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What to Do When a Smoker's CT Scan Is “Normal”?

2012; Elsevier BV; Volume: 141; Issue: 5 Linguagem: Inglês

10.1378/chest.11-1863

1931-3543

Joanna H. Zurawska, Rachel Jen, Stephen Lam, Harvey O. Coxson, Jonathon Leipsic, Don D. Sin,

Occupational and environmental lung diseases

Lung cancer is the leading cause of cancer-related mortality in the United States and around the world. There are > 90 million current and ex-smokers in the United States who are at increased risk of lung cancer. The published data from the National Lung Screening Trial (NLST) suggest that yearly screening with low-dose thoracic CT scan in heavy smokers can reduce lung cancer mortality by 20% and all-cause mortality by 7%. However, to implement this program nationwide using the NLST inclusion and exclusion criteria would be extremely expensive, with CT scan costs alone > $2 billion per annum. In this article, we offer a possible low-cost strategy to risk-stratify smokers on the basis of spirometry measurements and emphysema scoring by radiologists on CT scans. Lung cancer is the leading cause of cancer-related mortality in the United States and around the world. There are > 90 million current and ex-smokers in the United States who are at increased risk of lung cancer. The published data from the National Lung Screening Trial (NLST) suggest that yearly screening with low-dose thoracic CT scan in heavy smokers can reduce lung cancer mortality by 20% and all-cause mortality by 7%. However, to implement this program nationwide using the NLST inclusion and exclusion criteria would be extremely expensive, with CT scan costs alone > $2 billion per annum. In this article, we offer a possible low-cost strategy to risk-stratify smokers on the basis of spirometry measurements and emphysema scoring by radiologists on CT scans. Hounsfield Unit National Lung Screening Trial non-small cell lung cancer relative risk Lung cancer is a global public health problem, causing 1.2 million deaths per year.1Youlden DR Cramb SM Baade PD The International Epidemiology of Lung Cancer: geographical distribution and secular trends.J Thorac Oncol. 2008; 3: 819-831Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar In the early stages, it can be cured with surgery; however, most non-small cell lung cancer (NSCLC) cases are diagnosed in advanced stages when curative therapy is usually not feasible. Thus, the best hope of reducing the burden of lung cancer in the United States and elsewhere is with prevention and early detection. The publication by the National Lung Screening Trial (NLST) offers new hope for reducing lung cancer mortality through screening of heavy smokers.2National Lung Screening Trial Research Team Reduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6940) Google Scholar The study showed that yearly lung cancer screening with low-dose thoracic CT scan for 3 years reduced lung cancer mortality by 20% and all-cause mortality by 7% compared with screening with chest radiography alone in ex-smokers and current smokers between the ages of 55 and 74 years who had at least 30 pack-years of smoking history.2National Lung Screening Trial Research Team Reduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6940) Google Scholar However, these promising data are counterbalanced by some sobering realities. In the United States, there are approximately 9 million people who fulfill the entry criteria for the NLST study. To screen these individuals, the CT scan costs alone could be > $2 billion per year.3Black WC Cost effectiveness of screening in the National Lung Screening Trial, 2011. National Cancer Institute Web site.http://deainfo.nci.nih.gov/advisory/ncab/158_0611/presentations/1230dBlack.pdfGoogle Scholar These costs do not include subsequent follow-up CT scans and other diagnostic imaging studies such as PET scans or invasive procedures such as bronchoscopy, mediastinoscopy, or needle biopsies, which are often needed in the work-up of suspicious-appearing lung nodules. Another important conundrum is what to do with individuals who have “normal” or near-normal baseline CT scans. What advice should be given to such individuals? Should they be told that their risk of lung cancer is negligible and that additional screening CT scans are not needed? Or should they be advised to have yearly CT scans until age 75 years? Or screening CT scans every 2 to 5 years? Neither NLST nor the Dutch Belgian randomized lung cancer screening trial (Nederlands Leuvens Longkanker Screenings Onderzoek [NELSON])4Dutch Belgian randomised lung cancer screening trial (NELSON). NELSON Web site.http://www.nelsonproject.nl/Google Scholar will be able to address this critically important question adequately. However, the early findings from NLST suggest that a “normal” baseline CT scan offers no guarantees to the patients. In that study, many who did not have a suspicious lesion on the baseline CT scan developed new suspicious lesions in subsequent years of screening. Thus, a negative CT scan did not negate the need for future CT scans. A reasonable solution to this conundrum is accurate risk stratification. If we can find a low-cost but highly accurate clinical or biochemical “filter” (ie, algorithm) that can be applied to risk-stratify current and ex-smokers for screening, then low-dose CT screening may become economically acceptable. In this article, we evaluate the possible role of two low-cost strategies, spirometry and emphysema scoring on thoracic CT scans and for risk assessment of lung cancer in those who have already received a baseline CT scan. It has been known for years that reduced lung function is a significant risk factor for lung cancer independent of smoking history.5Wasswa-Kintu S Gan WQ Man SF Pare PD Sin DD Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis.Thorax. 2005; 60: 570-575Crossref PubMed Scopus (239) Google Scholar However, the value of FEV1 as a screening tool for lung cancer remains controversial. A study examined 3,806 subjects as part of an early lung cancer detection program6Calabrò E Randi G La Vecchia C et al.Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes.Eur Respir J. 2010; 35: 146-151Crossref PubMed Scopus (71) Google Scholar and found that reduced FEV1 was a significant risk factor for lung cancer in a linear dose-dependent fashion. Even a relatively small reduction in lung function (eg, as little as 10%) resulted in a tripling of the risk of lung cancer, imposing an attributable risk for lung cancer of 37%. In this study, the c-statistic for FEV1 (ie, the ability of FEV1 to discriminate patients with lung cancer from those without) was 0.70, indicating good discrimination. The most optimal FEV1 cutoff in predicting lung cancer was 85% of predicted, which had a sensitivity of 53% and specificity of 79%.6Calabrò E Randi G La Vecchia C et al.Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes.Eur Respir J. 2010; 35: 146-151Crossref PubMed Scopus (71) Google Scholar Interestingly, in this analysis, the relationship between reduced FEV1 and this risk of lung cancer was driven by lung cancers other than adenocarcinomas. The study by Tammemagi et al7Tammemagi MC Lam SC McWilliams AM Sin DD Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction.Cancer Prev Res (Phila). 2011; 4: 552-561Crossref PubMed Scopus (50) Google Scholar provided supporting data on the role of FEV1 as a screening tool for lung cancer that complemented the findings of Calabrò et al.6Calabrò E Randi G La Vecchia C et al.Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes.Eur Respir J. 2010; 35: 146-151Crossref PubMed Scopus (71) Google Scholar They found that although the risk of lung cancer was associated with reduced lung function, the relationship was modified by sex. In men, the relationship between reduced FEV1 and the risk of lung cancer was exponential, whereas in women the relationship was linear and relatively flat.7Tammemagi MC Lam SC McWilliams AM Sin DD Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction.Cancer Prev Res (Phila). 2011; 4: 552-561Crossref PubMed Scopus (50) Google Scholar By including an interaction term of FEV1 and sex, the c-statistic of the baseline model increased significantly from 0.70 to 0.75. Importantly, by considering FEV1 in the risk prediction model, smokers could be more accurately risk-stratified such that among those who were deemed low risk only 1.3% developed lung cancer during 8 years of follow-up (compared with 1.5% in a model that did not include FEV1), whereas 8.2% of high-risk smokers developed lung cancer (compared with 7.0% in a model that did not include FEV1) and 1.6% of those deemed intermediate risk developed lung cancer (compared with 2.6% in a model that did not include FEV1). If these findings can be validated in a large prospective study, it may be reasonable and cost-effective to target screening for the high-risk individuals, which in the study by Tammemagi et al7Tammemagi MC Lam SC McWilliams AM Sin DD Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction.Cancer Prev Res (Phila). 2011; 4: 552-561Crossref PubMed Scopus (50) Google Scholar constituted 60% of the cohort. By doing this, we may be able to reduce the overall cost of the screening program by 40%. As this study did not include emphysema assessment on CT scans, the incremental improvement in the risk classification with the addition of emphysema scores is not known. Nevertheless, the relative low cost of spirometry makes FEV1 an attractive tool for risk stratification. The predominant risk factor for lung cancer is cigarette smoking, but although approximately 85% of lung cancer occurs in smokers, the majority of smokers do not develop lung cancer.8Alberg AJ Ford JG Samet JM American College of Chest Physicians Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd ed).Chest. 2007; 132: 29S-55SAbstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar Smoking is also a shared etiologic factor for emphysema, which is one of the major morphologic phenotypes of COPD. Some epidemiologic studies suggest a significant relationship between emphysema and lung cancer. Is there a plausible mechanism to link emphysema to lung cancer? The exact pathogenic mechanisms underlying the relationship between emphysema and lung cancer remain obscure. One theory is that emphysematous lungs demonstrate impaired ciliary clearance of particles and carcinogens and as such may be more susceptible to oncogenesis.5Wasswa-Kintu S Gan WQ Man SF Pare PD Sin DD Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis.Thorax. 2005; 60: 570-575Crossref PubMed Scopus (239) Google Scholar, 9Lee G Walser TC Dubinett SM Chronic inflammation, chronic obstructive pulmonary disease, and lung cancer.Curr Opin Pulm Med. 2009; 15: 303-307Crossref PubMed Scopus (143) Google Scholar Another theory suggests that the main pathway is through shared risk factors, including cigarette smoking and aging. The proinflammatory cascade triggered by cigarette smoke unleashes a cascade of cytokines, reactive oxygen species, and proteolytic stress that may promote lung destruction causing emphysema on one hand, and DNA mutagenesis causing lung cancer on the other.10Herbst RS Heymach JV Lippman SM Lung cancer.N Engl J Med. 2008; 359: 1367-1380Crossref PubMed Scopus (2087) Google Scholar The fact that emphysema is associated with lung cancer, even when adjusted for smoking exposure, suggests that there is substantial interindividual variation in the risk imposed by cigarette smoke and that other factors, such as those related to genetic polymorphisms, may also be involved.11Schwartz AG Ruckdeschel JC Familial lung cancer: genetic susceptibility and relationship to chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2006; 173: 16-22Crossref PubMed Scopus (102) Google Scholar Indeed, there are certain genetic loci that have been linked to both emphysema and lung cancer.12Lambrechts D Buysschaert I Zanen P et al.The 15q24/25 susceptibility variant for lung cancer and chronic obstructive pulmonary disease is associated with emphysema.Am J Respir Crit Care Med. 2010; 181: 486-493Crossref PubMed Scopus (90) Google Scholar, 13Wauters E Smeets D Coolen J et al.The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema.Eur Respir J. 2011; 38: 924-931Crossref PubMed Scopus (24) Google Scholar Emphysema has traditionally been defined pathologically as permanent destruction of distal airspaces beyond the terminal bronchioles. With the advent of noninvasive chest imaging techniques, CT scanning has emerged as the radiographic tool of choice for the diagnosis and quantification of emphysema. In general, there are two methods of emphysema identification and quantification: one based on a visual scoring system performed by radiologists and the other based on a computer analysis of the overall density of the lungs (ie, densitometry). To understand the lung cancer risk imposed by emphysema, we searched the literature for English language articles examining the relationship between CT scan-diagnosed emphysema and lung cancer. Our search identified six studies that were eligible for analysis, two of which used a longitudinal design, whereas the other four were case-control studies (Table 1).14de Torres JP Bastarrika G Wisnivesky JP et al.Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest.Chest. 2007; 132: 1932-1938Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 15Wilson DO Weissfeld JL Balkan A et al.Association of radiographic emphysema and airflow obstruction with lung cancer.Am J Respir Crit Care Med. 2008; 178: 738-744Crossref PubMed Scopus (394) Google Scholar, 16Mizuno S Takiguchi Y Fujikawa A et al.Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer.Respirology. 2009; 14: 377-383Crossref PubMed Scopus (37) Google Scholar, 17Maldonado F Bartholmai BJ Swensen SJ Midthun DE Decker PA Jett JR Are airflow obstruction and radiographic evidence of emphysema risk factors for lung cancer? A nested case-control study using quantitative emphysema analysis.Chest. 2010; 138: 1295-1302Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 18Li Y Swensen SJ Karabekmez LG et al.Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment.Cancer Prev Res (Phila). 2011; 4: 43-50Crossref PubMed Scopus (73) Google Scholar, 19Wilson DO Leader JK Fuhrman CR Reilly JJ Sciurba FC Weissfeld JL Quantitative computed tomography analysis, airflow obstruction, and lung cancer in the Pittsburgh lung screening study.J Thorac Oncol. 2011; 6: 1200-1205Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Of the 910 total lung cancer cases reported in the studies, 113 (12%) were small cell lung cancer, and 797 (88%) were NSCLC. The relative risk (RR) for lung cancer according to “any emphysema” reported by radiologists ranged from 1.9 to 4.7, with a pooled RR of 2.34 (95% CI, 1.46-3.76) (Fig 1). Two studies reported prevalence of “≥ 10% emphysema” of 20% and 37% for a mean prevalence of 24%. The pooled RR for lung cancer according to “≥ 10% emphysema” was 1.50 (95% CI, 1.36-1.65). All four of the semiquantitative studies found that emphysema was independently associated with lung cancer in multivariate analyses, with all of these studies adjusting for smoking status. Adjusted OR for lung cancer according to “any emphysema” ranged from 1.73 to 3.14 (Table 2). Two of the studies14de Torres JP Bastarrika G Wisnivesky JP et al.Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest.Chest. 2007; 132: 1932-1938Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar, 15Wilson DO Weissfeld JL Balkan A et al.Association of radiographic emphysema and airflow obstruction with lung cancer.Am J Respir Crit Care Med. 2008; 178: 738-744Crossref PubMed Scopus (394) Google Scholar made adjustments for the presence of airflow limitation on spirometry and still showed a significant relationship between CT scan-based emphysema diagnosis and the risk of lung cancer. In contrast, quantitative analysis of emphysema using a computerized algorithm was not associated with lung cancer (Fig 2). However, these studies were limited by small sample sizes and there were substantial differences in the cutoffs of low attenuation areas used to categorize emphysema across these studies.Table 1Baseline Characteristics of Studies Evaluating the Relationship of CT Scan-Based Emphysema Diagnosis and the Risk of Lung CancerBaseline Patient CharacteristicsEmphysema EvaluationStudy/YearPopulationDesignNo. PatientsNo. Lung Cancer Cases% NSCLC Cases% MenAge, yaMean, unless otherwise specified% Current SmokersAssessment MethodCT Scan ProtocolSTROBE Scorede Torres et al14de Torres JP Bastarrika G Wisnivesky JP et al.Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest.Chest. 2007; 132: 1932-1938Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar/2007Smokers aged ≥ 40 y in lung cancer screening trial; SpainCohort1,16623837454NRSemiquantitative; visual scoring of emphysema by two separate readers using five-point scaleSomatom Plus 4, Somatom Volume Zoom, Siemens scanner (single-slice helical), 20/43 mA, 120/140 kVp, 1.25/8 mm collimation20Wilson et al15Wilson DO Weissfeld JL Balkan A et al.Association of radiographic emphysema and airflow obstruction with lung cancer.Am J Respir Crit Care Med. 2008; 178: 738-744Crossref PubMed Scopus (394) Google Scholar/2008Smokers aged 50–79 y in lung cancer screening trial; Pittsburgh, PACohort3,638998751.4NR60.2Semiquantitative; visual scoring of emphysema by three separate readers using five-point scaleGE Systems scanner (multidetector helical), 40 mA, 140 kVp, 2.5 mm collimation20Mizuno et al16Mizuno S Takiguchi Y Fujikawa A et al.Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer.Respirology. 2009; 14: 377-383Crossref PubMed Scopus (37) Google Scholar/2009Controls from lung cancer screening trial, cases from admissions to academic hospital; JapanCase-control5641418975.9Median 63 (cases), 62 (controls)31.7Semiquantitative; based on % low-attenuation area using defined scoring system; threshold −700 HU; assessed by four separate readersLightSpeed, GE Healthcare scanner, 110 mA,120 kVp, 1.25 mm collimation (cases); Aquilion, Toshiba scanner (both multidetector helical), 50 mA,120 kVp, 2 mm collimation (controls)18Maldonado et al17Maldonado F Bartholmai BJ Swensen SJ Midthun DE Decker PA Jett JR Are airflow obstruction and radiographic evidence of emphysema risk factors for lung cancer? A nested case-control study using quantitative emphysema analysis.Chest. 2010; 138: 1295-1302Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar/2010Smokers aged ≥ 50 y in lung cancer screening trial; Rochester, MNCase-control441648838.362.458Quantitative; % low-attenuation voxels/total lung volume on 3D reconstruction; threshold < −900 HUHigh Speed Advantage, GE Systems scanner (helical mode), 40 mA, 120 kVp, 5 mm collimation20Li et al18Li Y Swensen SJ Karabekmez LG et al.Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment.Cancer Prev Res (Phila). 2011; 4: 43-50Crossref PubMed Scopus (73) Google Scholar/2011Controls from lung cancer screening trial in smokers aged ≥ 50 y, cases from observational lung cancer study; Rochester, MNCase-control1,015565876066.842.7Semiquantitative; visual estimate of % emphysema assessed by one reader; threshold < −950 HUNot specified; all scans obtained using standard-dose protocol20Wilson et al19Wilson DO Leader JK Fuhrman CR Reilly JJ Sciurba FC Weissfeld JL Quantitative computed tomography analysis, airflow obstruction, and lung cancer in the Pittsburgh lung screening study.J Thorac Oncol. 2011; 6: 1200-1205Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar/2011Smokers aged 50–79 y in lung cancer screening trial; Pittsburgh, PACase-control2341178752.1NR82.1Semiquantitative; visual scoring of emphysema by three separate readers using 5-point scale; quantitative; % low-attenuation voxels/total lung volume on 3D reconstruction; threshold < −910 HUGE LightSpeed scanner (multidetector helical), mean 24.4 mA, 120/140 kVp, 2.5 mm collimation183D = three-dimensional; HU = Hounsfield Units; NR = not reported or impossible to ascertain.a Mean, unless otherwise specified Open table in a new tab Table 2Multivariate Analysis of Lung Cancer Risk According to CT Scan-Diagnosed EmphysemaStudyExtent of EmphysemaOR95% CICovariatesSemiquantitative/visual de Torres et al14de Torres JP Bastarrika G Wisnivesky JP et al.Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest.Chest. 2007; 132: 1932-1938Abstract Full Text Full Text PDF PubMed Scopus (347) Google Scholar/2007Any2.511.01–6.23Age, sex, smoking history, airflow obstruction Wilson et al15Wilson DO Weissfeld JL Balkan A et al.Association of radiographic emphysema and airflow obstruction with lung cancer.Am J Respir Crit Care Med. 2008; 178: 738-744Crossref PubMed Scopus (394) Google Scholar/2008Any3.141.91–5.15Age, sex, smoking history, airflow obstruction< 10%2.481.37–4.4910%–25%4.432.53–7.79≥ 25%2.561.26–5.20 Mizuno et al16Mizuno S Takiguchi Y Fujikawa A et al.Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer.Respirology. 2009; 14: 377-383Crossref PubMed Scopus (37) Google Scholar/2009Any1.731.02–2.94Age, sex, smoking history, airflow obstruction, lung restriction, fibrosis/ground glass attenuation Li et al18Li Y Swensen SJ Karabekmez LG et al.Effect of emphysema on lung cancer risk in smokers: a computed tomography-based assessment.Cancer Prev Res (Phila). 2011; 4: 43-50Crossref PubMed Scopus (73) Google Scholar/2011Any2.792.05–3.81Pack-years, other lung disease, family history of lung cancer≥ 5%3.82.78–5.19≥ 10%3.332.30–4.82Quantitative Maldonado et al17Maldonado F Bartholmai BJ Swensen SJ Midthun DE Decker PA Jett JR Are airflow obstruction and radiographic evidence of emphysema risk factors for lung cancer? A nested case-control study using quantitative emphysema analysis.Chest. 2010; 138: 1295-1302Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar/2010% Emphysema as continuous variable1.04 (NS)0.82–1.33Age, sex, smoking history< 5%1.00 (NS)NR5%–9%1.90 (NS)0.90–4.0310%–14%2.17 (NS)0.96–4.91≥ 15%1.57 (NS)0.73–3.37Lung volume as continuous variable1.021.00–1.03NS = not statistically significant. See Table 1 legend for expansion of other abbreviation. Open table in a new tab Figure 2The relationship between LAA on CT scans and the risk of lung cancer. LAA = low attenuation area; WMD = weighted mean difference.View Large Image Figure ViewerDownload Hi-res image Download (PPT) 3D = three-dimensional; HU = Hounsfield Units; NR = not reported or impossible to ascertain. NS = not statistically significant. See Table 1 legend for expansion of other abbreviation. The reason for the discordance in the finding between visual scoring of emphysema and quantitative emphysema scores is unclear. However, in general, radiologists look beyond low-attenuation areas for more subtle but complex signs of emphysema, such as “holes” in the parenchyma.20Gietema HA Müller NL Fauerbach PV Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators et al.Quantifying the extent of emphysema: factors associated with radiologists' estimations and quantitative indices of emphysema severity using the ECLIPSE cohort.Acad Radiol. 2011; 18: 661-671Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar This approach, although seemingly more crude than quantitative assessment of emphysema, may be more discerning than a Hounsfield Unit (HU)-based threshold, especially in experienced hands. A diagnosis of emphysema on CT scan relies on the identification of very specific CT scan findings. These are clearly defined by the Fleischner Society as focal areas or regions of low attenuation, typically without visible walls.21Hansell DM Bankier AA MacMahon H McLoud TC Müller NL Remy J Fleischner Society: glossary of terms for thoracic imaging.Radiology. 2008; 246: 697-722Crossref PubMed Scopus (2735) Google Scholar This strict definition allows the radiologist to differentiate emphysema from other low-attenuation abnormalities in the chest, such as pulmonary cysts, areas of air trapping, mosaicism with oligemia, and image noise. All of these abnormalities pose a significant issue for a HU threshold-based computerized segmentation algorithm. Going forward, several issues need to addressed and clarified before CT scan-based emphysema scores (both visual- and quantitative-based scoring systems) can be used to risk-stratify patients for lung cancer. First, it is essential that future studies use similar or preferably the same scoring system to estimate emphysema on CT scans. For the visual approach, one reasonable scoring system is that proposed by Goddard et al.22Goddard PR Nicholson EM Laszlo G Watt I Computed tomography in pulmonary emphysema.Clin Radiol. 1982; 33: 379-387Abstract Full Text PDF PubMed Scopus (370) Google Scholar It is a four-point quartile scoring system with a score of 1 given if < 25% of the lobe is affected and 4 if > 75% of a lobe is affected. Although this scoring system is rudimentary, it is reproducible and affords a consistent estimation of the burden of disease. For quantitative analysis, the extent of emphysema can be estimated using the threshold method quantifying the percent of voxels with an apparent x-ray attenuation value below certain thresholds (eg, −950 HU), and the size of the emphysematous lesions may be estimated using the low-attenuation cluster method, which takes the slope of the relationship between the cumulative size of the low attenuation areas plotted against the cumulative number of lesions on a log-log scale. If possible, both of these measures should be used in future lung cancer studies, as they provide complementary information. Lung cancer screening with annual CT scans will be prohibitively expensive unless some filters are in place to target high-risk subjects for screening. No such tools currently exist that can guide policy makers and clinicians to develop rational and cost-effective screening strategies. There are some very intriguing data on FEV1 and CT scan-based emphysema scores that suggest that with additional studies these measurements could be incorporated into clinically useful decision aids for clinicians (Fig 3). Until more data are available, a reasonable strategy for lung cancer screening with CT scans is to first identify a group at high risk for lung cancer. As suggested by NLST, such a group may be composed of current or ex-smokers between the ages of 55 and 74 years2National Lung Screening Trial Research Team Reduced lung-cancer mortality with low-dose computed tomographic screening.N Engl J Med. 2011; 365: 395-409Crossref PubMed Scopus (6940) Google Scholar with ≥ 30 pack-years of smoking history.23Tammemagi CM Pinsky PF Caporaso NE et al.Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation.J Natl Cancer Inst. 2011; 103: 1058-1068Crossref PubMed Scopus (219) Google Scholar The screening tool can be further refined using additional sociodemographic and clinical data24Bach PB Kattan MW Thornquist MD et al.Variations in lung cancer risk among smokers.J Natl Cancer Inst. 2003; 95: 470-478Crossref PubMed Scopus (487) Google Scholar, 25Spitz MR Hong WK Amos CI et al.A risk model for prediction of lung cancer.J Natl Cancer Inst. 2007; 99: 715-726Crossref PubMed Scopus (321) Google Scholar (eg, environmental smoke exposure) as well as FEV1 as suggested by Tammemagi et al.7Tammemagi MC Lam SC McWilliams AM Sin DD Incremental value of pulmonary function and sputum DNA image cytometry in lung cancer risk prediction.Cancer Prev Res (Phila). 2011; 4: 552-561Crossref PubMed Scopus (50) Google Scholar, 23Tammemagi CM Pinsky PF Caporaso NE et al.Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation.J Natl Cancer Inst. 2011; 103: 1058-1068Crossref PubMed Scopus (219) Google Scholar For those with prior CT scans (and without suspicious nodules), the presence of emphysema can be incorporated into a risk-management strategy for future CT scan-based screening. There are > 94 million adult Americans who are current or ex-smokers and, thus, are at enhanced risk of lung cancer. More than $28 billion per annum would be required to screen these individuals annually with a low-dose CT scan, making this a cost-prohibitive strategy. There is a pressing need to develop some clinical filters for screening. With the available CT scan and spirometry data, NELSON, NLST, and other study groups have an opportunity to determine whether FEV1 and emphysema scores are indeed predictive of lung cancer and most importantly can be used, in addition to traditional markers such as smoking status and age, to develop a simple clinical algorithm for accurate risk-stratification. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Coxson is a recipient of GlaxoSmithKline Clinical Scientist Award. Dr Sin is supported by a Canada Research Chair in COPD. Drs Zurawska, Jen, Lam, and Leipsic have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or in the preparation of the manuscript.