original article
Annals of Oncology 22: 1420–1426, 2011 doi:10.1093/annonc/mdq613 Published online 18 January 2011
Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4) P. Bertuccio1,2, C. La Vecchia1,2, D. T. Silverman3, G. M. Petersen4, P. M. Bracci5, E. Negri1, D. Li6, H. A. Risch7, S. H. Olson8, S. Gallinger9, A. B. Miller10, H. B. Bueno-de-Mesquita11,12, R. Talamini13, J. Polesel13, P. Ghadirian14, P. A. Baghurst15, W. Zatonski16, E. T. Fontham17, W. R. Bamlet4, E. A. Holly5, E. Lucenteforte1,2, M. Hassan6, H. Yu7, R. C. Kurtz18, M. Cotterchio10,19, J. Su3, P. Maisonneuve20, E. J. Duell21, C. Bosetti1 & P. Boffetta22,23* Department of Epidemiology, Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan, Italy; 2Department of Occupational Health, Section of Medical Statistics, University of Milan, Milan, Italy; 3National Cancer Institute, Bethesda; 4Mayo Clinic, Rochester; 5University of California, San Francisco; 6The University of Texas M.D Anderson Cancer Center, Houston; 7Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven; 8Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, USA; 9Toronto General Hospital; 10Dalla Lana School of Public Health, University of Toronto, Toronto, Canada; 11National Institute for Public Health and the Environment (RIVM), Bilthoven; 12Department of Gastroenterology and Hepatology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands; 13Unit of Epidemiology and Biostatistics, Centro di Riferimento Oncologico (CRO), Aviano, Italy; 14Epidemiology Research Unit, Research Centre (CRCHUM), Montre´al, Canada; 15Public Health, Women’s and Children’s Hospital, Adelaide, Australia; 16Cancer Center & Institute of Oncology, Warsaw, Poland; 17Louisiana State University, School of Public Health, New Orleans; 18Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA; 19Cancer Care Ontario, Toronto, Canada; 20European Institute of Oncology, Milan, Italy; 21Catalan Institute of Oncology (ICO), Barcelona, Spain; 22 International Prevention Research Institute, Lyon, France; 23The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, USA
original article
1
Received 25 June 2010; revised 8 September 2010; accepted 10 September 2010
Background: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco.
Materials and methods: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case–control studies (6056 cases and 11 338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. Results: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2–2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4–1.6). The OR was 1.1 (95% CI 0.69–1.6) for pipeonly smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ‡ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75–1.3). Conclusion: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use. Key words: cigar, pancreatic cancer, pooled analysis, smokeless tobacco, tobacco, pipe
introduction Cigarette smoking is the best-identified risk factor for pancreatic cancer [1–3]. A meta-analysis of 82 cohort and case–control studies [1] estimated a relative risk (RR) of 1.7 [95% confidence interval (CI) 1.6–1.9] for current smokers and 1.2 (95% CI 1.1–1.3) for former smokers, the association being consistent across geographic areas and sex. *Correspondence to: Dr P. Boffetta, The Tisch Cancer Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. Tel: +1-212-824-7073; Fax: +1-212-996-0407; E-mail:
[email protected]
Data for other tobacco products and pancreatic cancer risk are limited. In the above-mentioned meta-analysis, nine studies considered cigar smokers only, with the pooled RR of 1.5 (95% CI 1.02–2.3), and nine studies considered pipe smokers only, with a pooled RR of 1.4 (95% CI 0.94–2.1) [1]. Study quality tests suggested that the association was stronger for data from proxy interviews, indicating a possible role for bias. Data are even more limited for smokeless tobacco use [4–6]. An overview of six studies from the United States and Nordic countries [5] resulted in a summary RR of 1.6 (95% CI 1.1–2.2) for ever use of any type of smokeless tobacco. In two of these
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
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original article
Annals of Oncology
studies, a prospective cohort study of 10 136 Norwegian men recruited in 1966 and followed up to 2001 [7], and a cohort investigation of 279 897 male Swedish construction workers [8], pancreatic cancer was the only site associated with use of snus (the main smokeless tobacco product used in Northern Europe), with RRs of 1.7 (95% CI 1.1–2.5) and 2.0 (95% CI 1.2–3.3), respectively. This association may have been related to exposure to N-nitroso compounds, specifically N-nitrosamines that may have a specific carcinogenic effect on the pancreas [5]. Associations with smokeless tobacco were less consistent in studies from North America [5], particularly in case–control studies that had a lower prevalence of use [9]. Given the relatively low exposure prevalence, the assessment of the role of tobacco products other than cigarettes requires a large sample size, typically larger than in individual studies. We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and pancreatic cancer risk using data from a series of case–control studies that are part of the
International Pancreatic Cancer Case-Control Consortium (PanC4) [10]. We examined the effect of cigar and pipe smoking and smokeless tobacco use, alone and in combination with cigarettes and other tobacco products.
methods studies In PanC4, we identified 11 case–control studies of pancreatic cancer that collected data on cigarettes and other forms of tobacco use using structured questionnaires [11–23]. Eight studies were conducted in North America [including the unpublished Louisiana School of Public Health (LSU) study] [13–21, 23], two in Europe [12, 22] and one was a multicentric study from Canada, Europe and Australia [11]. A summary description of the individual studies is presented in Table 1. Briefly, the LSU study (E. T. Fontham, unpublished data) included 69 newly diagnosed cases with primary pancreatic cancer residents of eight South Louisiana counties who were >20 years of age and 158 population-
Table 1. Summary description of individual studies included in the International Pancreatic Cancer Case-Control Consortium (PanC4) on pancreatic cancer and cigar and pipe smoking and smokeless tobacco use Country study, reference
North America Louisiana LSU (E. T. Fontham, unpublished data) Minnesota Mayo Clinic [18] Texas MDACC [15, 16] New York MSKCC [17] Georgia, Michigan, New NCI [13, 14]
Study period Cases Men:women Age range (median)
Sources
78:80
Sources
2001–2006
33:36
2000–2007
624:513
29–92 (68) Hospital
626:665
29–97 (70) Hospital
2000–2006
539:335
28–87 (63) Hospital
495:295
31–84 (61) Hospital (visitors)
2003–2008 Jersey 1986–1989
264:245
32–89 (64) Hospital
142:206
27–84 (58) Hospital (visitors)
250:243
32–79 (63) Cancer registry
Connecticut Yale [23]
2005–2009
238:175
36–84 (68) 30 Connecticut hospitals + cancer registry
404:311
35–84 (68) Random digit dial
California UCSF [20, 21]
1995–1999
287:240
32–85 (65) Cancer registry
879:818
32–85 (66) Random digit dial (95% [24]. The Surveillance of Environmental Aspects Related to Cancer in Humans (SEARCH) study [11] was a collaborative study of the International Agency for Research on Cancer including 810 cases and 1679 controls matched by age and sex collected in the 1980s in Toronto and Montreal, Canada, Utrecht, The Netherlands, Opole, Poland and Adelaide, Australia, based upon a random sample from the population at risk. Participation rate in various centers varied between 50% and 80%. Proxy interviews were obtained for 60% of cases and 20% of controls. A total of 6056 participants with adenocarcinoma of the exocrine pancreas and 11 338 controls were included in these present analyses. Data may differ slightly from those in published reports of the same studies due to missing data for relevant variables. Cases and controls were interviewed
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in-person with the exception of the Toronto study that used selfadministered questionnaires and included 63 case proxy respondents [19] and the SEARCH study [11], where proxy interviews were conducted for 474 cases and 332 controls. The original datasets were restructured either by the original study investigators or by the central coordinators using a uniform format for data harmonization. Individual data were collected about sociodemographic characteristics, anthropometric measures, smoking and alcohol consumption, history of diabetes and of pancreatitis, family history of pancreatic cancer in first-degree relatives and histology and topography of the tumor (for cases).
exposure variables All studies provided information on cigar and pipe smoking. Ever smokers of cigars or pipes were defined as participants who had used these products on a regular basis for at least 6 months in the LSU study and in other three studies [14, 21, 23]; who smoked at least one cigar or pipe per day for at least 1 year in two studies [12, 22]; who smoked at least one cigar or pipe per month for at least 3 months in one study [19]; or who reported to have ever smoked at least one of these products in their lifetime in the remaining five studies [11,16–18]. For cigars and pipes, the amount of daily use (grams) and duration of exposure (years) were considered when data were available (no dose nor duration data for two studies [17, 18] and duration only for the LSU study and another study [19]). Questions about ever use of smokeless tobacco were available in the LSU study and other five studies [11, 14, 16, 18, 23] of the 11 studies included in our analysis, with three studies [14, 16, 18] and the LSU study having collected data about chewing tobacco and snuff separately and, one study collecting information for chewing or snuff combined [23] and the SEARCH study [11] having collected data about chewing tobacco only. In each study, ever users of smokeless tobacco were defined as for cigar and pipe smokers described above. Information on amount of smokeless tobacco used was provided in four of the six studies [11, 14, 16, 23], while information on duration was available in all studies except one [18]. Given some inconsistencies in the definition of the measurement unit for smokeless tobacco use, it was, however, not possible to pool dose–response data across studies. To create uniform variables across the multiple studies, one cigar or pipe full of tobacco was considered equivalent to 3 g of tobacco in European studies and to 5 g in non-European studies. For smokeless tobacco, we combined chewing and snuff in the analyses.
statistical analysis We conducted an aggregate analysis with data from all studies pooled into a single large dataset [25]. Those who had never used any kind of tobacco were the reference category for each tobacco product. The association between cigar, pipe and smokeless tobacco use (and their combinations) and risk of pancreatic cancer was assessed by estimating the odds ratios (OR) and the corresponding 95% CI using unconditional multiple logistic regression models [26] adjusted for study center, age (
