IL FUMO DI SIGARETTA E IL RISCHIO DI TUMORE DEL PANCREAS: DIVERSI APPROCCI DI ANALISI IN UNA POOLED-ANALYSIS

Background: To evaluate the dose–response relationship between cigarette smoking and pancreatic cancer risk and to examine the effects of temporal variables. Aim: The aim of my PhD thesis is to explore the effect of selected smoking variable (including dose, duration and time since quitting) on the risk of pancreatic cancer using the two-stage and the multilevel analysis, and to compare these results with those obtained using the “standard” aggregate analysis. Moreover, generalized additive models were used to analyse the relation between smoking and pancreatic cancer risk without any data constriction. Methods: Data from 12 case–control studies, within the International Pancreatic Cancer Case–Control Consortium (PanC4) and including 6507 pancreatic cases and 12 890 controls, were analyzed. In the aggregate analysis, smoking variables were categorized and odds ratios (ORs), and corresponding 95 confidence intervals (CIs), were calculated using logistic regression models adjusted for selected covariates (sex, age, ethnicity, education, body mass index, alcohol consumption, and history of diabetes and of pancreatitits) and study center. In the two-stage analysis, smoking variables were categorized, and summary ORs were calculated pooling study-specific ORs using random-effects models. Study-specific ORs were calculated using logistic regression models adjusted for the same covariates used for adjustment in the aggregate analysis. In the multilevel analysis, smoking variables were categorized and summary ORs were calculated using hierarchical models with two levels of hierarchy, considering study center as level 1, and subject as level 2. At level 2, models were adjusted the same covariates used for adjustment in the aggregate analysis. Finally, smoking variables were considered as continuous and generalized additive logistic regression were used to explore the nonlinear effects. Results - aggregate analysis: Compared with never smokers, the OR was 1.46 (95% confidence interval [CI] 1.36–1.57) for former smokers and 2.00 (96% CI : 1.83-2.19) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR = 3.17 for more than 40 cigarettes per day, P for trend <0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR = 2.02). Moreover, compared to current cigarette smokers, the risk decreased with increasing time since cigarette cessation, in fact the OR being 0.46 after 30 years. Results - two-stage analysis: Point estimates were similar to those obtained in the aggregate analysis, whereas interval ones were larger. There was substantial heterogeneity among studies, except for current smokers of less than 10 cigarette per day (p-value=0.0952) or more than 40 cigarette per day (p-value=0.2815), for current smokers who smoked for 20-<30 years (p-value=0.2309), and for ex-smokers who time since quitting 10-<15 years (p-value=0.0756) or 15-<20 years (p-value=0.0739). Results - multilevel analysis: Point ant interval estimates were similar to those obtained in the aggregate analysis. As regard number of cigarettes, risks were stronger among females, subjects with less than 65 years, and among subjects drinking 0-1 drinks of alcohol per day. No differences were found for duration and time since quitting. Though significant increasing trend in risk with increasing number of cigarettes, duration and time since quitting was observed, nonlinear relations were found. The risk of pancreatic cancer increased rapidly for each additional increment of one cigarette/day up to 25-30 cigarettes/day, and less rapidly for higher number of cigarettes/day. As regard duration, the risk increased rapidly for each year up to 25 years, then the risk increased less rapidly, plateaued at 35 years, and declined for subjects who smoked more than 40 years. Finally, a periodic effect was observed for years since quitting, although a decreased risk for each years was found. 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, with a nonlinear effect, increases with the number of cigarettes smoked and duration of smoking and decreases with time since quitting.