Chronic Obstructive Pulmonary Disease Is Associated with Lung Cancer Mortality in a Prospective Study of Never Smokers
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
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 were286 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
prevalence of self-reported physician-diagnosed chronic bron- 4. Alavanja MCR, Brownson RC, Boice JD Jr, Hock E. Preexisting lung
chitis in the control population of a United States case-control disease and lung cancer among nonsmoking women. Am J Epidemiol
1992;136:623–632.
study of lung cancer in lifetime nonsmoking women was 7.0
5. Brownson RC, Alavanja MCR. Previous lung disease and lung cancer
and 0.9% for emphysema (11). Using spirometric criteria in risk among women (United States). Cancer Causes Control 2000;11:
nonsmoking NHANES III participants, Behrendt (35) reported 853–858.
that approximately 4.7% of nonsmokers had mild COPD and 6. Mayne ST, Buenconsejo J, Janerich DT. Previous lung disease and risk
1.9% had moderate to severe COPD. of lung cancer among men and women nonsmokers. Am J Epidemiol
Few studies have attempted to validate self-reported diagno- 1999;149:13–20.
ses of chronic bronchitis or emphysema (25, 36). A validation of 7. Osann KE. Lung cancer in women: the importance of smoking, family
self-reported physician-diagnosed COPD in the Nurses’ Health history of cancer, and medical history of respiratory disease. Cancer
Res 1991;51:4893–4897.
Study found high rates of lung disease (emphysema, chronic
8. Samet JM, Humble CG, Pathak DR. Personal and family history of
bronchitis, and COPD) confirmed by medical records (36). How- respiratory disease and lung cancer risk. Am Rev Respir Dis 1986;
ever, the findings may not be generalizable to the overall popula- 134:466–470.
tion because health professionals may report their medical his- 9. Schabath MB, Delclos GL, Martynowicz MM, Greisinger AJ, Lu C, Wu
tories more accurately (36). Another study validating data from X, Spitz MR. Opposing effects of emphysema, hay fever, and select
a United States cohort in Tucson showed that low rates of self- genetic variants on lung cancer risk. Am J Epidemiol 2005;161:412–422.
reported physician-diagnosed chronic bronchitis met the symp- 10. Wu AH, Yu MC, Thomas DC, Pike MC, Henderson BE. Personal and
tom criteria (25). It was suggested that the term “chronic bronchi- family history of lung disease as risk factors for adenocarcinoma of
tis,” a popular term widely used by both the public and health the lung. Cancer Res 1988;48:7279–7284.
11. Wu AH, Fontham ETH, Reynolds P, Greenberg RS, Buffler P, Liff J,
professionals, may often be misapplied (25).
Boyd P, Henderson BE, Correa P. Previous lung disease and risk of
Misclassification of self-reported lung disease in the current lung cancer among lifetime nonsmoking women in the United States.
study, however, would likely be nondifferential and result in Am J Epidemiol 1995;141:1023–1032.
biases of the HRs toward the null. If present, this bias could 12. Wasswa-Kintu S, Gan WQ, Man SFP, Pare PD, Sin DD. Relationship
partially explain the lack of association found between chronic between reduced forced expiratory volume in one second and the
bronchitis and lung cancer mortality. It has also been suggested risk of lung cancer: a systematic review and meta-analysis. Thorax
that there may exist a large proportion of undiagnosed COPD 2005;60:570–575.
cases in the general population and in lifelong never smokers, 13. Brenner AV, Wang Z, Kleinerman RA, Wang L, Zhang S, Metayer C,
Chen K, Lei S, Cui H, Lubin JH. Previous pulmonary diseases and
which could also bias study results toward the null hypothesis of risk of lung cancer in Gansu Province, China. Int J Epidemiol 2001;
no association (36, 37). Detailed information on disease history, 30:118–124.
including age at diagnosis or those diagnosed during the follow- 14. Gao Y-T, Blot W, Zheng W, Ershow AG, Hsu CW, Levin LI, Zhang
up period, was not collected in this study. R, Fraumeni JF Jr. Lung cancer among Chinese women. Int J Cancer
Although age at baseline and attained age were examined as 1987;40:604–609.
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-
References reported diagnosis of chronic bronchitis? Chest 2002;122:1234–1239.
1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer 26. World Health Organization. International classification of diseases: man-
statistics, 2006. CA Cancer J Clin 2006;56:106–130. ual of the international statistical classification of diseases, injuries,
2. Thun MJ, Henley SJ, Burns D, Jemal A, Shanks TG, Calle EE. Lung and causes of death, ninth revision. Vol. 1. Geneva, Switzerland: World
cancer death rates in lifelong nonsmokers. J Natl Cancer Inst 2006; Health Organization; 1977.
98:691–699. 27. World Health Organization. ICD-10: international statistical classifica-
3. Thun M. Tobacco. In: Fraumeni D, editor. Cancer epidemiology and tion of diseases and related health problems. Geneva, Switzerland:
prevention. Oxford, UK: Oxford University Press; 2006. pp. 217–242. World Health Organization; 1992.290 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007
28. Pope CA III, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, 34. National Center for Health Statistics. Provisional report: summary health
Thurston GD. Lung cancer, cardiopulmonary mortality, and long-term statistics for US adults: National Health Interview Survey, 2005. Vital
exposure to fine particulate air pollution. JAMA 2002;287:1132–1141. and Health Statistics, Series 10. Number 232. Hyattsville, MD: Depart-
29. SAS Institute, Inc. SAS, version 8.2 [computer program]. Cary, NC: SAS ment of Health and Human Services; 2006.
Institute; 2004. 35. Behrendt C. Mild and moderate-to-severe COPD in nonsmokers: distinct
30. Calle EE, Rodriguez C, Jacobs EJ, Almon ML, Chao A, McCullough demographic profiles. Chest 2005;128:1239–1244.
ML, Feigelson HS, Thun MJ. The American Cancer Society Cancer 36. Barr R, Herbstman J, Speizer F, Camargo C Jr. Validation of self-
Prevention Study II Nutrition Cohort. Cancer 2002;94:2490–2501.
reported chronic obstructive pulmonary disease in a cohort study of
31. Santillan A, Camargo C Jr, Colditz G. A meta-analysis of asthma and
nurses. Am J Epidemiol 2002;155:965–971.
risk of lung cancer (United States). Cancer Causes Control 2003;
14:327–334. 37. Celli B, Halbert R, Nordyke R, Schau B. Airway obstruction in never
32. Turner MC, Chen Y, Krewski D, Ghadirian P, Thun MJ, Calle EE. smokers: results from the Third National Health and Nutrition Exami-
Cancer mortality among US men and women with asthma and hay nation Survey. Am J Med 2005;118:1364–1372.
fever. Am J Epidemiol 2005;162:212–221. 38. Chapman K, Tashkin D, Pye D. Gender bias in the diagnosis of COPD.
33. Whittemore AS, Perlin S, DiCiccio Y. Chronic obstructive pulmonary Chest 2001;119:1691–1695.
disease in lifelong nonsmokers: results from NHANES. Am J Public 39. Chapman K. Chronic obstructive pulmonary disease: are women more
Health 1995;85:702–706. susceptible than men? Clin Chest Med 2004;25:331–341.You can also read
