Exposure to secondhand tobacco smoke and lung cancer by histological type: a pooled analysis of the International Lung Cancer Consortium (ILCCO) (original) (raw)
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Int J Cancer. Author manuscript; available in PMC 2015 Oct 15.
Published in final edited form as:
PMCID: PMC4126868
NIHMSID: NIHMS574034
Claire H Kim,1,* Yuan-Chin Amy Lee,1,2,* Rayjean J Hung,3,* Sheila R McNallan,4 Michele L Cote,5 Wei-Yen Lim,6 Shen-Chih Chang,1 Jin Hee Kim,7 Donatella Ugolini,8,9 Ying Chen,10 Triantafillos Liloglou,10 Angeline S Andrew,11 Tracy Onega,11 Eric J Duell,12 John K Field,10 Philip Lazarus,13 Loic Le Marchand,14 Monica Neri,15 Paolo Vineis,16,17 Chikako Kiyohara,18 Yun-Chul Hong,19 Hal Morgenstern,20 Keitaro Matsuo,18,21 Kazuo Tajima,22 David C Christiani,23 John R McLaughlin,24 Vladimir Bencko,25 Ivana Holcatova,25 Paolo Boffetta,26,27 Paul Brennan,28 Eleonora Fabianova,29 Lenka Foretova,30 Vladimir Janout,31 Jolanta Lissowska,32 Dana Mates,33 Peter Rudnai,34 Neonila Szeszenia-Dabrowska,35 Anush Mukeria,36 David Zaridze,36 Adeline Seow,6 Ann G Schwartz,5 Ping Yang,4 and Zuo-Feng Zhang1
Claire H Kim
1Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, 650 Charles E Young Drive, South, Los Angeles, CA 90095, USA
Yuan-Chin Amy Lee
1Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, 650 Charles E Young Drive, South, Los Angeles, CA 90095, USA
2Department of Family and Preventive Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
Rayjean J Hung
3Samuel Lunenfeld Research Institute of Mount Sinai Hospital, 60 Murray Street, Toronto, Ontario M5T 3L9, Canada
Sheila R McNallan
4Mayo Clinic Cancer Center, Rochester, MN, USA
Michele L Cote
5Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Wei-Yen Lim
6Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore
Shen-Chih Chang
1Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, 650 Charles E Young Drive, South, Los Angeles, CA 90095, USA
Jin Hee Kim
7Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Korea
Donatella Ugolini
8Internal Medicine, University of Genoa, Genoa, Italy
9Unit of Epidemiology, Biostatistics and Clinical Trials, IRCSS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
Ying Chen
10Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Triantafillos Liloglou
10Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Angeline S Andrew
11Section of Biostatistics & Epidemiology, Dartmouth Medical School, Lebanon, NH, USA
Tracy Onega
11Section of Biostatistics & Epidemiology, Dartmouth Medical School, Lebanon, NH, USA
Eric J Duell
12Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
John K Field
10Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
Philip Lazarus
13Washington State University College of Pharmacy, Spokane, WA, USA
Loic Le Marchand
14University of Hawaii, Honolulu, HI, USA
Monica Neri
15Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy
Paolo Vineis
16MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College, London, UK
17HuGeF Foundation, Torino, Italy
Chikako Kiyohara
18Department of Preventive Medicine, Kyushu University, Fukuoka, Japan
Yun-Chul Hong
19Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
Hal Morgenstern
20Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
Keitaro Matsuo
18Department of Preventive Medicine, Kyushu University, Fukuoka, Japan
21Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
Kazuo Tajima
22Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
David C Christiani
23Department of Environmental Health, Harvard University, Boston, MA, USA
John R McLaughlin
24Cancer Care Ontario, Toronto, Ontario, Canada
Vladimir Bencko
25Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
Ivana Holcatova
25Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
Paolo Boffetta
26The Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of Medicine, New York, NY, USA
27International Prevention Research Institute, Lyon, France
Paul Brennan
28International Agency for Research on Cancer, Lyon, France
Eleonora Fabianova
29Department of Occupational Health and Toxicology, Regional Authority of Public Health, Banska Bystrica, Slovakia
Lenka Foretova
30Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic
Vladimir Janout
31Department of Preventive Medicine, Palacky University, Olomouc, Czech Republic
Jolanta Lissowska
32Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland
Dana Mates
33Occupational Health Department, Institute of Public Health, Bucharest, Romania
Peter Rudnai
34National Institute of Environmental Health, Budapest, Hungary
Neonila Szeszenia-Dabrowska
35Department of Occupational and Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lódz, Poland
Anush Mukeria
36Department of Epidemiology and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia
David Zaridze
36Department of Epidemiology and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia
Adeline Seow
6Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore
Ann G Schwartz
5Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
Ping Yang
4Mayo Clinic Cancer Center, Rochester, MN, USA
Zuo-Feng Zhang
1Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, 650 Charles E Young Drive, South, Los Angeles, CA 90095, USA
1Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, 650 Charles E Young Drive, South, Los Angeles, CA 90095, USA
2Department of Family and Preventive Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
3Samuel Lunenfeld Research Institute of Mount Sinai Hospital, 60 Murray Street, Toronto, Ontario M5T 3L9, Canada
4Mayo Clinic Cancer Center, Rochester, MN, USA
5Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
6Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, Singapore
7Institute of Environmental Medicine, Seoul National University Medical Research Center, Seoul, Korea
8Internal Medicine, University of Genoa, Genoa, Italy
9Unit of Epidemiology, Biostatistics and Clinical Trials, IRCSS Azienda Ospedaliera Universitaria San Martino-IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
10Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
11Section of Biostatistics & Epidemiology, Dartmouth Medical School, Lebanon, NH, USA
12Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
13Washington State University College of Pharmacy, Spokane, WA, USA
14University of Hawaii, Honolulu, HI, USA
15Clinical and Molecular Epidemiology, IRCCS San Raffaele Pisana, Rome, Italy
16MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College, London, UK
17HuGeF Foundation, Torino, Italy
18Department of Preventive Medicine, Kyushu University, Fukuoka, Japan
19Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
20Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA
21Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
22Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
23Department of Environmental Health, Harvard University, Boston, MA, USA
24Cancer Care Ontario, Toronto, Ontario, Canada
25Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
26The Tisch Cancer Institute and Institute for Translational Epidemiology, Mount Sinai School of Medicine, New York, NY, USA
27International Prevention Research Institute, Lyon, France
28International Agency for Research on Cancer, Lyon, France
29Department of Occupational Health and Toxicology, Regional Authority of Public Health, Banska Bystrica, Slovakia
30Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic
31Department of Preventive Medicine, Palacky University, Olomouc, Czech Republic
32Department of Cancer Epidemiology and Prevention, Cancer Center and Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland
33Occupational Health Department, Institute of Public Health, Bucharest, Romania
34National Institute of Environmental Health, Budapest, Hungary
35Department of Occupational and Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lódz, Poland
36Department of Epidemiology and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia
Corresponding Author: Zuo-Feng Zhang, M.D., Ph.D., Department of Epidemiology, Fielding School of Public Health, University of California at Los Angeles (UCLA), 71-225 CHS, Box 951772, 650 Charles E Young Drive, South, Los Angeles, CA, 90095-1772, USA; Phone: 310-825-8418; Fax: 310-206-6039; ude.alcu@gnahzfz
*The first three co-authors contributed equally to this study.
Abstract
While the association between exposure to secondhand smoke and lung cancer risk is well established, few studies with sufficient power have examined the association by histological type. In this study, we evaluated the secondhand smoke-lung cancer relationship by histological type based on pooled data from 18 case-control studies in the International Lung Cancer Consortium (ILCCO), including 2,504 cases and 7,276 controls who were never smokers and 10,184 cases and 7,176 controls who were ever smokers. We used multivariable logistic regression, adjusting for age, sex, race/ethnicity, smoking status, pack-years of smoking, and study. Among never smokers, the odds ratios (OR) comparing those ever exposed to secondhand smoke with those never exposed were 1.31 (95% CI: 1.17–1.45) for all histological types combined, 1.26 (95% CI: 1.10–1.44) for adenocarcinoma, 1.41 (95% CI: 0.99–1.99) for squamous cell carcinoma, 1.48 (95% CI: 0.89–2.45) for large cell lung cancer, and 3.09 (95% CI: 1.62–5.89) for small cell lung cancer. The estimated association with secondhand smoke exposure was greater for small cell lung cancer than for non-small cell lung cancers (OR=2.11, 95% CI: 1.11–4.04). This analysis is the largest to date investigating the relation between exposure to secondhand smoke and lung cancer. Our study provides more precise estimates of the impact of secondhand smoke on the major histological types of lung cancer, indicates the association with secondhand smoke is stronger for small cell lung cancer than for the other histological types, and suggests the importance of intervention against exposure to secondhand smoke in lung cancer prevention.
Keywords: lung cancer, secondhand smoke, environmental tobacco smoke, involuntary smoking, International Lung Cancer Consortium
Introduction
Lung cancer, with 1.59 million deaths in 2012, is the most common cause of cancer death worldwide.1 Active tobacco smoking has been established as a strong risk factor for lung cancer, with an average risk ratio (RR) of 15–30.2 Smoking is associated with increased risks of all major histological types of lung cancer, although it has been reported to be more strongly associated with small cell lung cancer (odds ratio [OR]=12.9, 95% confidence interval [CI]: 9.79–17.1) and squamous cell carcinoma (OR=11.3, 95% CI: 9.39–13.5) than with large cell lung cancer (OR=5.64, 95% CI: 4.15–7.67) and adenocarcinoma (OR=3.22, 95% CI: 2.62–3.98).3 However, about 25% of the world’s lung cancer cases are not attributable to active tobacco use.4 Even if lung cancer cases among never smokers are considered separately from those among ever smokers, lung cancer among never smokers ranks as the seventh most common cause of cancer death worldwide.4
The development of lung cancer in never smokers has stimulated myriad investigations on potential risk factors for lung cancer among those populations. Based on its review of numerous studies, the International Agency for Research on Cancer (IARC) concluded that involuntary smoking is carcinogenic to humans, with an increased risk of 20% for women and of 30% for men among never smokers who are exposed to secondhand smoke (i.e., environmental tobacco smoke) from their spouse.5 Based on an analysis of 37 epidemiological studies, Hackshaw et al. reported never smokers who lived with a smoker were at a 26% increased risk of lung cancer compared with those who did not live with a smoker (95% CI: 6–47%).6 Dose-response relationships were observed between lung cancer risk and both the number of cigarettes smoked by the spouse and the duration of exposure. The pooled relative risk was higher for squamous and small cell carcinoma (RR=1.58, 95% CI: 1.14–2.19) than for adenocarcinoma (RR=1.25, 95% CI: 1.07–1.46). Similarly, a pooled analysis of two case-control studies reported that duration of exposure showed consistent dose-response relationships with adenocarcinoma and squamous and small cell carcinomas and suggested a higher risk for squamous and small cell carcinomas than for adenocarcinoma.7 However, this previous analysis was limited by inadequate power for further analysis by each histological type of lung cancer. In most of the studies to date, the number of small cell lung cancer cases among never smokers has been too small to be studied in detail.8–10
In this study, we aim to investigate the relationship between exposure to secondhand smoke and risk of lung cancer by histological type (adenocarcinoma, squamous cell carcinoma, large cell lung cancer, and small cell lung cancer) among ever smokers and never smokers combined and among never smokers only, using the pooled database of the International Lung Cancer Consortium (ILCCO).
Material and Methods
Study Population
ILCCO was established in 2004 with the objective of sharing comparable data from ongoing lung cancer studies to increase the power for subgroup analysis. The consortium was established with funding from the National Cancer Institute (NCI) and the IARC. Investigators with eligible epidemiologic studies of lung cancer were invited to participate in the ILCCO data pooling project. A total of 56 lung cancer studies have each provided a study protocol for subject recruitment and a structured questionnaire for lifestyle information in order to participate in ILCCO. Details of the studies have been reported previously.11–20
Eighteen case-control studies in ILCCO provided the data for this analysis, all measured through structured questionnaires (table 1). Eight studies were conducted in North America; four studies were conducted in Europe; and six studies were conducted in Asia/Oceania. Eight studies recruited healthy controls from the general population; eight studies recruited controls from hospital patients or their family or friends who did not have any smoking-related illnesses; and two studies recruited controls from mixed sources. Fifteen studies matched cases with controls on potential confounders, such as age, sex, and ethnicity, while three studies did not use matching. Written informed consents were obtained from all study participants, and each study was approved by its respective local human subject review board.
Table 1
Summary of studies pooled
| Project/instituteby region | Studyname | Principalinvestigator | Controlsource | Studyperiod | Studylocation |
|---|---|---|---|---|---|
| North America | |||||
| Family Health Study | FHS | A.G. Schwartz | Population | 1984–1987, 1990–2003 | Detroit, MI, USA |
| University of California at Los Angeles | UCLA | Z.F. Zhang | Population | 1999–2004 | Los Angeles, CA, USA |
| Women’s Epidemiology of Lung Disease | WELD | A.G. Schwartz | Population | 2001–2005 | Detroit, MI, USA |
| New England Lung Cancer Study | NELCS | E. Duell | Population | 2005–2008 | New Hampshire & Vermont, USA |
| Samuel Lunenfeld Research Institute | SLRI | J. McLaughlin | Mixed | 1997–2002 | Toronto, Canada |
| Harvard | Harvard | D. Christiani | Hospital | 1992–2008 | Boston, MA, USA |
| Mayo Clinic | Mayo | P. Yang | Hospital | 1997–2006 | USA |
| Moffitt | Moffitt | P. Lazarus | Hospital | 1999–2003 | Florida, USA |
| Europe | |||||
| European Prospective Investigation into Cancer and Nutrition | GenAir | P. Vineis | Population | 1993–1998 | 10 European countries |
| Cancer of the Respiratory Tract Biorepository | CREST | M. Neri | Mixed | 1996–present | Northern Italy |
| Liverpool Lung Project | Liverpool | J. Field | Population | 1998–2016 | Liverpool, UK |
| International Agency for Research on Cancer | IARC | P. Boffetta | Hospital | 1998–2002 | Central/Eastern Europe |
| Asia and Oceania | |||||
| University of Hawaii | Hawaii | L. Le Marchand | Population | 1992–1997 | Hawaii, USA |
| Kyushu University | Kyushu | C. Kiyohara | Population | 1994–1996 | Japan |
| Genes and Environment in Lung Cancer, Singapore | GEL-S 1 | A. Seow | Hospital | 1996–1998 | Singapore |
| Genes and Environment in Lung Cancer, Singapore | GEL-S 2 | A. Seow | Hospital | 2005–2007 | Singapore |
| Aichi Cancer Center | Aichi | K. Tajima/K. Mastuo | Hospital | 2001–2005 | Aichi, Japan |
| Seoul University | Seoul | Y.C. Hong | Hospital | 2001–2008 | Seoul, Korea |
The most commonly used definition of never smokers was those who smoked less than 100 cigarettes in their lifetime (the FHS, UCLA, WELD, NELCS, SLRI, Harvard, Mayo, and IARC studies). Other definitions included those who smoked less than 180 cigarettes in their lifetime (the Hawaii study), those who smoked less than 200 cigarettes in their lifetime (the Seoul study), those who smoked less than 365 cigarettes in their lifetime (the Kyushu, Moffitt, and GEL-S studies), those who never smoked more than ten cigarettes per week regularly (the Liverpool study), or those who either smoked less than 400 cigarettes in their lifetime or less than one cigarette per day for one year (the CREST study). The Aichi and GenAir studies defined never smokers as those who reported they had never smoked.
We checked the data for inadmissible values, aberrant distributions, inconsistencies, and missing values and sent queries to the participating investigators to resolve all issues. We excluded from the analysis participants with unknown age (n=31) or race/ethnicity (n=251). We also excluded 10,442 participants with unknown secondhand exposure status, of whom 7,541 were from the IARC, Moffit, or GenAir study. The IARC and Moffitt studies collected information regarding secondhand smoke exposure from never smokers only, and the GenAir study collected information regarding secondhand smoke exposure from those who either never smoked or who had stopped smoking for at least ten years. The cases and controls excluded due to unknown exposure status had similar distributions of age, sex, and race/ethnicity as those included in the analysis.
The data for this study included 12,688 lung cancer cases and 14,452 controls, of whom 2,504 cases and 7,276 controls were never smokers and 10,184 cases and 7,176 controls were current or former smokers. Cases included patients with invasive tumors of the lung using either the International Classification of Diseases for Oncology (ICD-O) version 2 or the International Classification of Diseases (ICD), Ninth or Tenth Edition.
Statistical Analysis
We performed unconditional logistic regression to obtain odds ratios (OR) with 95% confidence intervals (CI) to assess the association between exposure to secondhand smoke and lung cancer risk. All models included age (continuous), sex, race/ethnicity (White/Caucasian, Latino, Black/African-American, Asian, Native American, or other), and study center. We examined the joint effects of active smoking and exposure to secondhand smoke and tested for multiplicative interaction. We assessed various aspects of secondhand smoke exposure, including location, duration, and childhood exposure. Exposure duration variables included duration of exposure at home, duration of exposure at the workplace, and duration of exposure at home and work combined. The combined duration of exposure variable was created by summing the values for duration of exposure at home and duration of exposure at work—thus, it is the maximum possible duration of exposure, since there could be overlap between exposure periods. We performed the analyses among the total sample and among never smokers separately. For analyses among the total sample, we further adjusted the models for cigarette smoking status (ever smoker or never smoker) and pack-years of cigarette smoking (continuous) in order to separate the qualitative difference between ever smokers and never smokers from the quantitative impact of smoking.21 The sub-analysis of never smokers allowed us to completely eliminate the confounding effect of active smoking, assuming there was no misclassification of ever/never smoking status.
We tested for heterogeneity across the study odds ratios by using the likelihood ratio test, in which we examined the difference between the log likelihood of a model with the product term between study and the variable of interest, and that of a model without such a product term. When there was evidence of heterogeneity in the study-specific odds ratios, we assessed the source of heterogeneity by stratified analyses. If the heterogeneity was not due to any study characteristic, we examined forest plots and performed influence analysis to assess the source of heterogeneity from any single study. For influence analysis, each study was excluded one at a time to assure that the magnitude of the overall summary estimate and P-value were not dependent on any one study.
We also conducted separate analyses by lung cancer histology to compare the estimated associations of secondhand smoke with different histological subtypes. We combined bronchioloalveolar carcinomas with the rest of the adenocarcinomas; excluding them had negligible effect on the results. When comparing small cell lung cancer with non-small cell lung cancers, we employed a case-case approach.22,23 All statistical analyses were performed with SAS v9.3. All P-values are two-sided.
Results
The distributions of basic characteristics of the lung cancer patients and controls among the overall population and among the subsample of never smokers are shown in table 2. The contribution of cases from the individual studies ranged from 1% to 33% and that of controls ranged from 1% to 16%. The majority of the cases and controls lived in North America. In both the overall population and the never smoker population, the proportion of older participants (65 years or above) was higher among the cases than among the controls. The proportion of men was higher in cases than in controls among the overall population, but lower among the never smoker population. The proportion of adenocarcinoma was higher among never smokers than among the overall population; the proportions of squamous cell carcinoma and small cell carcinoma were lower among never smokers than among the overall population; the proportions of large cell lung cancer were similar between the two populations.
Table 2
Distribution of characteristics of the overall population and never smokers
| All | Never smokers | |||||
|---|---|---|---|---|---|---|
| Cases, n (%) | Controls, n (%) | P-value1 | Cases, n (%) | Controls, n (%) | P-value1 | |
| Total | 12,688 | 14,452 | 2,504 | 7,276 | ||
| Study | ||||||
| FHS | 979 (7.72) | 1,173 (8.12) | <0.0001 | 377 (15.06) | 678 (9.32) | <0.0001 |
| UCLA | 609 (4.80) | 1,038 (7.18) | 109 (4.35) | 470 (6.46) | ||
| WELD | 571 (4.50) | 571 (3.95) | 52 (2.08) | 279 (3.83) | ||
| NELCS | 276 (2.18) | 251 (1.74) | 11 (0.44) | 95 (1.31) | ||
| SLRI | 439 (3.46) | 928 (6.42) | 152 (6.07) | 455 (6.25) | ||
| Harvard | 2,119 (16.70) | 1,517 (10.50) | 135 (5.39) | 479 (6.58) | ||
| Mayo | 4,192 (33.04) | 2,235 (15.46) | 635 (25.36) | 812 (11.16) | ||
| Moffitt | 117 (0.92) | 384 (2.66) | 39 (1.56) | 303 (4.16) | ||
| GenAir | 74 (0.58) | 702 (4.86) | 47 (1.88) | 466 (6.40) | ||
| CREST | 401 (3.16) | 551 (3.81) | 45 (1.80) | 237 (3.26) | ||
| Liverpool | 286 (2.25) | 888 (6.14) | 17 (0.68) | 247 (3.39) | ||
| IARC | 255 (2.01) | 1,012 (7.00) | 198 (7.91) | 831 (11.42) | ||
| Hawaii | 628 (4.95) | 587 (4.06) | 45 (1.80) | 224 (3.08) | ||
| Kyushu | 190 (1.50) | 108 (0.75) | 59 (2.36) | 57 (0.78) | ||
| GEL-S 1 | 261 (2.06) | 674 (4.66) | 149 (5.95) | 585 (8.04) | ||
| GEL-S 2 | 367 (2.89) | 748 (5.18) | 228 (9.11) | 642 (8.82) | ||
| Aichi | 453 (3.57) | 815 (5.64) | 117 (4.67) | 319 (4.38) | ||
| Seoul | 471 (3.71) | 270 (1.87) | 89 (3.55) | 97 (1.33) | ||
| Region | ||||||
| North America | 9,930 (78.26) | 8,684 (60.09) | <0.0001 | 1,555 (62.10) | 3,795 (52.16) | <0.0001 |
| Europe | 1,016 (8.01) | 3,153 (21.81) | 307 (12.26) | 1,781 (24.48) | ||
| Asia/Oceania | 1,742 (13.73) | 2,615 (18.09) | 642 (25.64) | 1,700 (23.36) | ||
| Age (years) | ||||||
| <45 | 1,021 (8.05) | 2,117 (14.65) | <0.0001 | 285 (11.38) | 1,154 (15.86) | <0.0001 |
| 45–49 | 898 (7.08) | 1,230 (8.51) | 209 (8.35) | 674 (9.26) | ||
| 50–54 | 1,096 (8.64) | 1,608 (11.13) | 255 (10.18) | 842 (11.57) | ||
| 55–59 | 1,609 (12.68) | 2,002 (13.85) | 300 (11.98) | 995 (13.68) | ||
| 60–64 | 1,763 (13.90) | 1,949 (13.49) | 306 (12.22) | 900 (12.37) | ||
| 65–69 | 2,181 (17.19) | 2,035 (14.08) | 387 (15.46) | 1,003 (13.79) | ||
| >=70 | 4,120 (32.47) | 3,511 (24.29) | 762 (30.43) | 1,708 (23.47) | ||
| Sex | ||||||
| Men | 6,378 (50.27) | 6,587 (45.58) | <0.0001 | 597 (23.84) | 2,308 (31.72) | <0.0001 |
| Women | 6,310 (49.73) | 7,865 (54.42) | 1,907 (76.16) | 4,968 (68.28) | ||
| Ethnicity | ||||||
| Non-Hispanic White | 9,478 (74.70) | 10,168 (70.36) | <0.0001 | 1,543 (61.62) | 4,696 (64.54) | <0.0001 |
| Asian | 2,131 (16.80) | 3,066 (21.22) | 766 (30.59) | 1,954 (26.86) | ||
| Black/African-American | 540 (4.26) | 627 (4.34) | 100 (3.99) | 330 (4.54) | ||
| Hispanic/Latino | 114 (0.90) | 261 (1.81) | 44 (1.76) | 132 (1.81) | ||
| Native American | 218 (1.72) | 47 (0.33) | 25 (1.00) | 16 (0.22) | ||
| Other | 207 (1.63) | 283 (1.96) | 26 (1.04) | 148 (2.03) | ||
| Histology | ||||||
| Adenocarcinoma | 6,006 (47.34) | 1,555 (62.10) | ||||
| Squamous cell carcinoma | 2,599 (20.48) | 211 (8.43) | ||||
| Large cell | 653 (5.15) | 95 (3.79) | ||||
| Other non-small cell | 790 (6.23) | 91 (3.63) | ||||
| Small cell | 1,177 (9.28) | 79 (3.15) | ||||
| Other/mixed/missing | 1,463 (11.53) | 473 (18.89) |
Table 3 shows the joint effects of active smoking and exposure to secondhand smoke. Exposure to secondhand smoke was associated with an increased risk of lung cancer among both ever smokers and never smokers, and multiplicative interaction was observed between active smoking and exposure to secondhand smoke (ratio of odds ratios [ROR]=1.33, 95% CI: 1.15–1.54).
Table 3
Joint effects of active smoking and exposure to secondhand smoke on lung cancer risk
| Activesmoking | Exposed tosecondhandsmoke | Cases | Controls | UnadjustedOR (95% CI) | AdjustedOR1 (95% CI) | ||
|---|---|---|---|---|---|---|---|
| Never | Never | 651 | 2,167 | 1.00 | Reference | 1.00 | Reference |
| Never | Ever | 1,817 | 4,890 | 1.24 | (1.12–1.37) | 1.27 | (1.14–1.42) |
| Ever | Never | 1,219 | 1,074 | 3.78 | (3.35–4.26) | 2.83 | (2.48–3.22) |
| Ever | Ever | 8,827 | 5,921 | 4.96 | (4.52–5.45) | 4.79 | (4.32–5.32) |
| Adjusted ratio of odds ratios1 (95% CI) | |||||||
| Overall: 1.33 (1.15–1.54) | |||||||
| Adenocarcinoma: 1.44 (1.20–1.72) | |||||||
| Squamous cell carcinoma: 1.12 (0.78–1.59) | |||||||
| Large cell lung cancer: 1.13 (0.64–2.01) | |||||||
| Small cell lung cancer: 0.79 (0.42–1.50) |
Table 4 reports the associations between exposure to secondhand smoke and lung cancer by histological subtype in the overall study population. Compared with those never exposed to secondhand smoke, those ever exposed were at a higher risk of lung cancer (OR=1.34, 95% CI: 1.24–1.45). Positive associations were also observed when the different histological types of lung cancer were considered separately (OR=1.35, 95% CI: 1.23–1.48 for adenocarcinoma; OR=1.36, 95% CI: 1.17–1.58 for squamous cell carcinoma; OR=1.36, 95% CI: 1.04–1.79 for large cell lung cancer; and OR=1.63, 95% CI: 1.31–2.04 for small cell lung cancer). Associations seemed to differ by exposure location. No association was observed for those exposed at work (OR=1.02, 95% CI: 0.93–1.13), but positive associations were observed for those exposed at home (OR=1.19, 95% CI: 1.08–1.31) and those exposed both at home and at work (OR=1.39, 95% CI: 1.27–1.52). However, there was heterogeneity across the studies (P<0.001). Risk of lung cancer increased with increasing years of exposure at home (P<0.001), at work (P=0.02), and at home and work combined (P=0.002). Positive associations were also detected for exposure during childhood when all histological types were combined (OR=1.15, 95% CI: 1.05–1.25) and when small cell lung cancer was examined separately (OR=1.35, 95% CI: 1.09–1.67). The positive association between exposure during childhood and lung cancer development persisted when all types of non-small cell lung cancer were combined (OR=1.12, 95% CI: 1.02–1.23; results not shown).
Table 4
Associations between exposure to secondhand smoke and lung cancer risk in the overall population by histological type
| All | Adenocarcinoma | Squamous cell carcinoma | Large cell lung cancer | Small cell lung cancer | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | |
| Ever exposed to secondhand smoke(based on all studies) | |||||||||||
| Never | 3,241 | 1,870 | 1.00 | 904 | 1.00 | 425 | 1.00 | 75 | 1.00 | 148 | 1.00 |
| Ever | 10,811 | 10,644 | 1.34 (1.24–1.45) | 5,039 | 1.35 (1.23–1.48) | 2,150 | 1.36 (1.17–1.58) | 565 | 1.36 (1.04–1.79) | 1,008 | 1.63 (1.31–2.04) |
| P for heterogeneity | 0.01 | 0.26 | 0.06 | 0.68 | 0.98 | ||||||
| Exposure location(based on all studies) | |||||||||||
| Never exposed | 3,241 | 1,870 | 1.00 | 904 | 1.00 | 425 | 1.00 | 75 | 1.00 | 148 | 1.00 |
| Home | 2,981 | 2,217 | 1.19 (1.08–1.31) | 1,125 | 1.20 (1.07–1.35) | 390 | 1.17 (0.97–1.41) | 127 | 1.27 (0.93–1.74) | 184 | 1.38 (1.06–1.80) |
| Work | 2,868 | 1,960 | 1.02 (0.93–1.13) | 860 | 1.00 (0.89–1.13) | 405 | 0.96 (0.79–1.15) | 102 | 0.97 (0.69–1.38) | 185 | 1.15 (0.87–1.52) |
| Home and work | 4,697 | 5,213 | 1.39 (1.27–1.52) | 2,449 | 1.39 (1.25–1.55) | 1,111 | 1.52 (1.29–1.79) | 310 | 1.60 (1.18–2.16) | 514 | 1.67 (1.31–2.12) |
| P for heterogeneity | <0.001 | <0.001 | <0.001 | 0.16 | 0.06 | ||||||
| Years of exposure at home(based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 661 | 374 | 1.00 | 161 | 1.00 | 94 | 1.00 | 14 | 1.00 | 9 | 1.00 |
| 1–20 years | 2,077 | 1,217 | 1.10 (0.89–1.36) | 498 | 1.02 (0.77–1.35) | 245 | 0.95 (0.65–1.40) | 111 | 1.23 (0.59–2.59) | 132 | 1.45 (0.65–3.24) |
| >20 years | 1,350 | 1,163 | 1.36 (1.11–1.65) | 461 | 1.31 (1.01–1.69) | 246 | 1.14 (0.81–1.62) | 66 | 1.90 (0.96–3.77) | 124 | 2.28 (1.04–4.98) |
| P for heterogeneity | 0.18 | 0.88 | 0.83 | 0.35 | 0.71 | ||||||
| P for trend | <0.001 | 0.004 | 0.19 | 0.01 | 0.001 | ||||||
| Years of exposure at work(based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 1,204 | 570 | 1.00 | 243 | 1.00 | 103 | 1.00 | 31 | 1.00 | 28 | 1.00 |
| 1–20 years | 2,239 | 1,205 | 1.03 (0.88–1.21) | 504 | 1.03 (0.83–1.28) | 187 | 0.97 (0.70–1.34) | 120 | 1.19 (0.71–1.99) | 133 | 1.04 (0.62–1.72) |
| >20 years | 1,511 | 1,192 | 1.19 (1.02–1.40) | 441 | 1.21 (0.98–1.49) | 299 | 1.25 (0.93–1.68) | 52 | 0.99 (0.58–1.66) | 131 | 1.39 (0.84–2.30) |
| P for heterogeneity | 0.02 | 0.17 | 0.14 | 0.71 | 0.31 | ||||||
| P for trend | 0.02 | 0.05 | 0.05 | 0.79 | 0.08 | ||||||
| Combined years of exposureat home and work (based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 517 | 231 | 1.00 | 121 | 1.00 | 47 | 1.00 | 10 | 1.00 | 6 | 1.00 |
| 1–20 years | 1,020 | 488 | 0.93 (0.73–1.19) | 262 | 0.87 (0.65–1.17) | 51 | 0.66 (0.40–1.10) | 33 | 0.53 (0.22–1.25) | 26 | 1.27 (0.46–3.52) |
| 21–40 years | 1,024 | 759 | 1.12 (0.89–1.42) | 351 | 0.99 (0.74–1.32) | 128 | 1.13 (0.72–1.76) | 53 | 0.75 (0.33–1.70) | 68 | 1.97 (0.76–5.13) |
| >40 years | 973 | 971 | 1.26 (0.99–1.60) | 406 | 1.12 (0.84–1.51) | 203 | 1.26 (0.81–1.96) | 40 | 1.03 (0.44–2.38) | 90 | 2.25 (0.87–5.77) |
| P for heterogeneity | 0.006 | 0.004 | 0.09 | 0.97 | 0.97 | ||||||
| P for trend | 0.002 | 0.09 | 0.01 | 0.13 | 0.01 | ||||||
| Childhood exposure(based on the FHS, UCLA, NELCS, SLRI, Mayo, Moffitt, and GenAir studies) | |||||||||||
| No | 2,076 | 2,081 | 1.00 | 1,029 | 1.00 | 420 | 1.00 | 80 | 1.00 | 159 | 1.00 |
| Yes | 3,752 | 4,156 | 1.15 (1.05–1.25) | 1,814 | 1.10 (0.99–1.22) | 822 | 1.10 (0.94–1.29) | 230 | 1.17 (0.88–1.54) | 457 | 1.35 (1.09–1.67) |
| P for heterogeneity | 0.60 | 0.74 | 0.80 | 0.24 | 0.93 |
Stratified analyses showed that the associations between exposure to secondhand smoke and lung cancer development did not differ significantly by sex (OR=1.23, 95% CI: 1.10–1.38 for males; OR=1.37, 95% CI: 1.23–1.52 for females; results not shown) or race/ethnicity (OR=1.43, 95% CI: 1.30–1.58 for Whites; OR=1.16, 95% CI: 1.00–1.34 for Asians; OR=0.99, 95% CI: 0.60–1.64 for Blacks; OR=0.75, 95% CI: 0.43–1.32 for Hispanic/Latinos; results not shown). When we stratified the overall population by age (<65 years old and ≥65 years old), positive associations were observed in both age groups (OR=1.22, 95% CI: 1.09–1.36 for <65 years old; OR=1.45, 95% CI: 1.30–1.63 for ≥65 years old; results not shown).
Table 5 presents the associations between exposure to secondhand smoke and lung cancer by histological type among never smokers only. Exposure to secondhand smoke was associated with an increased risk of lung cancer in this population as well (OR=1.31, 95% CI: 1.17–1.47). Positive associations were observed for all of the histological types examined, with the strongest association observed for small cell lung cancer (OR=1.26, 95% CI: 1.10–1.44 for adenocarcinoma; OR=1.41, 95% CI: 0.99–1.99 for squamous cell carcinoma; OR=1.48, 95% CI: 0.89–2.45 for large cell lung cancer; OR=3.09, 95% CI: 1.62–5.89 for small cell lung cancer). Exposure at home seemed to have a greater influence than exposure at work—the adjusted odds ratios were 1.21 (95% CI: 1.05–1.39) for those exposed at home, 1.10 (95% CI: 0.94–1.28) for those exposed at work, and 1.30 (95% CI: 1.12–1.50) for those exposed both at home and at work. Lung cancer risk tended to increase with increasing years of exposure (P=0.07 for exposure at home; P=0.08 for exposure at work; P=0.04 for exposure at home and work combined). We did not observe an apparent association between lung cancer risk and childhood exposure to secondhand smoke (OR=1.08, 95% CI: 0.92–1.26).
Table 5
Associations between exposure to secondhand smoke and lung cancer risk among never smokers by histological type
| All | Adenocarcinoma | Squamous cell carcinoma | Large cell lung cancer | Small cell lung cancer | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Controls | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | Cases | OR1 (95% CI) | |
| Ever exposed to secondhand smoke(based on all studies) | |||||||||||
| Never | 2,167 | 651 | 1.00 | 422 | 1.00 | 52 | 1.00 | 22 | 1.00 | 13 | 1.00 |
| Ever | 4,890 | 1,817 | 1.31 (1.17–1.47) | 1,119 | 1.26 (1.10–1.44) | 156 | 1.41 (0.99–1.99) | 72 | 1.48 (0.89–2.45) | 65 | 3.09 (1.62–5.89) |
| P for heterogeneity | 0.02 | 0.10 | 0.36 | 0.19 | 0.99 | ||||||
| Exposure location(based on all studies) | |||||||||||
| Never exposed | 2,167 | 651 | 1.00 | 422 | 1.00 | 52 | 1.00 | 22 | 1.00 | 13 | 1.00 |
| Home | 1,712 | 626 | 1.21 (1.05–1.39) | 405 | 1.20 (1.02–1.42) | 49 | 1.21 (0.79–1.86) | 26 | 1.24 (0.68–2.24) | 20 | 3.17 (1.46–6.85) |
| Work | 1,408 | 410 | 1.10 (0.94–1.28) | 215 | 1.00 (0.83–1.21) | 41 | 1.11 (0.71–1.74) | 17 | 1.45 (0.74–2.86) | 17 | 2.21 (1.01–4.86) |
| Home and work | 1,654 | 602 | 1.30 (1.12–1.50) | 386 | 1.25 (1.05–1.49) | 61 | 1.93 (1.29–2.91) | 23 | 1.57 (0.83–2.98) | 25 | 3.40 (1.66–6.94) |
| P for heterogeneity | <0.001 | <0.001 | 0.02 | 0.31 | 1.00 | ||||||
| Years of exposure at home(based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 390 | 130 | 1.00 | 63 | 1.00 | 19 | 1.00 | 7 | 1.00 | 4 | 1.00 |
| 1–20 years | 924 | 263 | 1.32 (0.97–1.81) | 133 | 1.21 (0.80–1.83) | 32 | 1.58 (0.80–3.14) | 15 | 0.84 (0.25–2.76) | 13 | 1.88 (0.54–6.63) |
| >20 years | 568 | 229 | 1.35 (1.01–1.82) | 128 | 1.34 (0.92–1.96) | 30 | 1.56 (0.81–3.01) | 11 | 1.18 (0.42–3.31) | 11 | 2.20 (0.66–7.39) |
| P for heterogeneity | 0.04 | 0.06 | 0.35 | 0.96 | 0.90 | ||||||
| P for trend | 0.07 | 0.13 | 0.22 | 0.66 | 0.22 | ||||||
| Years of exposure at work(based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 757 | 263 | 1.00 | 132 | 1.00 | 26 | 1.00 | 12 | 1.00 | 7 | 1.00 |
| 1–20 years | 1,059 | 274 | 1.15 (0.91–1.45) | 130 | 1.12 (0.81–1.54) | 29 | 1.54 (0.81–2.93) | 23 | 2.30 (0.95–5.57) | 16 | 1.68 (0.62–4.60) |
| >20 years | 579 | 185 | 1.26 (0.97–1.63) | 95 | 1.36 (0.98–1.90) | 38 | 1.88 (1.04–3.39) | 2 | 0.35 (0.07–1.66) | 12 | 2.13 (0.74–6.10) |
| P for heterogeneity | 0.03 | 0.41 | 0.14 | 0.90 | 0.99 | ||||||
| P for trend | 0.08 | 0.07 | 0.04 | 0.49 | 0.16 | ||||||
| Combined years of exposure at home and work(based on the FHS, UCLA, NELCS, SLRI, Moffitt, GenAir, CREST, Liverpool, IARC, and Hawaii studies) | |||||||||||
| Never | 315 | 80 | 1.00 | 51 | 1.00 | 9 | 1.00 | 5 | 1.00 | 1 | 1.00 |
| 1–20 years | 557 | 160 | 1.12 (0.78–1.61) | 80 | 0.90 (0.58–1.39) | 11 | 1.16 (0.44–3.11) | 8 | 0.71 (0.20–2.58) | 7 | 3.76 (0.42–33.63) |
| 21–40 years | 445 | 173 | 1.33 (0.93–1.89) | 93 | 1.16 (0.76–1.77) | 21 | 1.80 (0.75–4.31) | 11 | 1.18 (0.36–3.86) | 7 | 3.90 (0.45–33.53) |
| >40 years | 305 | 132 | 1.40 (0.96–2.04) | 69 | 1.25 (0.79–1.97) | 28 | 2.71 (1.17–6.28) | 4 | 0.81 (0.20–3.26) | 6 | 4.85 (0.57–41.40) |
| P for heterogeneity | 0.02 | 0.05 | 0.44 | 0.99 | 1 | ||||||
| P for trend | 0.04 | 0.13 | 0.006 | 0.84 | 0.17 | ||||||
| Childhood exposure(based on the FHS, UCLA, NELCS, SLRI, Mayo, Moffitt, and GenAir studies) | |||||||||||
| No | 1,081 | 485 | 1.00 | 318 | 1.00 | 26 | 1.00 | 12 | 1.00 | 8 | 1.00 |
| Yes | 1,611 | 563 | 1.08 (0.92–1.26) | 304 | 0.97 (0.81–1.18) | 35 | 1.19 (0.69–2.03) | 20 | 1.49 (0.70–3.15) | 17 | 1.76 (0.74–4.22) |
| P for heterogeneity | 0.29 | 0.48 | 0.65 | 0.59 | 0.63 |
Associations between exposure to secondhand smoke and lung cancer development among never smokers were similar in males versus females (OR=1.35, 95% CI: 1.07–1.71 for males; OR=1.27, 95% CI: 1.11–1.45 for females; results not shown). There was some indication of heterogeneity of associations by race/ethnicity, but the sample sizes were not large enough to obtain precise estimates for non-White populations (OR=1.36, 95% CI: 1.18–1.58 for Whites; OR=1.20, 0.98–1.45 for Asians; OR=0.52, 0.25–1.06 for Blacks; OR=1.57, 0.70–3.52 for Hispanic/Latinos; results not shown). A stronger association was observed within the older age group of never smokers than within the younger age group (OR=1.56, 95% CI: 1.31–1.86 for ≥65 years old; OR=1.10, 95% CI: 0.95–1.29 for <65 years old; results not shown).
Table 6 compares small cell lung cancer with non-small cell lung cancer in terms of their association with secondhand smoke exposure. The adjusted odds ratios comparing small cell lung cancer with non-small cell lung cancer were 1.28 (95% CI: 1.03–1.59) and 2.11 (95% CI: 1.11–4.04) in the overall population and among never smokers, respectively.
Table 6
Difference of associations with exposure to secondhand smoke between small cell lung cancer and non-small cell lung cancer
| Overall population | ||||||
|---|---|---|---|---|---|---|
| Histological type | Cases | Controls | Unadjusted | Adjusted2 | ||
| OR (95% CI) | OR1 (95% CI) | OR (95% CI) | OR1 (95% CI) | |||
| Small cell lung cancer | 1,156 | 14,052 | 2.04 (1.71–2.44) | 1.19 (0.99–1.43) | 1.63 (1.31–2.04) | 1.28 (1.03–1.59) |
| Non-small cell lung cancer | 9,941 | 1.72 (1.61–1.84) | 1.34 (1.23–1.46) | |||
| Never smokers | ||||||
| Histological type | Cases | Controls | Unadjusted | Adjusted3 | ||
| OR (95% CI) | OR1 (95% CI) | OR (95% CI) | OR1 (95% CI) | |||
| Small cell lung cancer | 78 | 7,057 | 2.22 (1.22–4.03) | 1.84 (1.01–3.37) | 3.09 (1.62–5.89) | 2.11 (1.11–4.04) |
| Non-small cell lung cancer | 1,931 | 1.20 (1.07–1.35) | 1.28 (1.13–1.45) |
Discussion
This pooled analysis is the largest collaborative effort investigating the association between exposure to secondhand smoke and the development of lung cancer by histological type. Exposure to secondhand smoke was associated with an increased risk of lung cancer among both ever smokers and never smokers. Among the overall population, exposure to secondhand smoke increased the risk of lung cancer by approximately 30% and 60% for non-small cell lung cancer and small cell lung cancer, respectively. Among never smokers, secondhand smoke exposure increased the risk by approximately 30% and 200% for non-small cell lung cancer and small cell lung cancer, respectively.
Results of our joint effects analyses suggest that exposure to secondhand smoke is associated with lung cancer risk in both ever smokers as well as never smokers. The strong association between secondhand smoke exposure and lung cancer risk among ever smokers might be related to the fact that smokers exposed to secondhand smoke tend to smoke more than unexposed smokers do, as was the case in the present analysis—the mean pack-years of smoking was 42.3 among those exposed to secondhand smoke, compared with 34.5 among those who were unexposed (t-test P<0.0001; results not shown). However, the association was very strong even after adjusting for pack-years of smoking (OR=1.40, 95% CI: 1.25–1.56; results not shown). Therefore, a potential alternative explanation for this finding is that mainstream smoke and sidestream smoke have a synergistic effect on lung cancer development.
Our results also indicate that the association with secondhand smoke exposure may be greater for small cell lung cancer than for the other histological types (P=0.02). This observation is consistent with the point estimates reported in previous studies by Hackshaw et al. and Brennan et al. which also evaluated the association between secondhand smoke exposure and lung cancer risk, but with small and squamous cell carcinomas combined.6,7 Detecting such clear associations has been particularly challenging for small cell lung cancer due to the small number of cases among never smokers. In our study, the difference in the magnitudes of the association among the overall population compared with never smokers may be due to chance or residual confounding.
Epidemiologic studies have consistently reported that cigarette smoking is most strongly associated with small cell lung cancer, followed by squamous cell carcinoma.3,10,23–28 The differences in the strengths of associations by histological type is thought to be related to tumor location. Small cell lung cancer and squamous cell carcinoma mainly occur in the large central bronchi whereas adenocarcinoma and large cell lung cancer arise from more peripheral sites. The aerodynamic diameters of cigarette smoke particles determine the sites of deposition in the regions of the lung.29 It has been hypothesized that sites that are more proximal in the respiratory tract are more heavily exposed to tobacco smoke particles, especially those of larger size, than are peripheral sites.25,30,31 De Stefani et al. suggested that the presence of carcinogenic radioactive compounds and heavy metals in tobacco smoke could also explain the strong relation between exposure to tobacco smoke and small cell lung cancer, since occupational exposure to these carcinogens are strongly associated with small cell lung cancer.23 Many of these carcinogens (e.g., nickel, chromium, and arsenic) are also major constituents of sidestream smoke.5 The results of our study suggest that cigarette smoke plays a major role in the development of small cell lung cancer not only in the form of mainstream smoke affecting active smokers but also in the form of sidestream smoke affecting both active and passive smokers.
Lung cancer histology seems to be dictated by genetic alterations and the type of cells in which they occur. In a study using precise laser capture microdissection and allelotyping, Wistuba et al. reported there were differences in specific genetic alterations detected in small cell lung cancer compared with non-small cell lung cancers, and the smoking-damaged bronchial epithelium of patients with small cell lung cancer showed considerably more genetic damage—in terms of allele loss and microsatellite alterations—than that of patients with non-small cell lung cancers.32 Furthermore, many genetic alterations were also frequently observed in histologically normal and mildly abnormal bronchial biopsies from current and former smokers.32 Rb and p53 mutations, which occur in up to 90% of human small cell lung cancers, are examples of genetic damage caused by smoking. In a study to establish a mouse model for small cell lung cancer, Meuwissen et al. demonstrated that concomitant loss of Rb and p53 in a broad range of mouse lung epithelial cells gave rise almost exclusively to small cell lung cancer.33 Although the cellular origin of lung cancer is largely unknown, it is speculated that different histological types arise from distinct cells of origin located in defined microenvironments, and small cell lung cancer is thought to have its origin in neuroendocrine cells.33–35
We also observed some variations in strengths of associations by the location and duration of secondhand smoke exposure. Exposure at home seemed to have a stronger effect than exposure at the workplace, probably because exposure at home—especially from a spouse—is more likely to be of greater duration and intensity than exposure at work. The results also suggest that people exposed to secondhand smoke both at home and at the workplace are more likely to develop lung cancer than those exposed at one location only. For both exposure at home and exposure at work, we observed dose-response relations between duration of exposure and lung cancer incidence. The trends were more evident among the overall population than among the subgroup of never smokers, possibly due to the difference in sample sizes. Brennan et al. also reported such dose-response relations among never smokers, but their method of categorizing duration of exposure differed from ours.7 When we used the same duration categories used by Brennan et al. (<16/16–30.9/≥31.0 years for exposure from the spouse—assumed to be comparable to our variable for exposure at home—and <8.0/8.0–20.9/≥21.0 years for exposure at work), we observed dose-response relations among never smokers for both exposure at home (P=0.04) and exposure at work (P=0.02). Lastly, exposure to secondhand smoke during childhood was associated with lung cancer among the overall population. Results from previous studies of exposure to secondhand smoke during childhood have been inconsistent, which could be, at least partially, due to the difficulty of recalling exposures that took place a long time ago.36–49 The inconsistency may also be due to chance, since some studies had low power.
This study has several limitations. Due to the nature of our case-control study design, the results might be influenced to some degree by recall bias. Since tobacco is an established risk factor for many diseases, hospital-based controls might be more likely than healthy controls to recall their exposure to secondhand smoke. If this is in fact the case, our results from hospital-based case-control studies might be more likely to be biased towards the null, compared to those from population-based studies. However, when we performed stratified analysis, the association between exposure to secondhand smoke and lung cancer development was even stronger within the stratum of hospital-based studies than that of population-based studies. Variations in the definition of never smokers across studies could also be a limitation. However, consistent results from influence analysis confirmed that the observed associations were not due to any particular study. Another potential source of bias might be the result of misclassification of ever smokers as never smokers due to misreporting. In addition, the concordance of smoking status within couples might lead to bias of the estimates. Although we were not able to assess this issue in this pooled population, a European validation study has suggested that such bias from smoker misclassification is not likely to be significant.50 If a disproportionate number of exposed controls had been classified as unexposed, then this might bias the estimated association away from the null. Finally, we excluded some participants from the analysis due to missing data, mostly on exposure status. Selection bias is possible if the data were not missing at random. However, comparing those excluded from the analysis with those included, the distributions of the covariates were similar between the two groups, except for study site.
The strength of this study is the relatively high power achieved through the pooling of individual-level data. Compared with meta-analyses, pooled analyses such as ours can achieve high power with less publication bias and more consistent covariate adjustment. Although our results point to the role of secondhand smoke in the development of lung cancer regardless of histological type, the extent of the relationship varies by histological type and is especially strong for small cell lung cancer.
While it is important to disseminate the public health message about the hazard of active and passive smoking in order to reduce the incidence of lung cancer, further investigation on the etiologic processes underlying the association between tobacco smoke and lung cancer are warranted. Future studies should also determine if exposure to secondhand smoke is associated with stage of lung cancer, as well as consider other potential risk factors, including indoor air pollution from other sources and genetic factors. In the ILCCO consortium, we have started the process of pooling genetic data in order to investigate the role of genetic polymorphisms in the DNA repair genes in the development of lung cancer among never smokers.
What’s new?
Few studies to date have measured precise estimates of the association between exposure to secondhand tobacco smoke and lung cancer risk by histological type. This study reports estimates of this association for all major histological types, including adenocarcinoma, squamous cell carcinoma, large cell lung cancer, and small cell lung cancer. Importantly, secondhand smoke was found to be more strongly associated with small cell lung cancer than with non-small cell lung cancer.
Acknowledgements
This work was supported by the National Institutes of Health (1U19CA148127-01); the German Research Foundation (GRK1034); the Canadian Cancer Society (CCSRI 020214); and Cancer Care Ontario Research Chair Award. Studies of the Wayne State University were supported by the Karmanos Cancer Institute (WSU/KCI-1, WSU/KCI-2) and the National Institutes of Health (R01CA060691, NIH R01CA87895, NIH N01-PC35145, NIH P30CA22453, CA125203). The UCLA study was supported by the National Institutes of Health (CA 11386, ES011667, CA 90833, and CA 09142) and Alper Research funds for Environmental Genomics. The Harvard study was supported by the National Institutes of Health (CA092824, CA74386 and CA090578). The Mayo Clinic (MAYO) studies were supported by the Mayo Foundation Fund and the National Institutes of Health (CA77118, CA80127, CA115857, CA084354 to P.Y.]. The New England Lung Cancer Study was supported by the National Institutes of Health (P20 RR018787). The Hawaii study was supported by the National Institutes of Health (R01CA 55874). The Liverpool Lung Project (LLP) was supported by the Roy Castle Lung Cancer Foundation UK. The Central Europe study (CE) was supported by the World Cancer Research Fund and the European Commission’s INCO-COPERNICUS Program (contract number IC15-CT96-0313). The Warsaw part of CE was supported by the Polish State Committee for Scientific Research (SPUB-M-COPERNICUS/P-05/DZ-30/99/2000). The Czech Republic part of CE was supported in part by the European Regional Development Fund and the State Budget of the Czech Republic, RECAMO (CZ.1.05/2.1.00/03.0101) and MH CZ - DRO (MMCI, 00209805). The Aichi study was supported in part by Grants-in-Aid from the Ministry of Health, Labor, and Welfare for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; the National Cancer Center Research and Development Fund; and Grant-in-Aid for Scientific Research on Priority Areas and on Innovative Area from the Ministry of Education, Science, Sports, Culture and Technology of Japan. The CREST study was supported by the University of Genoa and AIRC (Associazione Italiana per la Ricerca sul Cancro). The Genes and Environment in Lung Cancer, Singapore (GEL-S) study was supported by the National Medical Research Council, Singapore (NMRC/1996/0155, NMRC/0897/2004 and NMRC/1075/2006).
Abbreviations
| ILCCO | International Lung Cancer Consortium |
|---|---|
| IARC | International Agency for Research on Cancer |
| NCI | National Cancer Institute |
| RR | risk ratio |
| OR | odds ratio |
| ROR | ratio of odds ratios |
| CI | confidence interval |
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