Keywords: lung cancer; pleural plaques; asbestos; CT scan; screening

Transcription

1 &get_box_var; ORIGINAL ARTICLE Asbestos Exposure, Pleural Plaques, and the Risk of Death from Lung Cancer Jean-Claude Pairon 1,2,3, Pascal Andujar 1,2,3, Mickael Rinaldo 4,5,6, Jacques Ameille 7, Patrick Brochard 4,5,6, Soizick Chamming s 7,Bénédicte Clin 8,9,10, Gilbert Ferretti 11,12,13, Antoine Gislard 14, François Laurent 5,15,16, Amandine Luc 17,18, Pascal Wild 17,19, and Christophe Paris 17,18,20 1 INSERM, U955, Equipe 4, Créteil, France; 2 Faculté demédecine, Université Paris-Est Créteil, Créteil, France; 3 Service de Pneumologie et Pathologie Professionnelle, Centre Hospitalier Intercommunal Créteil, DHU A-TVB, Créteil, France; 4 Centre INSERM 897, Bordeaux, France; 5 Faculté demédecine, Université de Bordeaux, Bordeaux, France; 6 Service de Médecine du Travail et de Pathologies Professionnelles, CHU de Bordeaux, Bordeaux, France; 7 Institut Interuniversitaire de Médecine du Travail de Paris-Ile de France, Créteil, France; 8 INSERM U1086, Cancers et Populations, France; 9 Service de Santé au Travail et Pathologie Professionnelle, CHU Caen, Caen, France; 10 Faculté demédecine, Université de Caen, Caen, France; 11 INSERM U823, Grenoble, France; 12 Université Fourier, Grenoble, France; 13 Clinique Universitaire de Radiologie et Imagerie Médicale, CHU Grenoble, Grenoble, France; 14 Service des Maladies Professionnelles, CHU Rouen, Rouen, France; 15 Service d Imagerie Médicale Radiologie Diagnostique et Thérapeutique, CHU de Bordeaux, Bordeaux, France; 16 Centre de Recherche Cardio-thoracique de Bordeaux, INSERM U1045, Bordeaux, France; 17 EA7298 INGRES, Nancy, France; 18 CHU Nancy, Nancy, France; 19 INRS, Direction Scientifique, Vandœuvre-lès-Nancy, France; and 20 Faculté de Médecine, Université de Lorraine, Nancy, France Abstract Rationale: Although asbestos is a well-known lung carcinogen, the pleural plaque lung cancer link remains controversial. Objectives: This study was designed to examine this link in asbestos-exposed workers. Methods: A 6-year follow-up was conducted to study lung cancer mortality in the 5,402 male subjects participating in an asbestosrelated disease screening program conducted from October 2003 to December 2005 in four French regions. Chest computed tomography (CT) scan was performed in all subjects with randomized, independent, double reading of CT scans focusing on benign asbestos-related abnormalities. Cox model survival regression analysis was used to model lung cancer mortality according to the presence of pleural plaques, with age as the main time variable, adjusting for smoking and asbestos cumulative exposure index. All statistical tests were two-sided. Measurements and Main Results: Thirty-six deaths from lung cancer were recorded. Lung cancer mortality was significantly associated with pleural plaques in the follow-up study in terms of both the unadjusted hazard ratio of 2.91 (95% confidence interval = ) and the adjusted hazard ratio of 2.41 (95% confidence interval = ) after adjustment for smoking and asbestos cumulative exposure index. Conclusions: Pleural plaques may be an independent risk factor for lung cancer death in asbestos-exposed workers and could be used as an additional criterion in the definition of high-risk populations eligible for CT screening. Keywords: lung cancer; pleural plaques; asbestos; CT scan; screening ( Received in original form June 12, 2014; accepted in final form November 7, 2014 ) Supported by French National Health Insurance (Occupational Risk Prevention Department), French Ministry of Labor and Social Relations, French Agency for Food, Environmental, and Occupational Health and Safety, ANSES grant 07-CRD-51 and EST 2006/1/43. The study sponsors were not involved in study design (except concerning the choice of French regions in which the study was conducted), data collection, analysis, interpretation, or report writing. The corresponding author had final responsibility for the decision to submit the paper for publication. Authors Contributions: J.-C.P.: Study design, interpretation of data, and manuscript writing. P.A.: Interpretation of data and manuscript writing. M.R.: Expertise on occupational exposure. J.A.: Study design, interpretation of data, and participation in the editing and correction of the final text. P.B.: Study design, acquisition of data, interpretation of data, and participation in the editing and correction of the final text. S.C.: Acquisition of data. B.C.: Acquisition of data, interpretation of data, and participation in the editing and correction of the final text. G.F.: CT scan protocol. A.G.: Acquisition of data, interpretation of data, and participation in the editing and correction of the final text. F.L.: Coordination of CT scan protocol, interpretation of data, and participation in the editing and correction of the final text. A.L.: Statistical analysis and participation in the editing and correction of the final text. P.W.: Statistical analysis strategy and participation in the editing and correction of the final text. C.P.: Study design, statistical analysis strategy, and participation in the editing and correction of the final text. Correspondence and requests for reprints should be addressed to Jean-Claude Pairon, M.D., Ph.D., Service de Pneumologie et Pathologie Professionnelle, Centre Hospitalier Intercommunal de Créteil, 40 avenue de Verdun, Créteil Cedex, France. [email protected] This article has an online supplement, which is accessible from this issue s table of contents at Am J Respir Crit Care Med Vol 190, Iss 12, pp , Dec 15, 2014 Copyright 2014 by the American Thoracic Society Originally Published in Press as DOI: /rccm OC on November 10, 2014 Internet address: Pairon, Andujar, Rinaldo, et al.: Asbestos Exposure, Pleural Plaques, and Lung Cancer 1413

2 At a Glance Commentary Scientific Knowledge on the Subject: Pleural plaques are the most common manifestation of benign asbestos-related disease. The association between pleural plaques and lung cancer remains controversial. What This Study Adds to the Field: Our results indicate that asbestos-exposed subjects with pleural plaques are at high risk of mortality from lung cancer and may benefit from low-dose CT screening, particularly when they are smokers or former smokers. Occupational asbestos exposure is associated with several benign lung and pleural diseases, particularly asbestosis, pleural plaques, visceral pleural fibrosis, rounded atelectasis, and benign pleurisy, and several malignant diseases, mainly mesothelioma and lung cancer (1, 2). It has been clearly established that asbestosrelated interstitial fibrosis (i.e., asbestosis) is associated with an increased risk of lung cancer (3), although asbestos-related lung cancer may occur in the absence of asbestosis (4, 5). However, there is persistent controversy surrounding several aspects of asbestos-related diseases, particularly with respect to the consensus statement workers with asbestos-induced pleural abnormalities are at increased risk for lung cancer compared with workers with similar exposures without these pleural abnormalities (6). Pleural plaques are the lesions most commonly observed among asbestos-exposed subjects (1). Some chest X-ray based studies have shown that subjects with pleural plaques are at increased risk of lung cancer and pleural mesothelioma compared with the general population (4, 7, 8). This association was only to be expected, as subjects with pleural plaques corresponded to the asbestos-exposed population, whereas a large proportion of the reference population had no previous occupational exposure to carcinogens. Screening by low-dose chest CT scan was associated with a significant reduction of lung cancer mortality in some current or former heavy smokers (more than 30 packyears) between the ages of 55 and 75 years (9). After this study, several American scientific societies recommended CT screening in populations similar to the National Lung Screening Trial or other populations considered to be at high risk of lung cancer (10, 11). Recently, a systematic review and metaanalysis showed that CTbased lung cancer detection rates among asbestos-exposed workers were at least equal to the prevalence observed in heavy smokers (12). As CT screening is expected to be beneficial, it is essential to define populations at high risk of lung cancer. In view of the high frequency of pleural plaques in asbestos-exposed subjects (1), it is important to determine whether or not they confer an increased risk of lung cancer compared with individuals without pleural plaques but with similar levels of asbestos exposure, especially in relation to the current debate on CT screening and the definition of populations at risk of lung cancer. A large-scale pilot asbestos-related diseases screening program was initiated in four regions of France in 2003 after a national consensus conference on the clinical surveillance strategy for asbestosexposed workers that proposed periodic chest CT and pulmonary function tests for workers with moderate to high asbestos exposure (13, 14). We have previously reported a significant association between CT detection of pleural plaques and the incidence of mesothelioma in this cohort (15). The present study examined the association between pleural plaques and lung cancer mortality in a 6-year follow-up study of asbestos-exposed workers. Some preliminary results of this study have been previously reported in abstract form (16, 17). Methods Study Population An asbestos-related disease screening program was conducted from October 2003 to December 2005 in four French regions. Retired or unemployed workers with a history of occupational exposure to asbestos were eligible for this survey. Volunteers were invited to participate by means of various approaches and constituted the Asbestos-Related Diseases Cohort. They received a free medical checkup including chest CT and pulmonary function tests (13, 15, 18, 19). Subjects for whom a CT scan was sent to the regional coordinating centers constituted the Asbestos Post Exposure Survey (APEXS) population. The present study included all male subjects of the APEXS. The study was approved by the local hospital ethics committee, and all participants gave their written informed consent after receiving information about the study. Asbestos Exposure and Smoking As previously reported, industrial hygienists used standardized questionnaires to evaluate asbestos exposure on the basis of each subject s complete work history (15, 18). Additional information about asbestos exposure evaluation and tobacco consumption is available in the online supplement. CT Scanning As described previously, a group of chest radiologists designated by the Société Française de Radiologie (French Radiology Society) established a specific protocol (15). Interstitial or pleural abnormalities were registered on a standardized form according to the Fleischner Society glossary of terms (20). Pleural plaques were defined as circumscribed, quadrangular, pleural elevations, with clearly demarcated borders and tissue density, sometimes calcified, presenting a typical topography, at least on some of the images (21). Additional information about CT scan protocol is available in the online supplement. Data Collection and Lung Cancer Study A follow-up study of mortality was organized in the study population. In France, mortality data are available from the INSERM CépiDc Centre d épidémiologie sur les causes de décès, which collects all death certificates. The vital status of each subject of the cohort was collected in December 2012 from the national directory for identification of physical persons, and both underlying and contributing causes of death according to the death certificate were then obtained at the INSERM CEPI DC. Causes of deaths were available until 31 December Statistical Analysis The following variables were used to characterize asbestos exposure: duration of asbestos exposure, cumulative exposure index (CEI), and time since first exposure (TSFE) to asbestos until CT scan. Patients characteristics (age, smoking status at inclusion, asbestos exposure parameters) were compared between patients with lung cancer and subjects without lung cancer, 1414 American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 December

3 by means of Chi-square or two-sided Fisher-Freeman-Halton test, depending on the sample size. Statistical associations between pleural plaques and lung cancer mortality were tested in the follow-up study by survival regression analysis based on a Cox proportional hazards model (44,451 subject-yr). Age was the basic time variable and, according to the Cox model, was therefore modeled nonparametrically taking age into account in a non-prespecified manner, whereas duration of asbestos exposure, CEI [expressed as ln(cei 1 1)] and TSFE to asbestos were independent variables. Only TSFE to asbestos varied with time, as subjects were no longer exposed at the time of inclusion. Age at the time of lung cancer death or age at last news (i.e., 31 December, 2010) was used for each subject. The Cox proportionality assumption was verified graphically. Unadjusted and adjusted hazard ratios (HRs) for these variables (i.e., smoking status, CEI, and TSFE to asbestos) were calculated for the risk of lung cancer death associated with pleural plaques, compared with reference subjects without pleural plaques, according to age at the time of CT scan. The risk of lung cancer death was modeled according to the presence of pleural plaques, adjusted on asbestos exposure variables and tobacco smoking. Statistical analysis was performed with SAS version 9.3 software (SAS Institute, Inc, Cary, NC) and STATA for survival analyses (Stata statistical software, release 11, College Station, TX). All statistical tests were twosided, and statistical significance was defined as P, Results A total of 5,825 CT scans from the 7,225 subjects of the Asbestos-Related Diseases Cohort screening program in whom CT scan was performed were sent to the study centers (APEXS population). After exclusion of women, subjects with uninterpretable CT scan, and subjects considered by industrial hygienists to be unexposed to asbestos, the study population consisted of 5,402 men (Figure 1). Detailed data on occupations and sectors of activity of all jobs held by the subjects included in the study are available in the online supplement. A large proportion of subjects (23.8%) had worked in the construction industry at some time of their working history. General study population characteristics are shown in Table 1. A total of 1,118 subjects (20.7%) presented parietal pleural plaques with or without diaphragmatic pleural plaques. Subjects with pleural plaques were older than subjects without pleural plaques ( yr and yr, respectively; P, ), were more frequently ex-smokers or current smokers (66.8 and 7.5% in subjects with pleural plaques, 57.6 and 7.2% in subjects without pleural plaques; P, ), had a longer mean duration of asbestos exposure ( yr and yr, respectively; P, ) and also higher asbestos CEI ( exposure units 3 yr and exposure units 3 yr, respectively; P, ). A total of 36 cases of death from lung cancer were registered in the follow-up study, between the time of CT scan and 31 December No death from lung cancer was registered during the year after CT scan. The mean duration of asbestos exposure among lung cancer cases was years (range, 5 45 yr), and the mean latency (time between starting the first job considered to be exposed to asbestos and the date of lung cancer) was years (range, yr). Subjects with lung cancer were slightly older at inclusion in the study, tended to have higher asbestos CEI, and comprised a higher proportion of current and former smokers compared with subjects without lung cancer (mean age, yr and yr; P = 0.004; 7,225 subjects of the ARDCO cohort with CT scan 5,825 subjects with CT scan sent to the coordinating center (APEXS population) Study population n=5,402 mean CEI to asbestos, and exposure units 3 yr; P = 0.057; ex-smokers and current smokers, 80.6 and 66.6%, P = 0.09, respectively). No subjects with lung cancer death had interstitial abnormalities compatible with asbestosis on CT scan. The unadjusted lung cancer mortality in the presence or absence of pleural plaques is presented in Figure 2, indicating that the agerelated survival curve of the proportion of subjects not dying from lung cancer was significantly different between subjects with and without pleural plaques (P, 0.003, logrank test). The Cox proportional hazards model demonstrated a statistically significant association between pleural plaques and lung cancer mortality on unadjusted analysis (HR = 2.91, 95% CI = ) and after adjustment for smoking and CEI to asbestos (HR = 2.41, 95% CI = ) (Table 2). As expected, the risk of lung cancer increased with smoking (HR = 2.31 [95% CI = ] and HR = 5.96 [95% CI = ] in ex-smokers and current smokers, respectively). Restriction of the analysis to subjects with available data on smoking gave roughly similar results (data not shown). Discussion The main finding of this study is the significant association between pleural plaques 36 subjects with missing data for gender, age, job history 1,364 subjects with CT scan not sent to the coordinating center (95 women, 1,269 men) 261 women 53 subjects considered to be unexposed to asbestos by industrial hygienists 109 subjects with uninterpretable CT scan Figure 1. Study flow chart. APEXS = Asbestos Post-Exposure Survey; ARDCO = Asbestos-Related Diseases Cohort; CT = computed tomography. Pairon, Andujar, Rinaldo, et al.: Asbestos Exposure, Pleural Plaques, and Lung Cancer 1415

4 Table 1. Study Population Characteristics According to the Presence of Pleural Plaques Characteristics All Subjects (n = 5,402) No Pleural Plaques (n = 4,284) Pleural Plaques (n = 1,118) P Value* Age at inclusion, yr Mean 6 SD ,60 1,185 (21.9) 1,023 (23.9) 162 (14.5) ,023 (74.5) 3,151 (73.5) 872 (78.0) > (3.6) 110 (2.6) 84 (7.5) Smoking status Never smokers 1,384 (25.6) 1,164 (27.2) 220 (19.7) Ex-smokers 3,213 (59.5) 2,466 (57.6) 747 (66.8) Current smokers 392 (7.3) 308 (7.2) 84 (7.5) Missing data 413 (7.6) 346 (8.1) 67 (6.0) Duration of exposure to asbestos, yr Mean 6 SD , (14.9) 684 (16.0) 123 (11.0) ,080 (20.0) 893 (20.8) 187 (16.7) ,360 (43.7) 1,841 (43.0) 519 (46.4) >40 1,155 (21.4) 866 (20.2) 289 (25.8) CEI to asbestos, exposure units 3 yr Mean 6 SD ,104 (20.4) 980 (22.9) 124 (11.1) (17.9) 840 (19.6) 124 (11.1) ,028 (19.0) 859 (20.0) 169 (15.1) ,060 (19.6) 809 (18.9) 251 (22.4) >64 1,246 (23.1) 796 (18.6) 450 (40.2) TFSE until death from lung cancer or date of last follow-up, yr Mean 6 SD , (4.3) 215 (5.0) 19 (1.7) ,498 (27.7) 1,312 (30.6) 186 (16.6) ,885 (53.4) 2,256 (52.7) 629 (56.3) > (14.5) 501 (11.7) 284 (25.4) CT scan interstitial abnormalities No 4,915 (91.0) 3,923 (91.6) 992 (88.7) Abnormal parenchymal findings other than asbestosis 360 (6.7) 268 (6.3) 92 (8.2) Asbestosis 37 (0.7) 23 (0.5) 14 (1.3) Missing data 90 (1.7) 70 (1.6) 20 (1.8) Lung cancer No 5,366 (99.3) 4,265 (99.6) 1,101 (98.5) Yes 36 (0.7) 19 (0.4) 17 (1.5) Definition of abbreviations: CEI = cumulative exposure index to asbestos [ln(cei 1 1)]; CT = computed tomography; TSFE = time since first exposure to asbestos until lung cancer death or date of last news (i.e. 31 December 2012). Data are presented as n (%) unless otherwise noted. *Chi-square or two-sided Fisher-Freeman-Halton test. and lung cancer mortality in a large cohort of asbestos-exposed men, after adjustment for smoking status and asbestos exposure. The strong points of this study include the large study population (n = 5,402), individual estimation of cumulative occupational exposure to asbestos, and accurate determination of pleural plaques based on CT scans interpreted by thoracic radiology experts. However, some weaknesses need to be discussed. The first point concerns the rate of lung cancer in our cohort, as the lung cancer mortality was lower than expected when compared with national rates by standardized mortality ratio (data not shown). Several explanations can be proposed for this low lung cancer mortality. First, the constitution of the cohort was based on voluntary participation. It is also highly probable that a substantial proportion of subjects with lung cancer suspected at initial CT scan in APEXS decided not to return their CT scan to the regional coordinating center, resulting in a healthy worker effect in the study population. We collected information on lung cancer deaths in men for whom CT scan was not sent to the regional coordinating center (1,269 subjects): their mean age and CEI to asbestos were roughly similar to those of men for whom CT scan was sent to the regional coordinating centers. There were 17 lung cancer deaths among these 1,269 subjects, higher than the number of lung cancer deaths observed in the APEXS group, suggesting a selection bias that decreased with increasing duration of follow-up, as most of these cases were registered during the first years of follow-up. However, it is probable that the missing CT scans corresponding to these subjects with lung cancer were independent of the additional presence or absence of pleural plaques. We therefore believe that the potential bias related to the absence of these subjects for the analysis of the link between pleural plaques and lung cancer death in the follow-up study would be fairly limited. Moreover, previous papers have reported that mortality data may lead to erroneous 1416 American Journal of Respiratory and Critical Care Medicine Volume 190 Number 12 December

5 Fraction of subjects without lung cancer death No pleural plaques Pleural plaques Age (years) Figure 2. Proportion of subjects without lung cancer in the mortality study at any given age according to the presence of pleural plaques on CT scan (Kaplan Meier survival curve, log-rank test, P = 0.003, n = 44,451 subject-yr). At-risk subjects at different ages were as follows for the various groups: subjects with no plaques on CT scan: 363 at 55 years, 1,010 at 60 years, 2,286 at 65 years, 2,281 at 70 years, 773 at 75 years, 161 at 80 years, 36 at 85 years; subjects with parietal or diaphragmatic pleural plaques on CT scan: 35 at 55 years, 180 at 60 years, 506 at 65 years, 603 at 70 years, 304 at 75 years, 122 at 80 years, 38 at 85 years. estimations, due to inaccurate completion or competing causes of death (22, 23). Unfortunately, we had no access to individual medical files for subjects registered as having died from lung cancer. However, detailed analysis of four local cancer registries (representing 25% of our population and comprising comprehensive case recording) did not reveal any additional cases of lung cancer and identified a similar diagnosis in 12 out of 13 cases registered as having died from lung cancer. We consider that the use of death certificate data during follow-up may have led to several potential conservative but nondifferential biases according to the presence of pleural plaques on CT scan. A second limitation concerns estimation of exposure to carcinogens. Only asbestos exposure was taken into account in this study, and the role of coexposure to other occupational lung carcinogens therefore cannot be ruled out. Special attention must be paid to the level of asbestos exposure. Only 37 of the 5,402 subjects had asbestosis in this series, on the basis of CT data (14 of these 37 subjects also had pleural plaques). This was a very low prevalence and is again in favor of a selection bias on inclusion in the cohort, as subjects already followed for asbestosis would be expected not to participate in the study. No specific analysis can be performed due to the relatively small number of cases of asbestosis. Moreover, the overall frequency of pleural plaques in the subjects of this cohort was only about 20%, which is moderate, probably indicating that many subjects had experienced moderate levels of cumulative asbestos exposure. The most frequently reported jobs were in the construction industry, which represented one-fourth of the last jobs held by the male study population. Only a few workers were involved in the production of asbestoscontaining materials, which probably explains the pattern of exposure with few heavily exposed subjects more prone to asbestosis and considerably more cases of pleural plaques in these subjects, who presented a fairly high TSFE at the time of CT scan (more than 40 yr in more than 80% of subjects). However, these globally conservative considerations did not affect the specific study of the association of pleural plaques with lung cancer when performing internal Table 2. Association between Pleural Plaques and Lung Cancer Mortality: Cox Model CT Scan Pleural Findings, Smoking, and Asbestos Exposure Parameters Number of Cases* Unadjusted Adjusted for Smoking HR (95% CI) Adjusted for CEI Adjusted for TSFE Final Model Adjusted for Smoking and CEI No pleural plaques on CT 19 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) 1 (Reference) scan (n = 4,284) Parietal or diaphragmatic ( ) 2.71 ( ) 2.57 ( ) 2.97 ( ) 2.41 ( ) pleural plaques on CT scan (n = 1,118) Never smokers (n = 1,384) 4 1 (Reference) 1 (Reference) Ex-smokers (n = 3,213) ( ) 2.23 ( ) Current smokers (n = 392) ( ) 5.89 ( ) Missing data on smoking ( ) 2.77 ( ) (n = 413) CEI NA 1.15 ( ) 1.14 ( ) TSFE NA 0.99 ( ) Definition of abbreviations: CEI = cumulative exposure index to asbestos [ln(cei 1 1)]; CI = confidence interval; CT = computed tomography; HR = hazard ratio; NA = not applicable; TSFE = time since first exposure to asbestos until lung cancer death or date of last news (i.e., 31 December 2012). Parameters included in the final model were those with P, 0.20 in univariate models, and smoking status was a forced variable. Em dash indicates parameter not included in the Cox model. *Number of cases of lung cancer death registered until 31 December Pairon, Andujar, Rinaldo, et al.: Asbestos Exposure, Pleural Plaques, and Lung Cancer 1417

6 comparison inside the study population. We therefore assume that our results based on mortality data remain valid despite these multiple selection effects. Unfortunately, no systematic examination of pulmonary nodules was performed during randomized expert assessment of CT scans. We therefore cannot assume that all cases of lung cancer deaths were incident cases. However, no case of death from lung cancer was registered in the year after CT scan. As expected, pulmonary nodules identified on CT scan by the radiologists who performed CT scan were associated with an excess prevalence of lung cancer (24). As in the previous study on pleural mesothelioma, we had access to information concerning free medical care by National Insurance health system for lung cancer or occupational disease compensation for lung cancer in the study population, which was used as a surrogate for incidence data (morbidity) in the previous study (15). However, no centralized lung cancer registry is available in France, and therefore we could not control for the accuracy of the diagnosis according to these national health insurance sources in the present study. Moreover, 18.8% of subjects with pleural plaques who died from lung cancer in our cohort were not eligible for free medical care versus 3.5% of subjects without pleural plaques who died from lung cancer (P = 0.01, Fisher test). It therefore seems plausible that our cohort may have presented a differential bias specifically between pleural plaques, lung cancer, and compensation procedures. In particular, according to the French compensation system, several subjects who had received compensation for pleural plaques and who already received free medical care for benign pleural disease probably omitted to claim for free medical care when they developed lung cancer, resulting in underestimation of lung cancer cases in patients with known pleural plaques. We therefore assumed that estimation of lung cancer rates based on these procedures would be biased, and we decided not to use this parameter as our main outcome measure. Overall, considering the respective advantages and limitations of morbidity and mortality data, we considered that the accuracy and exhaustiveness of lung cancer diagnosis were considerably better using death certificates than data derived from free medical care and were less subject to bias and misdiagnosis of lung cancer (in particular, mortality data were independent of the diagnosis of pleural plaques). To our knowledge, no published study has documented an association between pleural plaques detected by CT scan and lung cancer, as only a few studies have examined the association between pleural plaques and lung cancer and were mostly based on chest X-ray (4, 7, 8, 25). In the Carotene and Retinol Efficacy Trial asbestos cohort, pleural plaques on baseline chest radiograph were reported to be an independent predictor of subsequent lung cancer after adjustment for duration of asbestos exposure and years since last asbestos exposure (25). However, these authors suggested potential residual confounding by subclinical asbestosis. Chest X-ray has been reported to be associated with a high risk of misclassification of subjects based on the presence or absence of pleural plaques, due to its low sensitivity and specificity for the detection of pleural abnormalities (26). Consequently, the potential link between pleural plaques and lung cancer can still not be considered to be formally demonstrated (27). More recent low-dose CT screening programs have been conducted in asbestos workers (28 32), mainly focusing on early detection of lung cancer and not allowing any conclusions on the possible association between pleural plaques and lung cancer. Certain experimental data from laboratory animals with asbestos fibers and carbon nanotubes support the hypothesis of a link between pleural accumulation of fibrous particles and subsequent development of pleural fibrosis and pleural cancer (33). However, other authors using various cell models have also suggested that protooncogene expression, and several pathways activated by asbestos were elevated in lung and pleura after exposure to asbestos (34). For example, initiation of asbestos-induced redox-dependent signal transduction cascades may therefore be involved in the initiation of several carcinogenic responses, including the lung target. Lung cancer screening remains controversial (35 38). However, as lowdose CT screening is associated with decreased lung cancer mortality among heavy smokers (9), several American and other national scientific societies have recommended low-dose CT to screen for lung cancer in populations similar to that used in the National Lung Screening Trial study (i.e., smokers with more than 30 pack-years aged 55 to 75 or 80 yr) (11, 39 41). Some societies have proposed lowdose CT scan in other populations at high risk of lung cancer (10). On the basis of our results, showing that asbestos-exposed subjects with pleural plaques are at high risk of mortality from lung cancer, subjects with pleural plaques should be considered to be at high risk of lung cancer and may consequently benefit from low-dose CT screening, particularly when they are smokers or former smokers. n Author disclosures are available with the text of this article at Acknowledgment: The authors thank the chest radiologists who participated in interpretation of CT scans (Y. Badachi, C. Beigelman-Aubry, A. Jankowski, V. Latrabe, M. Montaudon) and also thank the other members of the asbestos postexposure program for their contribution to the study design or data collection and the APEXS screening program: E. Abboud, B. Aubert, J. Baron, J. Benichou, A. Bergeret, A. Caillet, P. Catilina, G. Christ de Blasi, F. Conso, E. Guichard, N. Le Stang, M. Letourneux, M.F. Marquignon, M. Maurel, B. Millet, L. Mouchot, M. Pinet, A. Porte, J. L. Rehel, P. Reungoat, R. Ribero, M. Savès, E. Schorle, A. Sobaszek, A. Stoufflet, F.X. Thomas, L. Thorel, and National Health Insurance personnel (Aquitaine, Basse- Normandie, Haute-Normandie, and Rhône- Alpes). References 1. American Thoracic Society. Diagnosis and initial management of nonmalignant diseases related to asbestos. Am J Respir Crit Care Med 2004;170: Prazakova S, Thomas PS, Sandrini A, Yates DH. Asbestos and the lung in the 21st century: an update. Clin Respir J 2014;8: Weiss W. 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