Chronic Obstructive Pulmonary Disease Is Associated with Lung Cancer Mortality in a Prospective Study of Never Smokers

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Chronic Obstructive Pulmonary Disease Is Associated
with Lung Cancer Mortality in a Prospective Study of
Never Smokers
Michelle C. Turner1, Yue Chen2, Daniel Krewski1,2, Eugenia E. Calle3, and Michael J. Thun3
1
 McLaughlin Center for Population Health Risk Assessment, Institute of Population Health, and 2Department of Epidemiology and Community
Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada; and 3Department of Epidemiology and Surveillance Research,
American Cancer Society, Atlanta, Georgia

Rationale: Several studies have suggested that previous lung disease
may increase the risk of lung cancer. It is important to clarify the
                                                                                       AT A GLANCE COMMENTARY
association between previous lung disease and lung cancer risk in
the general population.                                                                Scientific Knowledge on the Subject
Objectives: The association between self-reported physician-
                                                                                       A number of factors, including a personal history of certain
diagnosed chronic bronchitis and emphysema and lung cancer mor-
                                                                                       nonmalignant lung diseases, have been postulated to corre-
tality was examined in a U.S. prospective study of 448,600 lifelong
nonsmokers who were cancer-free at baseline.                                           late with susceptibility for developing lung cancer.
Methods: During the 20-year follow-up period from 1982 to 2002,
1,759 lung cancer deaths occurred. Cox proportional hazards mod-
                                                                                       What This Study Adds to the Field
els were used to obtain adjusted hazard ratios (HRs) for lung cancer
mortality associated with chronic bronchitis and emphysema as                          Increased lung cancer risk is associated with nonmalignant
well as for both of these diseases together.                                           pulmonary conditions, especially emphysema, even in life-
Measurements and Main Results: Lung cancer mortality was signifi-                      long nonsmokers.
cantly associated with both emphysema (HR, 1.66; 95% confidence
interval [CI], 1.06, 2.59) and with the combined endpoint of emphy-
sema and chronic bronchitis (HR, 2.44; 95% CI, 1.22, 4.90) in analy-
ses that combined men and women. No association was observed
with chronic bronchitis alone (HR, 0.96; 95% CI, 0.72, 1.28) in the
                                                                                     be biased by residual confounding from smoking. Furthermore,
overall analysis, although the association was stronger in men
(HR, 1.59; 95% CI, 0.95, 2.66) than women (HR, 0.82; 95% CI, 0.58,
                                                                                     nearly all previous investigations are case-control studies and
1.16; p for interaction, 0.04). The association between emphysema                    may be subject to biases in exposure assessment because patients
and lung cancer was stronger in analyses that excluded early years                   with lung cancer may preferentially recall their experience of
of follow-up.                                                                        chronic lung diseases. Because lung cancer is highly fatal, many
Conclusions: This large prospective study strengthens the evidence that              of these studies use a large proportion of proxy respondents
increased lung cancer risk is associated with nonmalignant pulmonary                 (from 32 to 65%), or surviving cases only (4–6, 8, 10, 11). Patients
conditions, especially emphysema, even in lifelong nonsmokers.                       with symptoms of lung cancer can be misdiagnosed as having
                                                                                     other lung disease. Several, mostly small, prospective studies
Keywords: lung neoplasms; pulmonary disease, chronic obstructive;
                                                                                     including current and former smokers also reported inverse rela-
bronchitis, chronic; pulmonary emphysema; United States
                                                                                     tionships between lung function and lung cancer incidence or
Lung cancer is currently the leading cause of cancer death in                        mortality (12).
the United States (1). In 2006, it is estimated that a total of                          Studies in China have also reported similar findings; however,
174,470 new cases and 162,460 lung cancer deaths occurred (1).                       it has also been established that the high rates of both chronic
Although cigarette smoking accounts for the great majority of                        obstructive pulmonary disease (COPD) and lung cancer found,
lung cancer cases, there are many who smoke but who do not                           including in studies of lifelong nonsmokers, are believed to result
develop this disease; there are also nonsmoking lung cancer                          primarily from indoor air pollution due to coal burning and
cases (2). A number of other factors, including a personal history                   fumes from cooking oil (13–23). It is therefore unclear to what
of certain nonmalignant lung diseases, have been postulated to                       extent the COPD disease process may contribute to lung cancer
correlate with susceptibility for developing lung cancer (3).                        risk, or whether both COPD and lung cancer are a consequence
    Several studies have suggested that chronic bronchitis and                       of the underlying exposure, or perhaps a combination of both.
emphysema may increase the risk of lung cancer (4–11). Most                              It is important to clarify the association between chronic
of the lung cancer cases in published studies occurred in current                    bronchitis and emphysema and lung cancer in the general popu-
or former cigarette smokers; thus, the observed associations may                     lation. In this article, we examine the association between
                                                                                     chronic bronchitis and emphysema and lung cancer mortality in
                                                                                     a large population of lifelong nonsmokers in the United States
                                                                                     using data from the Cancer Prevention Study II (CPS-II) cohort.
(Received in original form December 11, 2006; accepted in final form May 3, 2007 )
Correspondence and requests for reprints should be addressed to Michelle C.          METHODS
Turner, M.Sc. McLaughlin Centre for Population Health Risk Assessment, Institute
of Population Health, University of Ottawa, One Stewart Street, Room 318A,           Study Population
Ottawa, ON, Canada K1N 6N5. E-mail: mturner@uottawa.ca
                                                                                     The CPS-II cohort is a prospective study of cancer mortality established
Am J Respir Crit Care Med Vol 176. pp 285–290, 2007
Originally Published in Press as DOI: 10.1164/rccm.200612-1792OC on May 3, 2007      by the American Cancer Society. Nearly 1.2 million study participants
Internet address: www.atsjournals.org                                                were enrolled by over 77,000 volunteers in 1982. Participants were
286                                                       AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007

recruited in all 50 states as well as the District of Columbia and Puerto      participant characteristics (Table 1). The prevalence of chronic
Rico. Participants were at least 30 years of age at baseline. A self-          bronchitis and emphysema diagnosis tended to increase with
administered questionnaire was completed at baseline that ascertained          increasing age. Females and alcohol consumers were more likely
a variety of demographic, medical, and lifestyle data. No sickness-            to report chronic bronchitis compared with males and non–
related exclusion criteria were applied for the baseline data collection.
The Emory University School of Medicine Human Investigations Com-
                                                                               alcohol consumers. Chronic bronchitis also tended to increase
mittee approved all aspects of the CPS II study.                               with increasing exposure to environmental tobacco smoke. Parti-
    The vital status of study participants is determined every 2 years.        cipants reporting previous occupational exposures tended to re-
The National Death Index has been used for computerized linkage and            port a greater prevalence of previous lung disease diagnosis at
follow-up since 1989 (24). Previously, volunteers ascertained the vital        baseline.
status of participants they had enrolled, with confirmation by obtaining            Table 2 describes the relation between lung cancer mortality
the corresponding death certificate. As of December 31, 2002, 385,245           and chronic bronchitis and emphysema measured at baseline in
participants had died (32.5%), 796,476 were alive (67.2%), and 2,840           never smokers. Lung cancer mortality was significantly associ-
(0.2%) had follow-up terminated in September of 1988 due to insuffi-            ated with emphysema (hazard ratio [HR], 1.66; 95% confidence
cient information to link to the National Death Index. Over 98% of
                                                                               interval [CI], 1.06, 2.59) and with the combined endpoint of
deaths have been assigned a cause.
    Participants were excluded if, at baseline, they reported prevalent        emphysema and chronic bronchitis (HR, 2.44; 95% CI, 1.22,
cancer (except nonmelanoma skin cancer) (82,340), were a current or            4.90) in analyses that combined men and women. No association
former smoker (607,261), or if their smoking status was unknown                was observed with chronic bronchitis alone (HR, 0.96; 95% CI,
(46,360). In total, 448,600 never smokers were retained for analysis,          0.72, 1.28).
among which 1,759 lung cancer deaths occurred.                                     Sensitivity analysis revealed the HR for emphysema alone
                                                                               without chronic bronchitis was 1.39 (95% CI, 0.78, 2.43). The
Ascertainment of Previous Lung Disease and Cancer Deaths                       HR for chronic bronchitis alone without emphysema was 0.86
The baseline questionnaire listed 25 different diseases and prompted           (95% CI, 0.63, 1.18). The association between emphysema and
the participant to indicate those for which he or she had ever been            lung cancer strengthened when analyses excluded early years of
diagnosed by a doctor. The listing included chronic bronchitis and             follow-up (Table 3). Few significant interactions were observed
emphysema. A combined category of both chronic bronchitis and em-
                                                                               (Table 3); however, the association between chronic bronchitis
physema was also constructed, because these diseases often coexist in
patients with COPD, and there may also be less misclassification among          and lung cancer was stronger in men (HR, 1.59; 95% CI, 0.95,
participants reporting both conditions (25).                                   2.66) than women (HR, 0.82; 95% CI, 0.58, 1.16; p for interaction
    Cancer deaths were classified by the underlying cause of death              ⫽ 0.04). Because the association between lung disease and lung
according to the International Classification of Diseases (ICD) (26, 27).       cancer mortality did not vary significantly by follow-up time, the
Lung cancer deaths were defined by the following ICD codes: 162 (ICD            proportional hazards assumption did not appear to be violated.
9 [9th revision]) and C33-C34 (ICD 10 [10th revision]).
                                                                               DISCUSSION
Statistical Analysis
Lung cancer death rates per 100,000 person-years were calculated ac-           The principal finding in this large prospective study is that in-
cording to lung disease status and were directly age-standardized to the       creased lung cancer mortality was associated with a history of
age distribution of the entire CPS-II cohort. Cox proportional hazards         emphysema, even among persons who had never been active
models were used to examine the independent effects of chronic bron-           smokers. The association was stronger among those who re-
chitis and emphysema, as well as the combined category of both chronic         ported both emphysema and chronic bronchitis, and increased
bronchitis and emphysema, on lung cancer mortality. The baseline               in analyses that excluded early years of follow-up, consistent
hazard in the proportional hazards regression models was stratified by
                                                                               with a causal relationship. Although no association was seen
1-year age categories, sex, and race (white vs. other). Follow-up time
since baseline (1982) was used as the time axis. The survival times of         between lung cancer and chronic bronchitis in the overall analy-
those still alive at the end of follow-up were censored. Estimated hazard      sis, there was some suggestion of a sex difference, with chronic
ratios were adjusted for education, marital status, body mass index,           bronchitis possibly being more strongly associated with lung
occupational exposures (asbestos, chemicals/acids/solvents, coal or            cancer in men than women.
stone dusts, coal tar/pitch/asphalt, formaldehyde, diesel engine ex-               Most (4–6, 9, 10) but not all (8) of the case-control studies
haust), alcohol consumption, passive smoking exposure, and quintiles           conducted in the United States have reported stronger associa-
of vegetable/fruit/fiber and fat intake (28).                                   tions between lung cancer and emphysema than with chronic
    To examine potential biases in lung disease diagnosis, sensitivity
                                                                               bronchitis. Self-reported emphysema was strongly associated
analyses were conducted focusing on the joint effects of chronic bronchi-
tis and emphysema on lung cancer mortality, and the effect of consecu-
                                                                               (odds ratio, 2.87; 95% CI, 2.20, 3.76) with lung cancer in the
tively excluding deaths (events or censored) in the first 1 to 5 years of       largest, hospital-based case-control study of both male and fe-
follow-up. In addition, interaction terms were entered into the multivar-      male cases from Texas (9), whereas no such association was
iate models to examine whether the association between previous lung           found for bronchitis. Four population-based studies of women
disease and lung cancer mortality was modified by sex, age at baseline          (4, 5, 10, 11) have reported relative-risk estimates ranging from
(⬍ 55 yr, ⭓ 55 yr), or attained age (⬍ 70 yr, 70–79 yr, ⭓ 80 yr) (2).          1.9 to 2.7 for emphysema, and from 0.9 to 1.7 for chronic bronchi-
Two-sided p values were calculated to assess the significance of the            tis. All but one (11) of these studies included current or former
interaction term at the p ⫽ 0.05 level using the likelihood ratio statistic.   smokers, as well as never smokers, and controlled for the effect
The proportional hazards assumption was tested by assessing the sig-
                                                                               of smoking in multivariate analyses. No clear patterns have been
nificance of an interaction term between previous lung disease and
follow-up time. All analyses were conducted using SAS version 8.2 (29).
                                                                               observed in analyses by histologic subtype of lung cancer (4, 6,
                                                                               11), although the number of cases within specific subtypes is
                                                                               small.
RESULTS
                                                                                   The current study using CPS-II data permitted an evaluation
Previous physician-diagnosed chronic bronchitis and emphy-                     of the association for the first time among a large cohort of
sema were reported by 2.7 and 0.5% of lifelong nonsmokers,                     lifelong never smokers, thereby avoiding complex interrelation-
respectively, at baseline. A total of 0.2% of nonsmokers reported              ships with smoking, which may obscure any causal inferences
having a diagnosis of both chronic bronchitis and emphysema.                   relating to lung disease and lung cancer risk. Although changes
The prevalence of reported lung disease varied according to                    in smoking status were not evaluated for the full CPS-II cohort,
Turner, Chen, Krewski, et al.: COPD and Lung Cancer Mortality                                                                                287

               TABLE 1. SELECTED CHARACTERISTICS OF NEVER-SMOKING PARTICIPANTS OF THE CANCER
               PREVENTION STUDY II AND PREVALENCE OF PREVIOUS LUNG DISEASE AT BASELINE (1982)
                                                                                         Prevalence of Previous Lung Disease (% )†

                                                         No. of Subjects    Chronic Bronchitis     Emphysema           Chronic Bronchitis
               Characteristics                           (n ⫽ 448,600)*       (n ⫽ 13,908)         (n ⫽ 2,430)     and Emphysema (n ⫽ 721)

               Overall                                                             2.7                 0.5                      0.2
               Age, yr
                 ⬍ 45                                        52,199                2.1                 0.1                      0.1
                 45–54                                      140,485                2.2                 0.2                      0.1
                 55–64                                      141,889                2.7                 0.5                      0.1
                 65–74                                       82,231                3.6                 1.0                      0.3
                 75⫹                                         31,796                4.1                 1.7                      0.4
               Sex
                 Male                                       121,780                1.7                 0.8                      0.2
                 Female                                     326,830                3.1                 0.4                      0.1
               Race
                 White                                      416,327                2.7                 0.5                      0.2
                 Other                                       32,273                2.2                 0.6                      0.2
               Education
                 High school graduate or less               188,047                2.8                 0.6                      0.2
                 Some college or more                       254,113                2.7                 0.4                      0.1
               Marital status
                 Married                                    361,315                2.6                 0.5                      0.1
                 Other                                       84,512                3.4                 0.6                      0.2
               Body mass index, kg/m2
                 ⬍ 18.5                                       8,257                3.5                 1.8                      0.5
                 18.5–24.9                                  226,394                2.5                 0.6                      0.2
                 25–29.9                                    150,157                2.6                 0.4                      0.1
                 30⫹                                         53,030                3.7                 0.5                      0.2
               Beer consumption
                 Yes                                         37,346                2.2                 0.6                      0.1
                 No                                         129,143                2.9                 0.6                      0.2
               Wine consumption
                 Yes                                         59,499                2.5                 0.5                      0.2
                 No                                         113,211                2.9                 0.6                      0.2
               Liquor consumption
                 Yes                                         45,089                2.4                 0.5                      0.1
                 No                                         124,817                2.9                 0.6                      0.2
               Vegetable/fruit/fiber intake, quintiles
                 1                                           81,502                2.6                 0.7                      0.5
                 2                                           81,446                2.6                 0.5                      0.1
                 3                                           81,579                2.7                 0.5                      0.1
                 4                                           78,129                2.7                 0.5                      0.1
                 5                                           82,385                2.8                 0.5                      0.1
               Fat intake, quintiles
                 1                                           81,008                2.7                 0.5                      0.2
                 2                                           81,008                2.8                 0.5                      0.2
                 3                                           81,008                2.6                 0.5                      0.1
                 4                                           81,008                2.7                 0.5                      0.1
                 5                                           81,008                2.7                 0.6                      0.2
               Passive smoke exposure
                 0h                                         207,567                2.4                 0.5                      0.2
                 ⬎ 0 to ⬍ 3 h                                92,937                2.6                 0.5                      0.1
                 3 to ⬍ 6 h                                  34,720                2.8                 0.5                      0.1
                 6⫹ h                                       113,376                3.3                 0.6                      0.2
               Asbestos
                 Yes                                         11,037                4.1                 1.2                      0.3
                 No                                         437,563                1.5                 1.7                      0.2
               Chemicals/acids/solvents
                 Yes                                         37,165                3.6                 0.9                      0.2
                 No                                         411,435                2.6                 0.5                      0.2
               Coal or stone dusts
                 Yes                                         11,911                4.6                 1.8                      0.4
                 No                                         436,689                2.7                 0.5                      0.2
               Coal tar/pitch/asphalt
                 Yes                                          4,370                4.0                 1.4                      0.3
                 No                                         444,230                2.7                 0.5                      0.2
               Formaldehyde
                 Yes                                         10,031                3.9                 0.9                      0.3
                 No                                         438,569                2.7                 0.5                      0.2
               Diesel engine exhaust
                 Yes                                         21,774                3.0                 1.1                      0.3
                 No                                         426,826                2.7                 0.5                      0.2

                 * Percentages not summing to total reflect missing data.
                 †
                   Percentages age-standardized to the age distribution of the entire Cancer Prevention Study II cohort (except for age).
288                                                        AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007

               TABLE 2. RELATION OF LUNG CANCER MORTALITY TO CHRONIC OBSTRUCTIVE PULMONARY
               DISEASE AMONG NEVER SMOKERS IN THE CANCER PREVENTION STUDY II COHORT,
               UNITED STATES, 1982–2002

                                                                                                                   Minimally Adjusted       Fully Adjusted
                                                       No. of Lung                                                   Hazard Ratio†          Hazard Ratio‡
               Previous Lung Disease                  Cancer Deaths         Person-Years     Death Rate*               (95% CI )              (95% CI )

               Chronic bronchitis
                 Yes                                           48              210,569            19.0             0.96 (0.72, 1.28)      0.96 (0.72, 1.28)
                 No                                         1,711            7,932,210            21.1                   1.00                   1.00
               Emphysema
                 Yes                                           20               35,418            42.0             1.71 (1.10, 2.66)      1.66 (1.06, 2.59)
                 No                                         1,739            8,107,361            21.0                   1.00                   1.00
               Chronic bronchitis and emphysema
                 Yes                                            8               10,585            52.6             2.50 (1.24, 5.02)      2.44 (1.22, 4.90)
                 No                                         1,751            7,907,377            21.1                   1.00                   1.00

                 Definition of abbreviation: CI ⫽ confidence interval.
                 * Per 100,000 person-years, age-standardized to the age distribution of the entire Cancer Prevention Study II cohort.
                 †
                   Age, sex, and race stratified.
                 ‡
                   Age, sex, and race stratified, and adjusted for education, marital status, body mass index, occupational exposures, beer, wine,
               and liquor consumption, vegetable/fruit/fiber intake, fat intake, and passive smoking.

they were assessed among a subset of participants enrolled in the                    combination of both, with or without inherited familial predispo-
Nutrition Cohort in 1992/1993 (2, 30). The prospective follow-up                     sition. Nonetheless, the findings suggest that lung dysfunction
also aided in eliminating many of the potential limitations of                       among lifelong nonsmokers is an important population health
previous studies, including differential recall bias and the use of                  issue.
large numbers of proxy respondents.                                                      Physician-diagnosed lung disease measured at baseline was
   Several investigations also reported a positive association                       ascertained by self-report and may be associated with a certain
between asthma and lung cancer risk (31) but these are subject                       degree of misclassification. The basis of the physician diagnosis
to many of the limitations described above. In our previous                          is also unknown. The prevalence of previous lung disease in the
analysis of the CPS-II cohort, we reported a modest association                      current study appears to be similar to, although slightly lower
(HR, 1.11; 95% CI, 0.79, 1.56) between a history of asthma and                       than, that reported in other studies in the United States (11, 33,
lung cancer mortality in never smokers (32).                                         34). The prevalence of self-reported physician-diagnosed chronic
   The main limitation of this study, and of other studies of this                   bronchitis or emphysema in lifelong nonsmokers in the U.S.
type, is that we are unable to distinguish whether COPD is in                        National Health and Nutrition Examination Survey (NHANES)
the causal pathway for lung cancer or whether both COPD and                          I and II, and the Hispanic Health and Nutrition Examination
lung cancer are related to an underlying exposure, or some                           Survey overall, was 3.7% in men and 5.1% in women (33). The

               TABLE 3. SENSITIVITY ANALYSES OF THE RELATION OF LUNG CANCER MORTALITY TO
               CHRONIC OBSTRUCTIVE PULMONARY DISEASE AMONG NEVER SMOKERS IN THE CANCER
               PREVENTION STUDY II COHORT, UNITED STATES, 1982–2002*

                                                    Chronic Bronchitis                        Emphysema                           Chronic Bronchitis and
                                                      (n ⫽ 12,199)                            (n ⫽ 2,430)                         Emphysema† (n ⫽ 721)

               Follow-up exclusions
                 1 yr                               0.91   (0.68,   1.23)                  1.43   (0.89,   2.32)                        2.16   (1.03,   4.55)
                 2 yr                               0.91   (0.68,   1.23)                  1.51   (0.93,   2.44)                        2.27   (1.08,   4.77)
                 3 yr                               0.90   (0.66,   1.23)                  1.59   (0.98,   2.57)                        2.38   (1.13,   5.02)
                 4 yr                               0.92   (0.68,   1.26)                  1.58   (0.96,   2.59)                        2.52   (1.20,   5.31)
                 5 yr                               0.95   (0.69,   1.30)                  1.68   (1.02,   2.76)                        2.70   (1.28,   5.68)
               Sex
                 Male                               1.59 (0.95, 2.66)                      1.42 (0.70, 2.88)                            3.60 (1.34, 9.73)
                 Female                             0.82 (0.58, 1.16)                      1.82 (1.03, 3.21)                            1.82 (0.68, 4.87)
                 p for interaction                        0.04                                    0.73                                        0.90
               Age at baseline
                 ⬍ 55 yr                            0.79 (0.35, 1.77)                      1.43 (0.20, 10.2)                                     —
                 ⭓ 55 yr                            1.07 (0.79, 1.46)                      1.93 (1.23, 3.04)
                 p for interaction                        0.56                                    0.71
               Attained age
                 ⬍ 70 yr                            0.86 (0.46, 1.61)                      3.83 (1.43, 10.26)                           4.76 (1.18, 19.10)
                 70–79 yr                           1.59 (1.04, 2.44)                      3.70 (1.91, 7.16)                            4.25 (1.36, 13.24)
                 ⭓ 80 yr                            0.93 (0.56, 1.52)                      1.41 (0.67, 2.98)                            2.22 (0.71, 6.90)
                 p for interaction                        0.19                                    0.11                                        0.62

                 Values represent hazard ratios, with 95% confidence intervals in parentheses.
                 * Age, sex, and race stratified, and adjusted for education, marital status, body mass index, occupational exposures, beer, wine,
               and liquor consumption, vegetable/fruit/fiber intake, fat intake, and passive smoking, where appropriate.
                 †
                   Small numbers precluded the evaluation of age at baseline interaction for chronic bronchitis and emphysema.
Turner, Chen, Krewski, et al.: COPD and Lung Cancer Mortality                                                                                                 289

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potential modifying factors, there were no significant findings in                    15. Wu-Williams AH, Dai XD, Blot W, Xu ZY, Sun XW, Xiao HP, Stone
this regard (2, 25, 36). A significant interaction with sex was                            BJ, Yu SF, Feng YP, Ershow AG, et al. Lung cancer among women
                                                                                          in North-East China. Br J Cancer 1990;62:982–987.
observed among those with chronic bronchitis, in which men
                                                                                    16. Kleinerman R, Wang Z, Wang L, Metayer C, Zhang S, Brenner A, Zhang
with the disease tended to experience an elevated, but not sig-                           S, Xia Y, Shang B, Lubin JH. Lung cancer and indoor exposure to coal
nificant, risk of lung cancer death compared with women. Al-                               and biomass in rural China. J Occup Environ Med 2002;44:338–344.
though the reasons for this finding are not clear, it is possible                    17. Luo R, Wu B, Yi Y, Huang Z, Lin R. Indoor burning coal air pollution
that there may exist sex differences in physician diagnosis of                            and lung cancer: a case-control study in Fuzhou, China. Lung Cancer
COPD (25, 36, 38, 39). The subgroup analyses were limited,                                1996;14(Suppl 1):s113–s119.
however, by low numbers of lung cancer cases with previous                          18. Wang T, Zhou B, Shi J. Lung cancer in nonsmoking Chinese women: a
lung disease among the different strata. Last, because histologic                         case-control study. Lung Cancer 1996;14(Suppl 1):s93–s98.
                                                                                    19. Xu Z, Blot W, Xiao H, Wu A, Feng Y, Stone B, Sun J, Ershow AG,
information was not available, we were unable to examine the
                                                                                          Henderson BE, Fraumeni JF Jr. Smoking, air pollution, and the high
association between previous lung disease and lung cancer mor-                            rates of lung cancer in Shenyang, China. J Natl Cancer Inst 1989;
tality by histologic subtype.                                                             81:1800–1806.
    In conclusion, the current, large, prospective study of lifelong                20. Zhang Y, Chen K, Zhang H. Meta-analysis of risk factors on lung cancer
nonsmokers provides further evidence for an association be-                               in non-smoking Chinese female [in Chinese]. Zhonghua Liu Xing Bing
tween COPD, especially emphysema, and lung cancer mortality.                              Xue Za Zhi 2001;22:119–121.
Additional prospective studies of never smokers, particularly                       21. Zhao Y, Wang S, Aunan K, Seip H, Hao J. Air pollution and lung cancer
with validated information on lung disease status, would help                             risks in China: a meta-analysis. Sci Total Environ 2006;366:500–513.
                                                                                    22. Zhou B, Wang T, Guan P, Wu J. Indoor air pollution and pulmonary
to confirm the findings of the current study, as well provide a
                                                                                          adenocarcinoma among females: a case-control study in Shenyang,
better understanding of the nature of COPD in nonsmokers.                                 China. Oncol Rep 2000;7:1253–1259.
Finally, further examination of the potential underlying biologi-                   23. Dai X, Lin C, Sun X, Shi Y, Lin Y. The etiology of lung cancer in
cal mechanisms may be warranted to better understand the basis                            nonsmoking females in Harbin, China. Lung Cancer 1996;14(Suppl 1):
for an association between COPD and lung cancer.                                          s85–s91.
                                                                                    24. Calle EE, Terrell DD. Utility of the National Death Index for ascertain-
Conflict of Interest Statement : None of the authors has a financial relationship         ment of mortality among Cancer Prevention Study II participants. Am
with a commercial entity that has an interest in the subject of this manuscript.
                                                                                          J Epidemiol 1993;137:235–241.
                                                                                    25. Bobadilla A, Guerra S, Sherrill D, Barbee R. How accurate is the self-
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