This collaborative-pooled analysis of data from the PanC4 case–control studies provides additional evidence, and more accurate quantitative estimates than previously available, on the association between heavy alcohol consumption and the risk of pancreatic cancer. Compared with abstainers or occasional drinkers, ORs of pancreatic cancer were at or near unity for participants who drank up to 4 drinks per day, and statistically significantly above unity for higher intakes, with up to a 60% increased risk among extremely heavy alcohol drinkers (≥9 drinks per day). No consistent relation was observed for duration of alcohol drinking using available data. This is not surprising, since for oral cancer and other alcohol-related neoplasms, the association between duration and risk is much less consistent than that with dose [65
Although the 2007 IARC Monograph Working Group concluded that there was inadequate evidence for alcohol carcinogenicity on pancreatic cancer [42
], an association between heavy alcohol consumption and risk of pancreatic cancer has been reported in some case–control [43
] and cohort [50
] studies. An IARC Monograph Working Group in 2009 concluded that there was limited evidence for a causal association between alcohol consumption and pancreatic cancer risk [68
], referring to a meta-analysis of 21 case–control and 11 cohort studies [69
] that showed an overall relative risk (RR) of 0.92 for consumption of <3 drinks/day, but of 1.22 (95% CI 1.12–1.34) for higher consumption. Likewise, the ‘Pooling Project of Prospective Studies of Diet and Cancer’ [70
], which included 14 cohort studies for a total of 2187 incident cases, found no association up to 30 g/day of alcohol consumption (~3 drinks/day) but a moderate positive association for the highest category of consumption (RR = 1.22, 95% CI 1.03–1.45). Moreover, in that study, it was not possible to investigate the higher consumption of alcohol (>3 drinks/day) due to the small number of heavy drinkers in most (American) cohort studies. The Pancreatic Cancer Cohort Consortium-nested case–control analysis based on 1530 pancreatic cases found no significant association between total alcohol intake and pancreatic cancer risk; and the OR was increased for the highest consumption though not significantly (OR = 1.38, 95% CI 0.86–2.23 for ≥60 g/day) [71
]. However, that study did report a significant excess risk for ≥45 g/day for liquor in men (OR = 2.23, 95% CI 1.02–4.87), but the number of subjects in the various levels of intake and analyses of type of beverages were too limited for definitive conclusions.
Our results based on a reanalysis of original data from a uniquely large pooled dataset provide additional data on heavier alcohol consumption (i.e. 6–>9 drinks per day) and pancreatic cancer risk. We also were uniquely able to evaluate whether the association between (heavy) alcohol consumption and pancreatic cancer risk was modified by pancreatitis or tobacco smoking. More importantly, we were able to uniformly define the modeling of the exposure, confounding, and outcome variables [61
]. Finally, our data harmonization and pooling allowed more detailed adjustment for tobacco smoking than in several individual studies and meta-analyses of alcohol and pancreatic cancer risk.
Heavy alcohol consumption is a recognized cause of chronic pancreatitis [9
], a known risk factor for pancreatic cancer. In our dataset, 242 cases and 95 controls reported a history of pancreatitis. Our results did not substantially change when we excluded these individuals from the analysis. Although several studies queried participants to ascertain physician-diagnosed acute or chronic pancreatitis and number of episodes, it is difficult to assess the validity of (self-reported) information on pancreatitis, because of the potential misclassification between the various forms of acute and chronic pancreatitis, and obstructive pancreatitis resulting from duct blockage due to the presence of a pancreatic tumor [73
]. To diminish the potential for reverse causation on effect estimates, pancreatitis diagnosed in the short term (at least 1 year) before diagnosis/interview was not considered.
Heavy alcohol drinking also may have a direct effect on pancreatic carcinogenesis. Acetaldehyde [75
]—the main metabolite of ethanol—is a known carcinogen and the induction of pancreatic injury from fatty acid ethyl esters [12
] and reactive oxygen species [77
] are possible mechanisms and might explain the association between heavy alcohol drinking and pancreatic cancer.
Cigarette smoking is an established risk factor for pancreatic cancer [1
] and is often positively correlated with alcohol drinking. In our analyses, the association between heavy alcohol drinking and pancreatic cancer was consistently elevated among ever, former, and current (moderate and heavy) smokers. Interestingly, the magnitude of the effect was lowest among heavy current smokers, moderate for never and current moderate smokers, and greatest for ex-smokers. This result argues against the hypothesis that the excess risk among heavy drinkers is due to the correlation between heavy alcohol drinking and heavy tobacco smoking. Furthermore, in subanalyses that included studies with more detailed information about tobacco smoking (frequency, duration, years since quitting, and non-cigarette tobacco use), the magnitude of the association between alcohol consumption and pancreatic cancer risk was similar to the results that we reported for all studies. Thus, residual confounding by tobacco smoking is an unlikely explanation for the observed association between heavy alcohol consumption and pancreatic cancer risk. Our results also show that other potential confounders such as age, sex, study area, education, BMI, and history of diabetes appear to not modify the effect of heavy alcohol consumption on pancreatic cancer risk. The association with heavy alcohol drinking was somewhat—although not significantly—stronger in Blacks than in Whites. This was previously reported in an National Cancer Institute-based study [43
], which contributed about half of the Blacks cases to the present pooled analysis in PanC4.
Both hospital- and population-based controls can introduce selection bias, e.g. by inclusion or exclusion of alcohol-related diseases in hospital controls, and by lower participation of individuals with alcohol dependency in population-based studies. In PanC4, three studies [32
] used hospital controls, one study selected controls from healthy individuals accompanying subjects to the hospital/clinic [47
], and six studies [30
] used general population controls. Our results were consistent regardless of the source of study controls.
Recall bias and misclassification also may have affected our results, particularly because alcohol drinking may be intentionally or unintentionally underreported by participants and proxies. However, our sensitivity analyses showed that it is unlikely that less complete information collected from proxies influenced the overall results. It is more difficult to assess whether differences in social acceptance of alcohol consumption may have influenced participants’ response to alcohol questions during in person interviews. For three studies [32
] included in the present analysis, reproducibility and validity of alcohol drinking were assessed and found satisfactory [78
]. Although similar information was not available for other studies, results from our sensitivity analysis (i.e. excluding each study from the analyses) showed no substantial change in the pooled risk estimates.
We applied the same estimate of ethanol content for each type of alcoholic beverage across all studies. Although the ethanol content of wine and beer is relatively consistent across countries and regions in the world [75
], there is a potential for variation in ethanol content from (hard) liquors. However, given the smaller number of liquor drinkers as compared with wine and beer drinkers, and little difference in the number of exclusive liquor drinkers by case–control status, this is not likely to have substantially influenced our results.
In summary, the results of this pooled analysis of case–control studies in PanC4 support a moderate increased risk of pancreatic cancer with heavy daily alcohol consumption that is in agreement with a previous pooled analysis of cohort studies [70
] and a recent meta-analysis of published case–control and cohort studies [69
]. Our data provide no evidence for a role of light or moderate alcohol drinking in pancreatic carcinogenesis, but rather, an increased risk only for heavy drinking, the effects being independent from those of tobacco smoking.