Document G52yxEVZ35k7wZNox4gmDnKx

CHEST Official publication of the American C ollege of Chest Physicians Progression of Asbestosis Predicts Lung Cancer Panu Oksa, Matti Klockars, Antti Karjalainen, Matti S. Huuskonen, Kimmo Vattulainen, Eero Pukkala and Henrik Nordman Chest 1998;113;1517-1521 DOI 10.1378/chest.113.6.1517 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/113/6/1517 Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright1998by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjoumal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692 Downloaded from chestjournal.chestpubs.org by guest on June 2, 2011 1998 by the American College of Chest Physicians Progression of Asbestosis Predicts Lung Cancer* Panu Oksa, MD; Matti Klockars, MD, FCCP; Antti Karjalainen, MD; Matti S. Huuskonen, MD, MSc, FCCP; Kimmo Vattulainen, PhLic; Eero Pukkala, PhD; and Henrik Nordman, MD Study objectives: To explore whether the progression of asbestosis correlates with the risk of lung cancer among patients with asbestosis. Design: A group of 85 asbestosis patients (78 men and 7 women) were radiographically followed up between 1979 and 1987. Two or three posteroanterior radiographs taken from each patient in 1978 to 1979, 1983 to 1984, and 1986 to 1987 were classified according to the International Labour Office 1980 classification and were used to divide the patients into progressors and nonprogressors. Follow-up for cancer was done automatically through the files of the Finnish Cancer Registry from the time of determination of the progression status to December 31, 1994. Predictors of lung cancer risk were studied with a logistic regression model, and the standardized incidence ratio (SIR) was calculated for lung cancer. Results: Of the 24 male patients with progressive small opacity profusion, 11 (46%) developed lung cancer, as opposed to 5 (9%) of the 54 male patients without progression. The SIR for lung cancer was 37 (95% confidence interval, 18 to 66) for the progressors and 4.3 (1.4 to 9.9) for the nonprogressors. In both groups, all the lung cancer cases occurred among smokers or ex smokers. None of the seven female patients showed progressive small opacity profusion. One of them developed lung cancer. In the logistic regression model including all 85 asbestosis patients, radiographic progression of small opacity profusion (p=0.0009) and current smoking (0.0021) were significant predictors of lung cancer morbidity. Conclusions: Asbestosis patients with radiographic progression of small opacity profusion over a few years are at a higher risk of lung cancer than those with a less aggressive course of the disease. The progression of pulmonary fibrosis may be an independent risk factor that, in addition to smoking history and the intensity of asbestos exposure, could be used to estimate lung cancer risk. (CHEST 1998; 113:1517-21) Key words: asbestosis; cohort study; follow-up; ILO classification; incidence; lung cancer; record linkage; smoking Abbreviations: CI=confidence interval; FIOH = Finnish Institute of Occupational Health; ILO=International Labour Office; SIR=standardized incidence ratio A sbestos exposure increases the risk of lung can cer. Some studies have found that the increased risk occurs only if evidence of pulmonary fibrosis is For editorial comment see page 1439 present,12 while others report that the risk is associ ated with exposure dose independently of fibrosis.3 4 *From the Finnish Institute of Occupational Health (Drs. Oksa, Karjalainen, Huuskonen and Nordman, and Mr. Vattulainen), the Department of Public Health (Dr. Klockars), University of Helsinki, and the Finnish Cancer Registry (Dr. Pukkala), Hel sinki, Finland. Supported by the Medical Research Fund of the Tampere University Hospital and the Finnish Work Environment Fund. Manuscript received April 8, 1997; revision accepted November 20, 1997. Reprint requests: Panu Oksa, MD, Tampere Regional Institute of Occupational Health, PO Box 486, 33101 Tampere, Finland A relation has been observed between the severity of asbestosis and death from lung cancer.5 One rela tionship that has yet to be established is whether the progression of pulmonary fibrosis among asbestosis patients correlates with lung cancer risk. This possi ble association was the focus of our present study. Materials and Methods In Finland, the diagnosis for asbestosis during the 1970s was based on a history of confirmed occupational exposure to asbestos and radiographic findings consistent with asbestosis. The occur rence of small opacities large enough to receive a grade of 1/0 or higher according to the radiographic classification of the Inter national Labour Office (ILO) was regarded as asbestosis. If, however, heavily exposed workers had restrictive lung function impairment, impairment of diffusion capacity or physical findings (rales/elubbing), asbestosis was diagnosed even if only minimal parenchymal findings (ILO small opacities grade <l/0) were CHEST/113/6/JUNE, 1998 Downloaded from chestjournal.chestpubs.org by guest on June 2, 2011 1998 by the American College of Chest Physicians 1517 Table 2--Asbestosis Patients With and Without Radiographic Evidence of Asbestosis Progression by Cancer Status Change of ILO Group Lung Cancer Other Cancer* No Cancer Total No. (%) Progressors 0-->1,2 1-- 3 4(17) 1-->2,3 94 5 18(75) 2-->3 1-- 1 2(8) Total 11 4 9 24(100) Nonprogressors 0->0 1-- 8 9(15) 1->1 4 5 35 44 (72) 2,3^2,3 1-- 7 8(13) Total 6 5 50 61(100) *Other cancers among the progressors: rectal cancer, pancreatic cancer, cancer of the thyroid gland, and lymphoma; other cancers among the nonprogressors: mesothelioma (two cases), pancreatic cancer, stomach cancer, and cancer of the uterine cervix. opacity progression, 13 patients were in the major ILO category 0. During the cancer follow-up, two of them (15%) developed lung cancer. Similarity, 13 of the 62 (21%) in ILO category 1 and 2 of the 10 (20%) in ILO category 2 at the beginning of the study developed lung cancer. There were no significant differences in the ILO categories of the progressors and nonprogressors at the beginning of the study, 72% of the nonprogressors and 75% of the progres sors being classified into ILO category 1 (Table 2). According to the forward stepwise logistic regres sion model, only small opacity progression and cur rent smoking were statistically significant predictors of lung cancer (Table 3). Smoking was not a signifi cant predictor of small opacity progression. Among the male patients, the SIR for lung cancer was 37 for the progressors and 4.3 for the nonpro gressors (Table 4). those without progression received a diagnosis of lung cancer during the follow-up. The proportions were even higher if only smokers were considered. In the follow-up of 17,800 North American insula tion workers, about 25% of deaths were due to lung cancer.11 The proportion of lung cancer deaths in that cohort, however, was not reported separately for patients with radiographic asbestosis, or according to smoking status, and thus it cannot be compared directly with that of our patients. All of our patients had been heavily exposed to asbestos, although the intensity of direct or indirect occupational exposure varied. The duration and type of exposure, however, were similar for the patients with progressive small opacity profusion and those without such progression. Differences in the inten sity or type of asbestos exposure are thus unlikely to explain the 10-fold difference in the risk of lung cancer between those with and those without pro gressive asbestosis. It has been reasonably well established that smoking correlates with the ILO small opacity score among patients with asbestosis.1214 If the progressor status were to correlate with the inten sity of smoking, our results would be explained at least partly by differences in smoking. There were slightly more current smokers among the progres sors than among the nonprogressors (42% vs 33%). The difference in the occurrence of lung cancer between the progressors and the nonprogressors, however, was observed among both current smok ers and ex-smokers. In the logistic regression analysis, smoking was not a significant predictor of the progression of small opacity profusion. The progression of asbestosis was a significant predic tor of lung cancer when smoking was included in the statistical model. Even though we could not adjust for the amount of smoking, it seems unlikely Discussion Our results show that asbestosis patients with radiographic progression over a few years have a higher risk of lung cancer than those with a less aggressive course of the disease. The observed risk for lung cancer is high for our asbestosis patients (SIR = 11) in comparison to that of asbestos-exposed cohorts, including both patients with and those without asbestosis. It corresponds, however, to the sixfold risk observed in an international meta-analysis of asbestosis cohorts,8 to the sevenfold risk for all notified Finnish asbestosis patients,9 and to the 10-fold risk observed in a cohort of Finnish asbesto sis patients.10 About 50% of our patients whose asbestosis showed progression, and about 10% of Table 3--Odds Ratios Derived From the Best-fitting Stepwise Logistic Regression Model for the Predictors Associated With Lung Cancer Among the Asbestosis Patients* Variable OR (95% Cl) Progression of small opacities (Yes vs no) Current smoker (Yes vs nonsmoker/ex-smoker) 9.6 (2.53-36.8) 8.3 (2.15-32.2) *The other variables included in the model (but found not to improve the fit significantly) were as follows: ever-smoker (yes/no), age (years) at the beginning of the radiographic follow-up, occupation (asbestos-sprayer/other), exposure time (years in the occupation), ILO minor category at the beginning of the follow-up, and time lag between the diagnosis of asbestosis and the beginning of the follow-up. OR=odds ratio. CHEST/113/6/JUNE, 1998 1519 Downloaded from chestjournal.chestpubs.org by guest on June 2, 2011 1998 by the American College of Chest Physicians Table 4--Observed Numbers of Lung Cancer Cases and the SIRs With the 95% Confidence Intervals for the Male Asbestosis Patients by Progression Category* Study Group Person- Years Obs SIR All Progressors Nonprogressors 582 136 446 16 11 11 37 5 4.3 *Obs=observed numbers of lung cancer cases. 95% Cl 6.2-18 18-66 1.4-9.9 that differences in the intensity of smoking would explain the observed association between the pro gression of asbestosis and the risk of lung cancer. Small opacity assessment according to the ILO classification is subject to interobserver and intraob server variation.15 The effect of this variation was reduced by using only the major categories 0, 1, 2, and 3 and a consensus-based classification. It is noteworthy that none of the patients had their last radiograph classified into a lower major or minor category than the first. By definition, all cases clas sified into the major ILO category of 3 in the first radiograph were classified as nonprogressors be cause category 3 is the highest classification possible. As patients with severe fibrosis may have had a higher risk of lung cancer, the effect of such a classification "bias" would be to reduce the observed difference between the progressors and nonprogres sors. As we studied only patients with asbestosis, the results do not contribute to the scientific discus sion on the association between asbestos and lung cancer in the absence of fibrosis. The carcinogenic processes of asbestos, tobacco smoke, and their interaction are probably complex, and both direct fiber effects and effects mediated through fibrosis may exist.14 At the cellular level, the processes of asbestos-related inflammation, fibrosis, and carci nogenesis seem to be at least somewhat connect ed.16 Our results suggest that the progression of pulmonary fibrosis may be an independent risk factor that, in addition to smoking history and the intensity of asbestos exposure, could be used to estimate lung cancer risk. The association between the risk of lung cancer and the progression of fibrosis may be due at least partly to a common individual susceptibility factor. Genetic factors like glutathione S-transferase and N-acetyltranseferase genotype seem to be related to both nonmalignant and malignant asbestos-related dis orders.17 Our results were obtained from a small cohort of heavily exposed asbestosis patients. The progres sion status was determined several years after the diagnosis of asbestosis, and the lung cancer cases were typically diagnosed >10 years after the diag nosis of asbestosis. Those with progressive asbes tosis had probably had a progressive course of disease already before the beginning of the radio graphic follow-up. The fact that those showing asbestosis progression were on the average 5 years younger than those without progression (Table 1) may indicate that they had had a more rapid course of the disease even before the start of the radiographic follow-up. Yet the ILO category at entry into the radiographic follow-up was similar for the patients with and those without progression (Table 2), and the ILO category at entry was not a significant predictor of lung cancer risk in the logistic regression analyses. Further studies are needed to confirm the pos sible independent role of asbestosis progression in the asbestos-associated risk of lung cancer. Such studies should also address the time factors in volved in the progression of fibrosis and the occurrence of lung cancer. The extremely high incidence of lung cancer among smokers with progressive asbestosis should be taken into ac count when screening or other secondary preven tion activities or studies are planned. References 1 Sluis-Cremer GK, Bezuidenhout BN. Relation between as bestosis and bronchial cancer in amphibole miners. Br J Ind Med 1989; 46:537-40 2 Hughes JM, Weill H. Asbestosis as a precursor of asbestos- related lung cancer: results of a prospective mortality study. Br J Ind Med 1991; 48:229-33 3 Wilkinson P, Hansell DM, Janssen J, et al. Is lung cancer associated with asbestos exposure when there are no small opacities on the chest radiograph. Lancet 1995; 345: 1074-78 4 Henderson DW, de Klerk NH, Hammar SP, et al. Asbestos- related lung cancer: is it attributable to asbestosis, or to asbestos fiber burden? In: Corrin B, ed. 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European Respiratory Soci ety, Annual Congress, Berlin, Sept 20-24, 1997 1520 Downloaded from chestjournal.chestpubs.org by guest on June 2, 2011 1998 by the American College of Chest Physicians Clinical Investigations 10 Oksa P, Pukkala E, Karjalainen A, et al. Cancer incidence and mortality among Finnish asbestos sprayers and in asbestosis and silicosis patients. Am J Ind Med 1997; 31:693-98 11 Selikoff IJ, Seidman H. Asbestos-associated deaths among insulation workers in the United States and Canada, 1967-87. Ann NY Acad Sci 1991; 643:1-14 12 Ducatman AM, Withers BF, Yang WN. Smoking and roentgenographic opacities in US Navy asbestos workers. Chest 1990; 97:810-13 13 Rosenstock L, Barnhart S, Heyer NJ, et al. The relation of pulmonary function, chest roentgenographic abnormalities, and smoking status in an asbestos-exposed cohort. Am Rev Respir Dis 1988; 138:272-77 14 Weiss W. Smoking and pulmonary fibrosis. } Occup Med 1988; 30:33-39 15 Jacobsen M. The International Labor Office classification: use and measure. Ann NY Acad Sci 1991; 643:100-07 16 Rom WN, Travis WD, Brody AR. Cellular and molecular basis of the asbestos-related diseases. Am Rev Respir Dis 1991; 143:408-22 17 Hirvonen A, Saarikoski S, Linnainmaa K, et al. Glutathione S-transferase and N-acetyltransferase genotypes and asbes tos-associated pulmonary disorders. J Natl Cancer Inst 1996; 88:1853-56 AMERICAN COLLEGE OF CHEST PHYSICIANS CONTINUING MEDICAL EDUCATION Occupational & Environmental Lung Disease June 18-20,1998 Tampa, Florida FOR INFORMATION CALL 800*343*2227 OR 847*498*1400 CHEST/113/6/JUNE, 1998 Downloaded from chestjournal.chestpubs.org by guest on June 2, 2011 1998 by the American College of Chest Physicians 1521 Progression of Asbestosis Predicts Lung Cancer Panu Oksa, Matti Klockars, Antti Karjalainen, Matti S. Huuskonen, Kimmo Vattulainen, Eero Pukkala and Henrik Nordman Chest 1998;113; 1517-1521 DOI 10.1378/chest.113.6.1517 This information is current as of June 2, 2011 Updated Information & Services Updated Information and services can be found at: http://chestjournal.chestpubs.org/content/113/6/1517 Cited Bys This article has been cited by 2 HighWire-hosted articles: http://chestjournal.chestpubs.org/content/113/6/1517#related-urls Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.chestpubs.org/site/misc/reprints.xhtml Reprints Information about ordering reprints can be found online: http://www.chestpubs.org/site/misc/reprints.xhtml Citation Alerts Receive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link to the right of the online article. 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