Document NGVGx5dGx1oNkL63x0ZQGLqLE

Lung Cancer and Cryptogenic Fibrosing Alveolitis A Population-based Cohort Study RICHARD HUBBARD, ANDREA VENN, SARAH LEWIS, and JOHN BRITTON EXHIBIT Division of Respiratory Medicine, Nottingham University, Nottingham, United Kingdom Cryptogenic fibrosing alveolitis has been reported to be associated with an Increased risk of lung cancer. However, It has recently become apparent that cigarette smoking may be a risk factor for cryptogenic fibrosing alveolitis as well as for lung cancer, and so may confound the association be tween these conditions. We have therefore estimated the independent increase in lung cancer Inci dence In patients with cryptogenic fibrosing alveolitis compared with the general population in a population-based cohort study Involving 890 subjects with cryptogenic fibrosing alveolitis and 5,884 control subjects drawn from the United Kingdom General Practice Research Database. The incidence of lung cancer was markedly Increased among patients with cryptogenic fibrosing alveolitis (rate ra tio [RR] 7.31, 95% confidence Interval [95% Cl] 4.47 to 11.93, p < 0.001), and adjustment for previ ous smoking history had little effect on this odds ratio (adjusted RR: 8.25,95% Cl 4.70 to 11.48, p < 0.001). This increase in lung cancer incidence remained when the analysis was restricted to current smokers (RR 7.36, 95% Cl 1.54 to 35.19, p = 0.012). This study provides clear evidence that the Inci dence of lung cancer is Increased In patients with ciyptogenlc fibrosing alveolitis, and that this effect is independent of the effect of cigarette smoking. Hubbard R, Venn A, Lewis S, Britton J. Lung cancer and cryptogenic fibrosing alveolitis: a population-based cohort study. AM I Rtim OUT CARE MED 2000;161&. Cryptogenic fibrosing alveolitis is now the commonest inter stitial lung disease seen in the United States, and appears to be increasing in prevalence in many developed countries (1, 2). For some years now it has been reported that the risk of lung cancer is high in patients with cryptogenic fibrosing alveolitis (3,4). This observation is important both to the prognosis and counseling of patients with cryptogenic fibrosing alveolitis, and may also be relevant to understanding the causes of lung can cer. However, not all studies have confirmed this finding (5), and recent evidence that cigarette smoking may be an inde pendent risk factor for cryptogenic fibrosing alveolitis (6-8) raises the possibility that the association between these two conditions may be due to confounding by smoking. To clarify the question of whether the incidence of lung can cer is increased in patients with cryptogenic fibrosing alveolitis independently from the effects of cigarette smoking, we have carried out a cohort study using longitudinal data for 890 patients with cryptogenic fibrosing alveolitis and 5,884 control subjects drawn from the UK General Practice Research Database. (Received in original form fune 14, 1999 and in revised form August 5, 1999) Supported by the United Kingdom National Health Service Research and Devel opment Project Grant and the Trent Region NHS R&D Research Scheme. 'orTespondence and requests for reprints should be addressed to Dr. Richard mbbard, Division of Respiratory Medidne, Clinical Sciences Building, City Hospital, HudtnallRoad, Nottingham NG5 IPS, UK. E-mail: Richard,Hubbard@No!tingham. ac.uk Am | Resplr Crit Care Med Vol 161. pp S-S, 2000 Internet address: www.atsjoumals.org METHODS The General Practice Research Database (GPRD) is the largest pri mary care population database in the United Kingdom (9, 10), com prising data from over 7 million patients. General practices (primary care centers) participating in the database are required to ensure that their patient records include details of at least 95% of prescribing and morbidity events. Once this level of data quality has been achieved, the practice is assigned an "up to standard" date, and thereafter monthly checks of data quality are carried out. Practices that do not comply with this quality control are removed from the database. The data for this study were extracted in April 1998 and set up as a relational data base using Microsoft Access. To establish a cohort of patients with cryptogenic fibrosing alveoli tis, alt subjects with a diagnosis of cryptogenic fibrosing alveolitis re corded anywhere in their GPRD record were identified. The date of diagnosis was defined as the date of the first mention of cryptogenic fibrosing alveolitis. A control cohort was established by identifying the six individuals of the same sex, attending the same general prac tice and closest in age to each subject For the purpose of standardiz ing data extraction, each control subject was assigned an "equivalent date of diagnosis" to match his or her case. Because the prognosis of patients with cryptogenic fibrosing alveolitis in association with a con nective tissue disease may be better than that for patients without connective tissue disease (11), all subjects in both cohorts with a re corded diagnosis of connective tissue were excluded. To validate the diagnosis of cryptogenic fibrosing alveolitis in cases, copies of hospital letters and discharge summaries sent to the general practitioners were obtained for a random sample of 36 cases (the expense of obtaining these data limited the sample size for diag nostic validation). Cases of cryptogenic fibrosing alveolitis were con sidered to be valid if the attending consultant physician reported the diagnosis to be cryptogenic fibrosing alveolitis, and in addition re ported that inspiratory crackles were audible on auscultation and that the chest radiograph appearance suggested cryptogenic fibrosing alve- HWBUI0009401 f 6 '' AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 161 2000 olitis. We did not include histological confirmation from an open lung biopsy in our diagnostic criteria because in clinical practice only a small minority of patients undergo this procedure (1,6). The accuracy of a recorded diagnosis of malignant disease, including lung cancer, has been shown to be high in the GPRD (12) and so we did not at tempt to verify the diagnoses of lung cancer in this study. Data on the earliest recorded entry for smoking habit before to the date ofdiagnosis and diagnosis of lung cancer were extracted from the data set Smoking habit was recoded as nonsmoker, current smoker, ex-smoker, pipe or cigar smoker, or missing. For some subjects more detailed information on the number of cigarettes smoked each day was available, and this was grouped as 1 to 10 per day, 11 to 20 per day, and greater than 21 per day. For each subject, the person-years contributed to the cohort was calculated as the difference between the date of registration at the practice or the practice date "up to stan dard," whichever was the later, and the date of diagnosis^! lung can cer or date of last data collection.. We performed a biological validation of the smoking data by esti mating the rate ratios (RR) for theassodation between smoking habit and lung cancer within the control cohort only, using Cox regression with adjustment for sex and age (in quartiles). We compared the smoking habits of patients with cryptogenic fibrosing alveolitis and control subjects using conditional logistic' regression. We compared the lung cancer incidence rate between the two cohorts using Cox re gression, controlling for age and sex and adding multiplicative terms as appropriate to test for. possible, interactions with age (in quartiles) and sex. To determine whether smoking habit confounded the associ ation between cryptogenic fibrosing alveolitis and lung cancer, we performed two additional analyses; first we added the variable for smoking status to the model, and second we restricted our analysis.to include only subjects who were reported to be current smokers. In the second of these analyses we also adjusted for the number of cigarettes smoked per day. All analyses were conducted using STATA and like lihood ratio tests were used for all tests of significance. For Cox re gression models the proportional hazards assumption was tested using the diagnostic section within STATA (phtest 1). The study protocol was reviewed and approved by the General Practice Research Database ethics committee. RESULTS A total of 998 subjects with cryptogenic fibrosing alveolitis and 5,988 control subjects were identified in the data set. One hundred and eight (10.8%) subjects with cryptogenic fibrosing alveolitis and 104 (1.7%) control subjects had a diagnosis of a connective tissue disease recorded and were excluded from sub sequent analyses, leaving cohorts of 890 and 5,884. The mean ( SD) person-years contributed to the cohort was 5.0 1-9 for subjects with cryptogenic fibrosing alveolitis and 6.0 1.7 for control subjects. The median age of subjects with cryptoge nic fibrosing alveolitis was 71 yr (interquartile range 64 to 78. yr) and 553 (62%) were male. We were able to obtain copies of hospital letters and dis charge summaries for 20 of the subsample of 36. The reason for unavailability was death in three cases, patients having left the practice in five cases, and lack of response from the prac tice in eight cases. Review of the available records confirmed the diagnosis in all but.one case, in which the patient had a di agnosis of extrinsic allergic alveolitis. Smoking data were available for 624 subjects with crypto genic fibrosing alveolitis (70%) and''3,752 control subjects (64%). There were 53 cases (0.9%) of lung cancer among the control subjects,'50 of which fell within the period of data up to standard. As expected, there was a marked increased inci dence of lung cancer in current smokers (RR 9.53,95% confi dence interval {95% Cl} 3.81 to 23.86) and ex-smokers (RR 5.89, 95% Cl 1.78 to 19.47) compared with the nonsmokers (Table 1). In addition.there was a strong dose-response rela tionship between the occurrence of lung cancer and the num ber of cigarettes smoked per day within the current smokers (Table 1). Overall there was a small and nonrignificant in crease in the proportion of current and' ex-smokers among the subjects with cryptogenic fibrosing alveolitis compared with control subjects (Table 2). There was no evidence of a doseresponse relationship between number of cigarettes smoked per day in current smokers and risk of cryptogenic fibrosing alveolitis. A total of 39 cases of lung cancer were identified among the subjects with cryptogenic fibrosing alveolitis (4.4%), 38 of which were within the period of data up to standard. The RR for the association between lung cancer and cryptogenic fi-; brosing alveolitis was 7.31 (95% Cl 4.47 to 11.93; p < 0.001).. This RR was'not reduced when smoking statds was added to the model (RR 8.25, 95% Cl 4.70 to 11.48), and there was no evidence of interaction with age or sex. 'When the analysis was restricted to current smokers alone, the association between cryptogenic fibrosing alveolitis and. lung cancer remained (RR 7.36,95% Cl 1.54. to 35.19, p = 0.012) pTable 3), anti this RR was not appreciably altered by adjusting for the number of cigarettes smoked each day (RR 6.67,95% Cl 1.19 to 37.52). J \ f c. DISCUSSION }f TABLE 1 This study provides strong evidence that the risk of lung can r SMOKING STATUS AND RISK OF . LUNG cer is increased markedly in patients with cryptogenic fibros | CANCER IN THE CONTROL SUBJECTS ing alveolitis, and that this effect is independent of smoking habit. The cases in this study represent the largest case popu 8(: - Smoking Status Lung Cancer m Rate Ratio* 95% Cl lation described in the literature to date. We validated, the di agnosis of cryptogenic fibrosing alveolitis according to our pre- Nonsmoker (n = 2,409) 8(0.3) 1 Current smoker (n = 909) 21 (2.3) 933 3.81 to 23.86 Ex-smoker (n = 327) Pipe or cigar smoker (n = 107) 5(1.5) 2(1-9) 5.89 6.92 1.78 to 19.47 1.36 to 35.21 TABLE 2 Missing data(n = 2,132) 17(0.8) SMOKING STATUS AND RISK OF likelihood ratio test p < 0.0001 CRYPTOGENIC FIBROSING ALVEOLITIS Current smokers with data on number of cigarettes smoked per day (n = 868) 1-10 cigarettes per day <n = 395) 6(1.5) 11-20 cigarettes per day (n = 376) 10(2.7) t 1.98 0.67 to 5.88 Smoking Status Nonsmoker Current smoker Ex-smoker Patients {%) (n 890) 382(43) 169(19) 64(7) Control Subjects (%) (n = 5,884) 2,409(41) 909(15) 327(6) Odds Ratio 1 .1.13 1.17 95% Cl * & 0.91 to 1.40 f; 0.85 to 1.61 > 21 cigarettes per day (n = 95) 5 (5.2) 5.40 1.45 to 20.05 Likelihood ratio test for trend p = 0.016 Pipe or cigar smoker Missing data 9(1) 266 (30) 107(2) 2,132(36) 031 0.25 to 1.03 * RRs adjusted (or age and sex. Likelihood ratio test p 0.08 HWBUI0009402 iOO '-Hubbard, Venn, Lewis, etui: lung Cancer and Cryptogenic Fibrosing Alveolitis TABLE 3 ASSOCIATION BETWEEN CRYPTOGENIC FIBROSING ALVEOLITIS AND LUNG CANCER BY SMOKING STATUS Number (%) of Number (%) of Cases of CFA Control Subjects lis- Smoking Status with Lung Cancer with Lung Cancer Rate Ratio 95% Cl p Value on Nonsmokers 12(3.1%) 8 (0.3%) 14.83 3.23 to 68.10 0.001 eft Ex-smokers 2 (3.1%) 5(1.5%) 1.00 0.06 to 15.99 0.9 ac- Pipe and dgar smokers 0 2(1.9%) ed Current smokers IS (6.9%) 21 (2.3%) 7.36 1.54 to 35.19 O.OI2 di- Definition of(abbreviation: CPA = cryptogenic fibrosing alveolitis. to ots defined criteria in a small subgroup of this data set, and found We did, however, find a marked increase in the incidence he the proportion of true positives to be high at 95%. Cryptoge of lung cancer among patients with cryptogenic fibrosing alve up nic fibrosing alveolitis is an uncommon disease and general olitis. Adjustment for the effects of smoking status in the sta ci~ practitioners will usually have only limited experience of it. It tistical'model had little impact on this increased risk, although ifi- IR \ is therefore unlikely that patients will be given the diagnosis without secondary referral to a pulmonary specialist, and so because of likely misclassification we cannot be sure that all of the effect of smoking has been-allowed for in this analysis, and srs the high validity of a positive diagnosis is not unexpected. This thus the potential for residual confounding remains. However, la- finding is also consistent with'previous studies of the accuracy because the association between lung cancer and cryptogenic lit of death certification and hospital discharge summaries which fibrosing alveolitis we found is strong (RR 7), and the associa ers r have demonstrated that patients assigned a diagnosis of cryp tions between cryptogenic fibrosing alveolitis and smoking in- togenic fibrosing alveolitis usualljrdo have the disease (13,14). demonstrated in previous studies (6-8) are weak (odds ratios he We were unable to assess how many control subjects had un less than two), in fact residual confounding is unlikely to have ith diagnosed cryptogenic fibrosing alveolitis (the false-negative a major impact on the association between cryptogenic fibros se:ed [ rate), but given that approximately 1 in 500 people die with cryp togenic fibrosing alveolitis (2) it is likely that there were some ing alveolitis and lung cancer. To. resolve this issue, however, we restricted our.analysis to current smokers alone, and in this ng undiagnosed cases. The effect of these missed cases will, how analysis the increased incidence of lung cancer among subjects ever, be small and will tend to bias the association between with cryptogenic fibrosing alveolitis remained. cryptogenic fibrosing alveolitis and lung cancer toward unity. The majority of patients with cryptogenic fibrosing alveoli The distribution of reported smoking habits in our data set tis are under review by pulmonary specialists and will be more is similar to those published for other studies of the GPRD likely to have chest radiographs than the general public. Lung (12, 15), but on closer inspection they appear incompatible cancer may therefore be more likely to be diagnosed earlier in with the likely lifetime smoking habits of a U.K. population patients with cryptogenic fibrosing alveolitis, but it seems un to with a median age of 70. Although the proportion of current likely that this can account for the strength of association we no smokers reported in the control group is consistent with re observed. Furthermore, the fact that the association is un 'as cent data from the general household survey (20% for people changed in current smokers, in whom investigation of symp en . age 60 yr and older), the level of ex-smokers (6%) is not (16). toms suggestive of lung cancer is likely to be relatively thor tR ? Immediately after the Second World War the majority of men ough for both cases and control subjects, suggests that this IR in the U.K-. were smokers, and even as late as the mid 1970s form of ascertainment bias did not have a major effect. of i . 45% of men and 38% of women were smokers (16). The ex Cryptogenic fibrosing alveolitis produces chronic inflam pected proportion of ex-smokers is therefore in the region of mation within the lungs over many years, and so if the parallel 40 to 50%, so it seems likely that the majority of ex-smokers is drawn with the increased risk of cancer of the colon ob have been misclassified as nonsmokers. served in patients with ulcerative colitis (17), an increase in ' As expected we found strong associations within the con lung cancer is perhaps not surprising. It seems likely that this m- trol cohort between both current and ex-smoking, and lung increase in malignancy is secondary to the chronic inflamma 3S- cancer. Although the size of these effects was large, they are tory and fibrotic processes that occur in the lung, just as the in ng u- likely to underestimate the true effect of smoking if there was extensive misclassification of ex-smokers as nonsmokers. How creased risk of lung cancer after asbestos exposure tends to be most marked in areas of lung-fibrosis (18). It has been specu dire~ ever, because the dose-response analysis of the number of cig arettes smoked per day was restricted to current smokers lated that the chronic inflammation in the lung produces ex tensive DNA damage leading in turn to overexpression and alone, estimates arising from this analysis will not be subject to mutation of the p53-gene resulting in carcinogenesis (19). An- this misclassification problem, and. therefore provide a more other possible explanation is that cryptogenic fibrosing alveo accurate assessment of the increased risk of lung cancer faced litis and lung cancer are both caused by a common etiological r by heavy smokers in comparison to light smokers. In contrast to the results of previous studies (6-8), our re agent Further research is required to determine the precise mechanisms that lead to the dramatic increase in lung cancer sults show only small increase in risk of cryptogenic fibrosing in patients with cryptogenic fibrosing alveolitis. alveolitis for both current and former smokers, which did not reach the conventional level of statistical significance. There are two potential explanations for this finding; either that Acknowledgment: The authors thank Hassy Devalia and Alison Bourke from the Epidemiology and Pharmacology Information Core (EPIC) for their ad there is no effect of cigarette smoking and that the previous vice In using the General Practice Research Database. findings (6-8) were the result of recall or selection bias, or, perhaps more likely, that the effect of smoking is relatively small (6-8) and our estimate of effect was biased toward unity References by misclassification of ex-smokers as nonsmokers. 1. 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