UK population [10]. Subsequent studies from Australia and Denmark have also demonstrated the utility of the Pancan model in screening studies. The guidelines also differ in the extent to which they promote use of semi-automated volumetry. No reference to volumetry is made in Lung-RADS assessment categories. Both the Fleischner and BTS guidelines acknowledge the better reproducibility of volumetry over diameter measurements and the superior sensitivity in detecting growth. Both however highlight the need to use identical software versions if comparing nodule volumes between scans due to clearly demonstrated variability between different software programs/versions. The Fleischner guidelines comment that robust validated volumetry is not currently widely used hence continuing to base recommendations predominantly on caliper long and short-axis diameter measurements, whereas the BTS guidelines have strongly recommended volumetry in an attempt to drive uptake of this technology. The definition of what constitutes nodule growth also differs between the guidelines. Lung-RADS and the Fleischner guidelines define growth as an increase is diameter of >1.5mm and ≥2mm respectively, reflecting possible inaccuracy in smaller increments in size according to caliper measurements. The threshold of 25% change in volume recommended in the BTS guideline is based on the nodule management stategy used in both NELSON and UKLS. By way of comparison, nodule growth from 7mm to 9mm represents a 113% increase in volume (from 180mm[3] to 381mm[3]). All four guidelines/assessment categories have been published within the last 5 years, and there have been few validation studies published to date. Lung-RADS was compared to the National Comprehensive Care Network guidelines for lung cancer screening and was shown to increase the positive predictive value without increasing false-negative results. Prospective comparisons between these guidelines/approaches are needed to guide future practice.

	Fleischner [1,2]	Lung-RADS [3]	BTS [4]	ACCP [5]
Remit	Incidentally detected nodules	Screen-detected nodules	Incidentally and screen-detected nodules	Incidentally and screen-detected nodules
Assessment of size	Average of long & short axis diameter	Average diameter	Semi-automated volumetry	As per Fleischner guidelines
Threshold for discharge	<6mm - optional follow-up below this size if high risk	<6mm (revert to annual screen)	<80mm[3]	<5mm - optional follow-up below this size if high risk
Selection of further investigation for larger nodules	>8mm consider PET, PET-CT or biopsy	≥8mm PET-CT, biopsy or assess with Brock/Pancan score	≥8mm Brock/ Pancan score to guide PET-CT/other tests	≥8mm clinical judge-ment or validated model (e.g. Mayo)
Assessment of growth	Increase in size of ≥2mm	Increase in size of >1.5mm	Increase in volume of >25%	Not specified
Pure Ground Glass Nodules	Surveillance only for 5 years duration	Revert to annual screen (unless >20mm)	Risk assess, but surveillance pref-erred (for 4 years)	CT surveillance for 3 years

Table 1: Summary of significant differences between nodule management strategies recommended by various guidelines/assessment categories Fleischner [1,2] Lung-RADS [3] BTS [4] ACCP [5] Remit Incidentally detected nodules Screen-detected nodules Incidentally and screen-detected nodules Incidentally and screen-detected nodules Assessment of size Average of long & short axis diameter Average diameter Semi-automated volumetry where possible As per Fleischner guidelines Threshold for discharge <6mm - optional follow-up below this size if high risk <6mm (revert to annual screen) <80mm3 <5mm - optional follow-up below this size if high risk Selection of further investigation for larger nodules >8mm - consider PET, PET-CT or biopsy ≥8mm - PET-CT, biopsy or assess with Brock/ Pancan score ≥8mm - Brock/ Pancan score to guide PET-CT/other tests ≥8mm - clinical judgement or validated model (e.g. Mayo) Assessment of growth Increase in size of ≥2mm Increase in size of >1.5mm Increase in volume of >25% Not specified Pure Ground Glass Nodules Surveillance only for 5 years duration Revert to annual screen (unless >20mm) Risk assess, but surveillance preferred (for 4 years) CT surveillance for 3 years References [1] MacMahon H, Naidich DP, Goo JM, et al. Guidelines for Management of incidental pulmonary nodules detected on CT images: from the Fleischner Society 2017. Radiology 2017;284:228-243 [2] Bankier AA, MacMahon H, Goo JM, et al. Recommendations for measuring pulmonary nodules at CT: a statement from the Fleischner Society. Radiology 2017, epub ahead of print. [3] American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS). Available at : https://www.acr.org/Quality-Safety/Resources/LungRADS . Release date April 28, 2014, Accessed August 1, 2017. [4] Gould MK, Donington J, Lynch WR, et al. Evaluation of individuals with pulmonary nodules: when is it lung cancer? Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e93s-e120S. [5] Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70:ii1-ii54 [6] Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a pre-specified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014;15:1332–41. [7] Walter JE, Heuvelmans MA, de Jong PA, et al. 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. Lancet Oncol. 2016;17:907-16. [8] Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–55. [9] McWilliams A, Tammemagi MC, Mayo JR, et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910–9. [10] Al-Ameri AMP, Malhotra P, Thygesen H, et al. Risk of malignancy in pulmonary nodules: a validation study of four prediction models. Lung Cancer 2015;89:27-30

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ES 02.03 - Radiologic Implications of the WHO Classification for Lung Cancer (ID 8026)

11:00 - 12:30 | Presenting Author(s): Kavita Garg

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Abstract:
Marked heterogeneity exists in clinical, radiologic, molecular, and pathologic features among adenocarcinoma cases. Therefore, a new Classification of Lung Adenocarcinoma was proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society in 2011 (1). The 2011 classification addressed three important weaknesses in the previous classification. First, it eliminated the term bronchioloalveolar carcinoma (BAC). Second, it added new terminologies of carcinoma-in-situ (CIS), and minimally invasive adenocarcinoma (MIA) to recognize that minimal invasion (< 5mm) had nearly similar clinical outcome as noninvasive nodules. Third, it replaced the terminology of mixed subtype of adenocarcinoma. In this revised classification, invasive lung ADCs were divided into the five subtypes; lepidic, acinar, solid, papillary, and micropapillary patterns primarily based on histologic features. The term predominant is appended to all categories of invasive ADC, as most of these tumors consist of mixtures of the subtypes (1). The widespread availability of MDCT and abundance of new information obtained especially from low-dose CT lung cancer screening programs, have increased our understanding of the types and management of small peripheral lung nodules encountered in daily clinical practice, in particular, the importance and prevalence of subsolid pulmonary nodules (atypical adenomatous hyperplasia (AAH), ground glass nodules (GGN) and part-solid nodules). Thin-section CT has emerged as a new biomarker for lung adenocarcinoma subtypes. The approval of CT as a screening tool for lung cancer was based primarily on National Lung Screening Trial (NLST) results. The NLST recently found that Low Dose Helical Computed Tomography (LDCT) reduces lung cancer specific mortality by 20% relative to chest x-ray screening in a cohort at high risk of lung cancer (2). However, significant concerns remain regarding its high false positive rate, overdiagnosis, cost effectiveness and concerns related to radiation burden from repeat CT screens. There is a trade-of between early detection of lung cancer vs unnecessary work-up of indeterminate nodules resulting in many side effects including anxiety, radiation exposure from CT follow-up to assess for growth, cost and morbidity and mortality related to biopsy or resection of a benign nodule. It is expected that false positive rate would decrease by 50% using more accurate phenotyping of a nodule using the lung CT reporting and data system (Lung-RADS) appropriately (3). One of the major changes proposed in Lung-RADS is the size threshold for positive screen, from 4 mm in NLST to 6 mm for solid nodules and 20 mm for nonsolid nodules. Tissue sampling would be used primarily for larger than 15 mm solid nodules or PET positive nodules with larger than 8 mm solid component. False positive rate would still be likely not acceptable for an individual using this approach. There is need for more accurate nodule assessment and risk stratification as given our current understanding that genetic make-up of a nodule is the ultimate determinant of clinical outcome (4). Further improvements in stage discrimination and management of lung nodules could be expected in the future, as more robust data related to texture analyses of tumors, their genetic profiles and impact of those on clinical outcome becomes available (5-8). Simple measuring the tumor size with one-dimentional (Response Evaluation Criteria in Solid Tumors (or RECIST) long-axis measurements do not reflect the complexity of tumor morphology or behavior. Also, it may not be predictive of therapeutic benefit. In contrast, the emerging field of radiomics is a high-throughput process in which a large number of shape, edge, and texture imaging features are extracted, quantified, and stored in databases in an objective, reproducible, and mineable form. Once transformed into a quantifiable form, radiologic tumor properties can be linked to underlying genetic alterations and to medical outcomes. Marked heterogeneity in genetic properties of different cells in the same tumor is typical and reflects ongoing intratumoral evolution. Clinical imaging is well suited to measure temporal and spatial heterogeneity. Subjective imaging descriptors of cancers are inadequate to capture this heterogeneity and must be replaced by quantitative metrics that enable statistical comparisons between features describing intratumoral heterogeneity and clinical outcomes and molecular properties. A recent study adds further support toward taking a conservative approach in the management and treatment of patients with part-solid nodules especially when the solid component is small. This strategy is already reflected in the Lung-RADS guidelines, which recommend focusing on the size of the solid component in the part-solid nodule instead of on the overall nodule size. For the future, the critical issue will be further refinements for the follow-up of nonsolid and part-solid nodules based on the size or volume that allow a process of shared decision making in selecting appropriate management and treatment (9-10). This lecture will address the radiologic implications of this new lung adenocarcinoma classification. References: 1. Travis W, Brambilla E, Noguchi M, et al. IASLC/ATS/ERS International multidisciplinary classification of lung adenocarcinoma. J Thoracic Oncol 2011;6:244-285 2. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395-409 3. American College of Radiology: Lung-RADS Version 1.0 Assessment Categories Release date: April 28, 2014. Accessed on 17 March, 2015 4. McWilliams, A. et al. Probability of cancer in pulmonary nodules detected on first screening CT. The New England journal of medicine 2013;369: 910-919, doi:10.1056/NEJMoa1214726 5. Lambin P, et al. Radiomics: extracting more information from medical images using advanced feature analysis. Eur J Cancer 2012;48 (4):441-446 6. Gatenby RA, Grove O, Gillies RJ. Radiology 2013;269:8-15 7. Bartholmai BJ, Koo CW, Johnson GB, et al. Pulmonary nodule characterization including computer analysis and quantitative features. J Thorac Imaging 2015;30 (2) 139-156 8. Song SH, Park H, Lee G, et al. Imaging phenotyping using Radiomics to predict micropapillary pattern within lung adenocarcinoma. JTO 2017;12:624-632 9. Rowena Yip, Henschke CI, Xu DM, et al. Lung cancers manifesting as part-solid nodules in the National Lung Screening Trial. AJR 2017;208:1011-1021 10. American College of Radiology website. Lung CT Screening Reporting and Data System (Lung-RADS). Accessed January 11, 2016 11. MacMahon H, Naidich DP, Goo JM, et al. Guidelines for management of incidental pulmonary nodules detected on CT images: FROM THE Fleischner Society 2017. Radiology 2017;284:228-243

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ES 02.04 - Interventional Radiology on Personalized Medicine for Lung Cancer (ID 7590)

11:00 - 12:30 | Presenting Author(s): Tae Jung Kim

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Recent advances molecular target therapies have provided a remarkable benefit to patients harboring specific genetic alterations. Most patients treated against molecular targets eventually develop resistance even after initial dramatic response. T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy. Osimertinib has been recently approved and demonstrated dramatic response in NSCLC patients with T790M mutation. In tumors with anaplastic lymphoma kinase (ALK) or ROS-1 rearrangement, cereitinib has been approved and recommended in case of crizotinib resistance. Therefore, clinical demand for rebiopsy to identify these druggable mutations has been increasing, and rebiopsy plays an important role in clinical application for exploring resistant mechanisms and determining further therapeutic strategies. This session will focus on rebiopsy issues in relapsed NSCLCs. We will describe the growing need for rebiopsy and review the current data about rebiopsy, both published and unpublished. We will discuss the technical aspects of interventional radiology-guided rebiopsy; patient selection, guiding-modalities, lesion targeting, and tissue sampling. Hurdles and solutions for rebiopsy will be discussed with appropriate examples. Current role of liquid biopsy in comparison with conventional tissue biopsy will be briefly covered. Finally, we will discuss how to collaborate more effectively as a lung cancer multidisciplinary team from radiologists’ perspective.

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ES 02.05 - MRI and Advanced Applications for Lung Cancer (ID 7591)

11:00 - 12:30 | Presenting Author(s): Yoshiharu Ohno

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Since magnetic resonance imaging (MRI) was introduced for the assessment of thoracic and lung diseases, various limitations. However, from 2000, various techniques have been demonstrated their utility for lung cancer evaluations, and is now covered by health insurance in many countries including North America, Eastern Asia and Europe. In this lecture, I will show you these recent advances in lung MRI focusing on its application in lung cancer evaluation, especially with regard to 1) pulmonary nodule detection, 2) pulmonary nodule and mass assessment, and 3) lung cancer stage and recurrence evaluations.

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Shuji Sakai

Moderator of

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

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ES 02.01 - The Dutch-Belgian Lung Cancer Screening Trial (NELSON) (ID 7587)

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ES 02.02 - The Fleischner Guideline / Lung-RADs (ID 7588)

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ES 02.03 - Radiologic Implications of the WHO Classification for Lung Cancer (ID 8026)

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ES 02.04 - Interventional Radiology on Personalized Medicine for Lung Cancer (ID 7590)

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ES 02.05 - MRI and Advanced Applications for Lung Cancer (ID 7591)

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

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WS 01.29 - Session 5: The Current Global Implementation of CT Lung Cancer Screening Programs (ID 10674)

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