Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4)

C. Bosetti 0 E. Lucenteforte 0 D. T. Silverman 0 G. Petersen 0 P. M. Bracci 0 B. T. Ji 0 E. Negri 0 D. Li 0 H. A. Risch 0 S. H. Olson 0 S. Gallinger 0 A. B. Miller 0 H. B. Bueno-de- Mesquita 0 R. Talamini 0 J. Polesel 0 P. Ghadirian 0 P. A. Baghurst 0 W. Zatonski 0 E. Fontham 0 W. R. Bamlet 0 E. A. Holly 0 P. Bertuccio 0 Y. T. Gao 0 M. Hassan 0 H. Yu 0 R. C. Kurtz 0 M. Cotterchio 0 J. Su 0 P. Maisonneuve 0 E. J. Duell 0 P. Boffetta 0 C. La Vecchia 0 0 The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology Background: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. Methods: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. Results: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR = 3.4 for 35 cigarettes per day, P for trend <0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR = 2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. Conclusions: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of - introduction Cigarette smoking is the best established risk factor for pancreatic cancer [1, 2]. A meta-analysis of 82 cohort and casecontrol studies published between 1950 and 2007 [3] reported a summary relative risk (RR) of pancreatic cancer of 1.7 (95% confidence interval [CI] 1.61.9) for current smokers and of 1.2 (95% CI 1.11.3) for former smokers. It also showed that the risk persisted for up to 10 years after quitting smoking, although no detailed analysis of the dose and durationrisk relations was conducted. In the International Pancreatic Cancer Cohort Consortium nested casecontrol study [4], that included 1481 cases and 1539 controls, the RR was 1.1 (95% CI 0.91.3) for former smokers and 1.8 (95% CI 1.42.3) for current smokers. Significant trends in risk were observed with increased number of cigarettes smoked and duration of exposure, the RR being 1.75 for 30 or more cigarettes smoked per day and 2.1 for 50 or more years of smoking, whereas the RR for those who had quit smoking for >15 years was similar to that of never smokers. To further evaluate the doseresponse relationship between cigarette smoking and pancreatic cancer and the role of various temporal factors, such as age at starting and time since stopping, we analyzed the original data from a series of case control studies within the International Pancreatic Cancer CaseControl Consortium (PanC4) [5, 6]. This uniquely large dataset allowed us to investigate in detail cigarette smoking on pancreatic cancer, with careful adjustment for major potential confounding factors for pancreatic cancer. methods The PanC4 identified 12 casecontrol studies (including the unpublished Louisiana State University study) of pancreatic cancer that collected data on cigarette smoking using structured questionnaires [718]. Eight studies [714] (including the unpublished Louisiana State University study) were conducted in North America, two in Europe [15, 16], and one in China [17], and one was the International Agency for Research on Cancercoordinated Surveillance of Environmental Aspects Related to Cancer in Humans (SEARCH) study from Canada, Europe, and Australia [18]. A summary description of the individual studies is presented in Table 1. The present pooled analysis included a total of 6507 cases of adenocarcinoma of the exocrine pancreas and 12 890 controls. The data included in the pooled analysis may differ slightly from those in published reports of the individual studies due to missing data for relevant variables. In all studies, cases and controls were interviewed in person, with the exception of the Ontario, Canada study that used self-administered questionnaires and included 63 case proxy respondents [14]; the SEARCH study [18], where proxy interviews were conducted for 474 cases and 332 controls; and the Shanghai study [17], where 155 cases and 150 controls were proxy interviewed. The original datasets were restructured either by the original study investigators or by the central coordinators using a uniform format for data harmonization. In addition to the smoking-related data, for each study, we considered individual data on sociodemographic characteristics, anthropometric measures, alcohol consumption, and history of diabetes and pancreatitis. exposure variables All studies in this pooled analysis provided information about cigarette smoking status (never, former, and current smoker), number of cigarettes smoked per day, duration of smoking, age at start smoking, and years since quitting or age at quitting smoking for former smokers. Though questions about cigarette smoking were similar across studies, we conducted a careful and detailed examination of the comparability of smoking-related questions to harmonize the data from the multiple studies included in this pooled analysis. For the present analyses, ever cigarette smokers were defined as participants who had smoked at least 100 cigarettes in their lifetime [79, 11, 13, 14, 17] or more than one cigarette per day for at least 1 year [15, 16, 18]. In the National Cancer Institute (NCI), information was only available for regular smokers, i.e. those who smoked at least one cigarette per day for at least 6 months [10]. Former cigarette smokers were defined as those who had quit smoking for at least 1 year before interview in all studies. statistical analysis To estimate the association between cigarette smoking and pancreatic cancer risk, we used a two-stage modeling approach [19]. In the first stage, we assessed the association between cigarette smoking and pancreatic cancer for each study by estimating the odds ratios (ORs) and the corresponding 95% CIs using multivariable unconditional logistic regression models [20]. These models included terms for age (<50, 5054, 5559, 6064, 6569, 7074, 75 years), sex, education (8th grade, 9th 11th grade, 12th grade or high school graduates, some college or college graduates, 1 year of graduate school), race/ethnicity (non-Hispanic white, Hispanic, non-Hispanic black, other), body mass index (BMI; <20, 20 to <25, 25 to <30, 30 kg/m2), history of diabetes (1 year before diagnosis/ interview), alcohol consump (...truncated)