Our results have demonstrated that heavy alcohol consumption and binge drinking were associated with increased risk estimates for pancreatic cancer in men but not among women. Our data further suggested that either binge or consistent heavy alcohol consumption was associated with persistent increased risk of pancreatic cancer regardless of the temporal proximity of consumption to pancreatic cancer diagnosis. Results from smoking-stratified analyses that suggested a possible interaction between current smoking and heavy drinking should be interpreted with caution and require further validation in larger pooled studies, particularly given that the p
-interactions for these analyses were >0.3. The association between alcohol consumption and pancreatic cancer in earlier studies has been discordant, with some hospital-based [24
] and population-based case–control [3
] and cohort studies [4
] showing no association, and other hospital-based [29
] and population-based case–control [15
] and cohort [20
] studies suggesting increased risk. Discordant observations in the published literature may be due to small numbers of cases, residual confounding by risk factors associated with alcohol consumption such as smoking and chronic pancreatitis, unmeasured genetic factors, or absence of detailed data on alcohol exposure [16
Discordant results due to residual confounding associated with smoking are less likely given that, as one of the few identified risk factors, most epidemiologic studies have included tobacco use in their analyses of alcohol consumption and pancreatic cancer risk. Indeed, in several studies that reported a positive association between alcohol and pancreatic cancer, the association persisted even among non-smokers [16
]. In our study, data were consistent with persistent increased risk among non-smokers, but not statistically significant. Notably, the number of never smokers available for analysis in our study required pooling of data from never smokers with those who quit smoking over 15 years prior to interview; this may have biased our estimates comparing risk among non-smokers to smokers toward finding a smaller risk difference than actually present. However, because there was a small sample of never smokers, and the ability to adjust for more detailed smoking characteristics (such as pack-years of smoking) was limited, it is possible that residual confounding due to smoking cannot be completely excluded.
Unmeasured molecular and genetic characteristics within individuals and their cancers also may explain some discordant observations. For example, particular mutations in the K-ras oncogene may be more common in alcohol consumers with pancreatic cancers, and may be initiating or end mediators of pancreas cancer associated with heavy alcohol exposure [23
Misclassification of alcohol consumption related to recall bias or inadequate measurement of detailed alcohol consumption over time may be a more likely explanation for the discordant published results. The potential for recall bias is inherent to all retrospective studies and also has been noted in several prospective cohort studies [9
]. The extensive measures taken in our study to diminish the effects of recall bias are noted below.
Measurement error with respect to characterization of the dose, duration, and pattern of alcohol consumption may explain some discordant findings between alcohol consumption and pancreatic cancer risk [40
]. Few population-based studies have analyzed the relationship between pancreas cancer and binge alcohol consumption [6
]. Of these, one study observed that increased risks were mainly in the highest categories of alcohol consumption, and were stronger among African Americans than for whites [16
]. Although the authors reported no association between pancreatic cancer and binge drinking [16
], the definition of binge drinking that was used (≥3 drinks/week) was lower than that used in our analyses based upon the United States Behavioral Risk Factor Surveillance System study [50
]. Our observation that binge drinking (≥5 drinks/episode, >70 g of alcohol)—even when occurring years before diagnosis or among moderate alcohol consumers—was associated with increased cancer risk, suggests that the pattern of drinking may be an important mediator of effect. Averaging alcohol exposure over weeks, months, or years, classifying consumption into broad categories, and/or computing lifetime alcohol exposures to measure total consumption, may not accurately assess toxicity that results from high and/or binge doses of alcohol. Thus, use of these methods may limit the ability to identify associations between alcohol exposure and pancreatic cancer.
Several biologic mechanisms have been proposed to explain the observed increased risk of pancreatic cancer related to heavy alcohol consumption. Alcohol may initiate inflammatory responses that result in overt chronic pancreatitis or diabetes mellitus, perhaps via induction of mitogenic stimuli [22
]. Alcohol consumption also may lead to asymptomatic chronic pancreatitis that then leads to pancreatic cancer [66
], although the prevalence of the history of pancreatitis is small in the overall population of pancreatic cancer patients. In addition, oxidative and non-oxidative pancreatic damage due to metabolism of alcohol can initiate inflammatory and fibrotic cascades that may result in subsequent carcinogenesis [22
]. Further detailed study of alcohol consumption, including dose, duration, and pattern of exposure, is needed to discern the biologic mechanisms that are important in pancreatic cancer development.
A null or protective association for alcohol and pancreatic cancer among women has been noted in most, [6
], but not all [16
] earlier studies. In our study, the proportion of women who reported heavy and/or binge drinking was much lower than for men. Therefore, the lack of an observed association may be attributable to sample size constraints. Further research is necessary to understand differences in pancreatic cancer risk between men and women.
Possible limitations of case–control studies should be considered when interpreting our results. Recall bias may be a problem in studies that query people about past events, although the effects of recall bias may have been diminished by requesting that participants report detailed alcohol consumption in multiple ways and over multiple time periods. Interviewers were highly trained and monitored to avoid interviewer bias and data were collected using a standardized questionnaire that included recent and past exposures. Because our results showed consistent trends between pancreatic cancer and dose and duration of alcohol exposure and, as noted earlier, underreporting would have diminished the risk estimates toward the null, recall bias may have had limited influence. Although rapid case ascertainment methods were used, similar to other population-based studies of pancreatic cancer, a large number of patients had died prior to initial contact due to the aggressive nature of the disease. The potential effect of these non-interviewed patients on risk estimates is unknown, as alcohol consumption data were not available for non-interviewed cases who died shortly after diagnosis. Our prior comparison of demographic data from SEER abstracts for interviewed and non-interviewed cases who were identified as part of our study showed that non-interviewed cases tended to be slightly older, with a slightly greater proportion of women than men, somewhat more minorities, fewer known tumor characteristics, and shorter survival times [44
In summary, our findings support an association between heavy alcohol consumption and pancreatic cancer among men that may be mediated by dose, duration, and pattern of alcohol consumption, including binge drinking. If the observed relationship with heavy alcohol consumption and binge drinking is confirmed by other large studies that have collected detailed alcohol exposure data, targeted interventions to reduce heavy drinking and binge drinking (which is prevalent and increasing in frequency [51
]) may be of even greater importance than previously recognized. The difficulty of early diagnosis, and the rapid progression from diagnosis to death calls for concerted cancer prevention efforts to identify and intervene on all potentially modifiable risk factors for pancreatic cancer, including alcohol consumption.