IASLC | International Association for the Study of Lung Cancer

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MS15.01 - NLST, USPSTF Recommendations - Is Screening Going to Happen in USA? (ID 1912)

14:20 - 14:40 | Author(s): J. Mulshine

Abstract
Presentation

Abstract:
In the wake of the demonstrated 20% mortality reduction benefit reported from the randomized National Lung Screening Trial (NLST), the United States Preventive Services Task Forces gave a “B” recommendation for low dose CT screening of for lung cancer in high risk populations (1). This favorable endorsement in turn led the Centers for Medicare and Medicaid Service to fully reimbursement the cost of providing this service by federal and commercial insurers for high risk smokers between the ages of 55-77 who have been smoking within the last 15 years. With these provisions, national lung cancer screening is now being implemented in the United States. The protocol and screening process used for the NLST was fixed at the time of study initiation in 2002 when 4-detector scanners were the default CT device and screening management was delivered based on the existing community standard (2). In the time since the NLST was conducted there have been a number of developments that have improved the process of lung cancer screening services (3). These innovations range from the introduction of more capable CT scanners, lower medical radiation scanning protocols, more effective and efficient diagnostic work up approaches, as well as improved and more tailored surgical approaches. The aggregate effect of all of these advances is that the cost efficiency of this process is also improving (4). Further improvements with clinical management may occur as the use of quantitative CT imaging allows for more consistent measurement of suspicious pulmonary nodules, as size criteria is emerging as a key determinant guiding invasive screening work-up (5). However implementing national CT screening to ensure delivery of high quality, best-practice early lung cancer detection in the target population of tobacco-exposed individuals constitutes a profound challenge. Still the public health impact of tobacco-exposure is singularly lethal. In the United States alone over 438,000 annual deaths are related to tobacco-exposure with lung cancer being the most common cause of tobacco-related death approaching 30% of this total mortality burden. Advocacy groups have worked with academic medical centers as well as community hospitals to address this implementation challenge by creating a consortium of institutions that are conducting screening programs to systematically adopt best standard of screening practice for all components of clinical management (6). A critical aspect of the “Framework” process includes the expectation that participating institutions will prospectively acquire clinical follow-up information so that the outcomes of lung cancer screening efforts can be accessed and reported (6). This effort builds on previous models of cooperative research such as with using institutional feedback to accelerate learning curve in allowing new screening institutions to rapidly implement effective screening process. The best example to date of this approach with screening is the use of the recent I-ELCAP screening outcomes to evaluate the most favorable pulmonary nodule size to use as a threshold for a more invasive diagnostic work-up (7). Increasing the nodule size as the threshold for further diagnostic work-up markedly improves the efficiency of the screening management while reducing the rate of false positive work-ups, cost and morbidity (7). An indispensible element in the national implementation of screening is the simultaneous provision of best practice smoking cessation services for those individuals that continue to smoke. Pyenson and co-workers have reported that routine integration of smoking cessation with the annual CT screening process can improve the cost utility ratio of quality adjusted life years by close to 40% (4). Indisputably implementing national annual CT screening in high risk populations is a significant societal cost. However there are attractive opportunities to leverage this new pattern of care to further benefit health outcomes in this at-risk cohort. For example, the annual CT visit provides a scaffolding to support more intensive research to define better smoking cessation measures. In asymptomatic tobacco-exposed individuals, a growing body of research suggests that the CT scan done to evaluate for early lung cancer also commonly finds individuals with evidence of asymptomatic COPD/emphysema or coronary artery disease (8, 9). These diseases along with lung cancer account for close to 70% of the excess mortality in heavily tobacco-exposed populations. Lung cancer screening will permit additional research opportunities in this tobacco-exposed cohort including catalyzing the development for more effective drugs to manage the early stage of lung cancer. With screening, the frequency of finding early stage lung cancer is greatly increased and focusing on these early stage patients could allow for much more rapid evaluation of new targeted therapeutic agents compared to the current setting. For the same reason, lung cancer screening will also find many more early asymptomatic COPD patients and quantitative CT provides an economical biomarker to allow much more efficient COPD drug development research than is currently possible. Particular classes of drug targets such as immunomodulators could conceivably show benefit in arresting the progression of both early lung cancer and COPD. This time of initial US national screening dissemination is allowing a full national discussion not only about how to provide high quality lung cancer screening services, but also about how to thoughtfully leverage this newly reimbursed screening service to extend the utility of the thoracic imaging encounter and greatly accelerate progress with improving health outcomes in heavily tobacco-exposed populations. At the very least, evidence for one or more of these additional diseases on annual screening may heighten a smoker’s motivation to stop that habit. Other life style interventions such as diet modification and exercise are being successfully employed to manage the consequence of asymptomatic coronary calcification. Life style counseling could also emerge as integral part of the annual CT evaluation as these interventions can have markedly positive impact for a range of tobacco-dependent conditions. The emergence of lung cancer screening as a public health tool has evoked a lively global debate regarding its potential merits. While this healthy debate should continue, there are potentially unprecedented opportunities arising with this new approach to the lethality of chronic tobacco exposure that merit serious consideration. References: 1) Moyer VA. Screening for lung cancer: U.S. preventive services task force recommendation statement. Ann Intern Med. 2013 Dec 31. 2) Aberle D, Adams A, Berg C et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011; 365(5): 395-409. 3) Mulshine JL, D'Amico TA. Issues with implementing a high-quality lung cancer screening program. CA Cancer J Clin. 2014 Jun 27. 4) Villanti AC, Jiang Y, Abrams DB, Pyenson BS. A cost-utility analysis of lung cancer screening and the additional benefits of incorporating smoking cessation interventions. PLoS One. 2013 Aug 7; 8(8): e71379. PMCID: PMC3737088. 5) Mulshine JL1, Avila R, Yankelevitz D et al. Lung Cancer Workshop XI: Tobacco-Induced Disease: Advances in Policy, Early Detection and Management. J Thorac Oncol. 2015 May;10(5):762-7. doi: 10.1097/JTO.0000000000000489. 6) Rights and expectations for excellence in lung cancer screening and continuum of care.[homepage on the Internet]. Available from: http://www.screenforlungcancer.org/national-framework/. 7) Henschke CI. Definition of a positive test result in computed tomography screening for lung cancer: A cohort study. Ann Intern Med. 2013; 158(4): 246-252. 8) Zulueta J, Wisnivesky J, Henschke C, et al. Emphysema scores predict death from COPD and lung cancer. Chest. 2012; 141(5): 1216-1223. 9) Htwe Y, Cham MD, Henschke CI, et al. Coronary artery calcification on low-dose computed tomography: comparison of Agatston and Ordinal Scores. Clin Imaging. 2015 Apr 18. pii: S0899-7071(15)00098-4. doi: 10.1016/j.clinimag.2015.04.006. [Epub ahead of print]

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MS15.02 - NELSON Emerging Data (ID 1913)

14:40 - 15:00 | Author(s): H. De Koning, U. Yousaf-Khan

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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MS15.03 - UKLS Impact of Utilization of Risk Assessment in Trial Selection (ID 1914)

15:00 - 15:20 | Author(s): J.K. Field, A. Devaraj, D.R. Baldwin, S. Duffy

Abstract
Presentation

Abstract:
Future implementation of lung cancer screening programmes will require accurate identification of the population who will benefit the most, to ensure that the benefits outweigh the harms [1]. In the USA, the current criteria for Medicare reimbursement [2], for screening are: age 55 to 77, a smoking history of 30 pack-years or more and smoking within 14 years of entry [3]. However, an in-depth analysis of the NLST showed that there was marked variation in individual risk of lung cancer death, with some screened that had only a low chance of benefit: 20% of participants at lowest risk accounted for only 1% of prevented lung-cancer deaths). [4]Conversely, 88% of the prevented deaths were in the 60% of participants that were at highest risk. The only risk prediction model so far utilised in the recruitment of participants into a CT Lung Cancer Screening RCT, is the LLP~v2~ risk model in the pilot UK lung cancer screening trial (UKLS) [5]. The Liverpool Lung Project (LLP) risk model was based on a case-control study [6]. The LLP~v1~ model utilised conditional logistic regression to develop a model based on factors that were significantly associated with lung cancer (smoking duration, prior diagnosis of pneumonia, occupational exposure to asbestos, prior diagnosis of cancer family history of lung cancer (early onset <60 years) and exposure to asbestosis [6]. The multivariable model was combined with age-standardised incidence data to estimate the absolute risk of developing lung cancer. The discrimination of the LLP was evaluated and demonstrated its predicted benefit for stratifying patients for CT screening by using data from three independent studies from Europe and North America [7]. The LLP~v2~ was used to select subjects with ≥5% risk of developing lung cancer in the next five years for UKLS [8]. This method may improve cost-effectiveness by limiting screening to high-risk individuals. The UKLS approached 247,354 individuals in the two pilot sites, 75,958 people (30.7%) responded positively to the screening invitation. Demographic factors associated with positive response were: higher socioeconomic status, age 56-70 years, and ex-smokers. Those from lower socioeconomic groups and current smokers were less likely to respond. 8,729 (11.5%) positive responders were calculated as high risk of lung cancer. The high risk individuals were more often elderly, current smokers, of lower socioeconomic status and males (2.4x females). 4,055 were randomised into the UKLS. Forty two UKLS participants have been diagnosed with confirmed lung cancer, 34 of these were detected at baseline or three months, giving a baseline prevalence of 1.7% which is significantly higher than that reported by the NLST[9]or NELSON [10]trials. To date, 2.1% of all individuals screened have been diagnosed with lung cancer. 36/42 (85.7%) of the screen-detected cancers were identified at stage 1 or 2. Of those with a confirmed cancer, 17/42 (40.5%) were from the most deprived Index of Multiple Deprivation (IMD) quintile. Figure 1 Figure 1: Percentage of UKLS positive responders (n=75,958) with an LLP risk of >5%, by individual year of age. The positive response rate increased steadily with higher socioeconomic status: 21.7% of individuals in the lowest (most deprived) IMD quintile gave a positive response compared with 39.7% in the highest quintile (p<0.001;) (Figure 2). The proportion of individuals with a high LLP risk score decreased with higher socioeconomic status; ranging from 18.2% in the most deprived quintile to 8.3% in the least deprived quintile (p<0.001;). LLP risk were offset by, the socio-demographic spectrum of the individuals attending the clinic, which was in proportion to that of the original approached sample. People recruited into the UKLS trial therefore spanned all IMD quintiles in roughly equal numbers, including a representative proportion from more deprived postcodes. However, in the high risk sub group of individuals invited for screening, there was a trend towards individuals of higher socioeconomic status being more likely to consent to participate in the trial. Figure 2 Figure 2: Impact of socioeconomic status upon initial response rate (lower line), LLP risk (bars) and trial consent rate (upper line). The demographic and response data from the UKLS pilot trial enable specific recommendations to be made regarding the implementation of any future UK-wide lung LDCT screening programme. Such a programme would need to target those most at risk who may be least likely to take up offers of screening (i.e. the most deprived, current smokers, and the over 70s), and women.

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MS15.04 - Screening in Japan - The JECS Study (ID 1915)

15:20 - 15:40 | Author(s): M. Sagawa, T. JECS Study Group

Abstract
Presentation

Abstract:
Background Lung cancer is the leading cause of cancer death in Japan as well as western countries. To decrease the lung cancer mortality, lung cancer screening using low-dose thoracic computed tomography (CT) may be a promising measure. Several randomized controlled trials (RCTs) are being conducted in the US and Europe to evaluate the efficacy of lung cancer CT screening, and one of those trials, National Lung Screening Trial (NLST), recently reported favorable results. However, the focus of all trials has been the efficacy in smokers.　Adenocarcinomas have increased worldwide in non-smokers, especially in Japan and other Asian countries, and a powerful lung cancer screening modality for non-smokers is also desired. In a recent Japanese cohort study, mortality reduction by thoracic CT screening was suggested even in non-smokers/smokers under 30 pack-years (personal communication). Therefore, we are now conducting the JECS Study (The Japanese randomized trial for evaluating the Efficacy of low-dose thoracic CT Screening for lung cancer in non-smokers and smokers under 30 pack-years). Methods The aim of the JECS study is to assess the efficacy of lung cancer screening tests using low-dose thoracic CT once every five years, compared with chest roentgenography (XP), in people aged 50–64 with a smoking history under 30 pack-years. This study is a multi-regional prospective randomized controlled trial (RCT). The design of the RCT was described elsewhere (Jpn J Clin Oncol 42: 1219-21, 2012). Briefly, participants were recruited from people who ranged from 50-64 years old with smoking history under 30 pack-years, and underwent regular lung cancer screening using chest x-ray in the previous year (this latter requirement may be deleted after 2015). A letter for recruitment to participate in the trial was mailed to each citizen in the target municipalities, who was 50-64 years old with a smoking history under 30 pack-years. The letter explained the eligibility criteria, randomization, follow-up, possible benefit and harm including false-positive, radiation exposure and overdiagnosis. Several meetings were held for those who were interested in the trial for further explanation. People with a history of lung cancer or other malignant diseases as well as a history of thoracic CT screening were excluded. Appropriate written informed consent was completed by each participant who chose to take part in the trial. The participants were randomly assigned into one of 2 groups, a CT group and an XP group. The duration of this screening-follow-up period is 10 years. For the intervention arm, low-dose thoracic CT is provided for each participant in the first year and the sixth year. For the control arm, chest XP is provided for each participant in the first year. All of the participants are encouraged to receive annual routine lung cancer screening using chest XP in the other years. Thoracic CT findings were interpreted by two physicians, based upon the “Low-dose CT Lung Cancer Screening Guidelines for Pulmonary Nodules Management” established by the Japanese Society of CT Screening. A positive rate under 5% is preferred. The interpretation of chest XP findings is performed according to “The Manual of the Lung Cancer Screening” section in the “General rule for clinical and pathological record of lung cancer” published by the Japan Lung Cancer Society. The lung cancer incidence and mortality would be compared. The design of the trial was approved by the Institutional Review Board of the Kanazawa Medical University in 2009, and was registered on the University Hospital Medical Information Network Clinical Trial Registration (UMIN-CTR), Japan in 2011 (registration number: UMIN000005909). The sample size, 17,500 subjects for each arm, is required to detect a 60% mortality reduction after 10 years. At the first step, 3,000 subjects are needed for evaluating QOL and value of contamination of the study. Results As of March 1, 2015, local governments of 20 municipalities in 7 prefectures in Japan permitted that we sent invitation letters for the JECS Study to residents. A letter for recruitment was mailed to each of 9,268 people who were 50-64 years old with a smoking history under 30 pack-years and underwent regular lung cancer screening in the previous year. Of them, 1,812 people (19.6%) sent us a reply letter and wanted to attend one of the meetings for further explanation. One thousand five hundred people actually attended one of the meetings. Finally 1,458 people participated in the JECS Study (15.7% of people who was invited and 97.2% of people who attended a meeting). Of them, 720 people were assigned to CT group and remaining 738 people were assigned to XP group. The screening results of 48 of the 720 people who received low-dose thoracic CT screening (6.7%) were positive, whereas 20 of 738 people who underwent chest XP screening (2.7%) were positive. Until now, three lung cancer patients were diagnosed and 22 patients were under follow-up for the suspicion of having lung cancer in this whole cohort. Comments The results of the NLST demonstrated the efficacy of thoracic CT screening in smokers. However, the efficacy in non-smokers is still completely unknown. Therefore, we started to conduct a randomized trial, the JECS study, to evaluate the efficacy of low-dose thoracic CT screening for lung cancer in non-smokers/smokers under 30 pack-years. This is a first RCT in the world for not heavy-smokers. The preliminary results of this study indicated that 15.7% of the people who received the recruitment letter participated in the RCT. The compliance rate was high in comparison to that in the PLCO or the ITALUNG trial (0.3-7.2%). Over 97% of the 1,500 people who attended a meeting participated in the RCT, which was extremely high. This indicated that the letter for recruitment was effective both for excluding ineligible subjects and for explaining the contents of the trial. The compliance in the preliminary results for this study was very high, and the above RCT appears to be feasible in Japan, if the sufficient budget is obtained. This study was supported in part by the Health and Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare, Japan.

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

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MS15.01 - NLST, USPSTF Recommendations - Is Screening Going to Happen in USA? (ID 1912)

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MS15.02 - NELSON Emerging Data (ID 1913)

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MS15.03 - UKLS Impact of Utilization of Risk Assessment in Trial Selection (ID 1914)

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MS15.04 - Screening in Japan - The JECS Study (ID 1915)

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MINI 22 - New Technology (ID 134)

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MINI22.09 - Discussant for MINI22.05, MINI22.06, MINI22.07, MINI22.08 (ID 3534)

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