The role of alcohol as a risk factor in pancreatic cancer: a systematic review based on cohort and case-control studies

Introduction

Background

Today, the prevalence of pancreatic cancer is lower than that of many other cancers, but it is the fourth leading cause of cancer-related death worldwide (1,2). Pancreatic cancer is a very aggressive malignancy that tends to invade the tissues surrounding the pancreas (3,4). The incidence of pancreatic cancer is higher in people over 80 years old, and the incidence and mortality rates are also higher in men than in women (5-7). In general, pancreatic cancer is divided into two groups: pancreatic adenocarcinoma, which occurs in the exocrine glands of the pancreas and is more common, and pancreatic neuro-tumor, which occurs in the endocrine tissue of the pancreas and is less common (8). Pancreatic ductal adenocarcinoma is very fatal and more than 60% of patients with it die within a few months (9). Pancreatic cancer in its early stages usually has no symptoms, and nonspecific symptoms of the disease, including jaundice, weight loss, light stools, abdominal pain, and fatigue, appear gradually as the tumor progresses (10,11) and is often diagnosed at an advanced stage (12). Currently, there is no effective and definitive method to treat pancreatic cancer, but surgery, chemotherapy and radiotherapy are used to increase survival or relieve the symptoms of patients (13,14). Surgical removal of the tumor at an early stage is currently the only effective treatment (4,12).

Rationale and knowledge gap

Pancreatic cancer occurs due to various hereditary and environmental factors such as age, obesity, diabetes, smoking, chronic pancreatitis, reduced physical activity, low consumption of vegetables, and other factors (15). Some studies have shown that genetics play a greater role in the occurrence of cancer, but it is estimated that only 5–10% of pancreatic cancer cases are hereditary and the remaining 90–95% is due to environmental risk factors that are largely modifiable and new medical studies have also observed a great relationship with the occurrence of pancreatic cancer and environmental factors, including dietary patterns (1,16,17). Sugary drinks, including carbonated soft drinks, are one of the most important dietary factors that contribute to the occurrence of many cancers, including pancreatic cancer (18,19). Lifestyle significantly affects the risk of pancreatic cancer, so it is estimated that more than a quarter of pancreatic cancer cases could be prevented if people in the general population were non-smokers and had a healthy diet, normal weight, etc. (7). Alcohol consumption is a significant public health concern globally, with global consumption increasing moderately from 2005 to 2010 (20). This is while a decrease in alcohol consumption has been observed in some Asian and African countries (21).

Objective

Many studies have investigated the relationship between alcohol consumption and pancreatic cancer, and the results have been conflicting (22-24). The aim of this study was to investigate the relationship between alcohol consumption and the risk of pancreatic cancer, focusing on different doses of alcohol consumption (low, moderate, and high). Given the inconsistencies in the results of previous studies, this article attempts to compile and analyze the available evidence by conducting a comprehensive systematic review to reach a clearer conclusion about the impact of alcohol consumption on pancreatic cancer. This understanding is essential for the development of effective screening and treatment strategies. We present this article in accordance with the PRISMA reporting checklist (available at https://apc.amegroups.com/article/view/10.21037/apc-24-31/rc).

Methods

This study is a systematic review conducted in October 2023. Four world-renowned scientific databases, including Scopus, PubMed, The Institute for Scientific Information (ISI), and Google Scholar were selected to search for related articles. The selected keywords after considering the Medical Subject Headings (MeSH) guidelines were included “pancreatic cancer”, “pancreatic neoplasm”, “cancer of the pancreas”, “alcohol”, “alcoholic drink”, “alcohol drinking”, “cohort” and “case-control”. The OR operator was used between synonymous keywords and the AND operator was used to combine strategies. Two trained teams conducted the article search. The initial and final screening of the studies was conducted by two trained researchers. In cases of disagreement between the two, a third individual was consulted to make the final decision. All articles were imported into EndNote version 8, and duplicate entries were removed using the software.

The inclusion criteria for the studies were as follows: (I) the study design had to be cohort or case-control or their subtypes; (II) the article had to be written in English; (III) the full text of the article had to be accessible; and (IV) the study had to report the risk ratio or odds ratio (OR) of pancreatic cancer associated with alcohol consumption. Also, articles published until October 2023 were eligible for inclusion in the study.

The exclusion criteria included: (I) inability to access the full text of the article (even after attempting to request it from the author or reputable sources); (II) articles published in conference or congress proceedings; and (III) review articles, meta-analyses, clinical trials, and other primary observational studies (such as cross-sectional and ecological studies).

Risk of bias

The quality of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Form. This assessment tool comprises three sections: selection (4 questions), comparability (1 question), and outcome/exposure (3 questions). Studies are categorized into three quality levels based on their scores: good quality: studies scoring 3 or 4 stars in the selection domain, 1 or 2 stars in the comparability domain, and 2 or 3 stars in the outcome/exposure domain. Fair quality: studies scoring 2 stars in the selection domain, 1 or 2 stars in the comparability domain, and 2 or 3 stars in the outcome/exposure domain. Poor quality: studies scoring 0 or 1 star in the selection domain, 0 stars in the comparability domain, or 0 or 1 star in the outcome/exposure domain (25).

In order to reduce the publication bias, we tried to select and review the articles in all stages of the study implementation, regardless of whether the results are significant or not, and if they meet the inclusion criteria. It was also made to consider ethical considerations in the stages of design, data extraction, and implementation of the study.

Results

Characterization of the included studies

A total of 716 articles were initially retrieved (Appendix 1). After eliminating duplicates, 433 articles proceeded to the next stage for evaluation. During this phase, the titles and abstracts were reviewed, resulting in the removal of 176 articles as they were deemed irrelevant to the topic under investigation. From the remaining 257 articles, 177 were excluded for failing to meet the study’s inclusion criteria, such as study type (n=101), article language (n=26), or full-text availability (n=50). Ultimately, 80 articles were chosen for the final review and data extraction (Figure 1). Table available at https://cdn.amegroups.cn/static/public/apc-24-31-1.pdf summarizes the role of alcohol in the incidence of pancreatic cancer based on the results of cohort and case-control studies. The studies span several decades, from 1983 to 2009, and include diverse populations from countries such as Norway, Sweden, the USA, Japan, Italy, and others. The studies vary in design, including cohort and case-control studies, and involve different sample sizes, ranging from a few hundred to over 100,000 participants. The populations studied include both males and females, with ages typically ranging from 40 to 79 years. The duration of follow-up in cohort studies varies, with some studies following participants for up to 30 years. The main outcomes assessed include the association between alcohol consumption and the risk of pancreatic cancer, with some studies also considering the impact of smoking and other lifestyle factors.

Figure 1 Flow chart of study selection.

Quality assessment

In general, 59 of the selected papers had a good quality while 21 had a fair quality (Table S1).

Positive impacts

Several studies reported positive associations between alcohol consumption and an increased risk of pancreatic cancer. For instance, Heuch et al. (26) found that alcohol use showed the strongest positive association with pancreatic cancer, with a relative risk (RR) of 5.4 (P<0.001). Similarly, Zheng et al. (27) observed that consuming 3 or more drinks a day significantly increased the death rate from pancreatic cancer, with adjusted RRs ranging from 2.0 to 3.7 depending on the amount consumed. Porta et al. (28) also reported that consuming 15 or more drinks a day significantly increased the death rate from pancreatic cancer, with ORs ranging from 2.93 to 4.45. These findings suggest that heavy alcohol consumption is associated with a higher risk of pancreatic cancer.

Negative impacts

On the other hand, many studies found no significant association between alcohol consumption and the risk of pancreatic cancer. For example, Hiatt et al. (29) reported no significant associations between alcohol intake and the risk of pancreatic cancer, with RRs ranging from 0.9 to 2.6. Similarly, Cuzick et al. (30) found no significant associations between alcohol intake and pancreatic cancer risk, with RRs close to 1.0 across different levels of alcohol consumption. Olsen et al. (31) also reported no significant associations, with ORs ranging from 0.73 to 2.69. These studies suggest that moderate alcohol consumption may not be a significant risk factor for pancreatic cancer, although heavy drinking could still pose a risk.

In summary, while some studies indicate a positive association between heavy alcohol consumption and pancreatic cancer risk, many others found no significant link, particularly for moderate drinking. The variability in findings may be due to differences in study design, population characteristics, and the definition of alcohol consumption levels.

Literature review

Alcohol consumption is currently one of the 5 leading causes of death in the world, and according to reports, in 2019, about 43% of the world’s adults consumed alcohol (32). In general, the standard dose of alcohol consumption is different for each person based on gender, race, etc. However, the World Health Organization (WHO) prohibits the consumption of more than 20 g of ethanol per day for men and women (33,34). Also, according to the statistics of the National Center for Health Statistics, consumption of less than or equal to 3 drinks/week for both sexes is reported as light alcohol consumption; consumption of 4 to 7 drinks/week for women and 4 to 14 drinks/week for men is also reported as moderate consumption, and consumption more than this is reported as heavy consumption (32). In addition, the National Institute of Alcohol Abuse has also defined alcohol consumption to the extent that its concentration in the blood is greater than or equal to 8 g/dL as drinking too much alcohol (32). After checking different databases, finally 80 studies were found, among which there were 47 cohort studies and 33 case-control studies. Most of the studies were in Europe and the United States, and only a few were conducted in the East. In general, there are conflicting reports about the effect of alcohol on pancreatic cancer. For example, Hassan et al., designing a case-control study on 808 patients with pancreatic cancer and 808 controls, reported that consuming 60 mg of ethanol per day or more significantly increases the risk of pancreatic cancer [OR: 1.6, 95% confidence interval (CI): 1.1–2.5] but consuming less than this does not have a significant effect on pancreatic cancer (35). In this regard, Gapstur et al., in a cohort study, followed women and men over 30 years of age for 24 years and finally found that low and moderate alcohol consumption had no effect on pancreatic cancer, but high alcohol consumption (3 or more drinks per day) increases the risk of pancreatic cancer (3 drinks/day: OR =1.25, 95% CI: 1.11–1.42; ≥4 drinks/day: OR =1.17, 95% CI: 1.06–1.29) (36). Also, another case-control study in Italy, which was conducted on 326 patients with pancreatic cancer and 652 controls, also confirmed that only high alcohol consumption (≥21 drinks/week) has an effect on pancreatic cancer (21–34 drinks/week: OR =2.03, 95% CI: 1.10–3.74; ≥35 drinks/week: OR =3.42, 95% CI: 1.79–6.55) (23). Eight review studies and meta-analyses also confirmed the claim of the above studies and stated that high alcohol consumption significantly increases the risk of pancreatic cancer, unlike low and moderate consumption (7,16,37-42). In addition, based on Go et al.’s study, since heavy alcohol consumption is a serious risk factor for chronic pancreatitis and type 2 diabetes, and these two diseases are directly related to pancreatic cancer, it can be concluded that high alcohol consumption is a risk factor. This is for cancer; also, alcohol metabolites (acetaldehyde and fatty ethyl esters) play a significant role in carcinogenesis (43). Two other meta-analysis studies also reported heavy alcohol consumption as a significant risk factor for pancreatic cancer, but on the other hand stated that low and moderate alcohol consumption may reduce the risk of pancreatic cancer (1,44). On the other hand, Yu et al. designed an in-vitro study and exposed normal pancreatic ductal epithelial cells to two different doses of ethanol (10 and 100 mmol/L) and after 6 months, the cells exposed to 100 mmol/L of ethanol became cancerous. As a result, they reported that high alcohol consumption can lead to the transformation of these cells and eventually pancreatic cancer. This transformation takes place through creating an inflammatory environment and increasing the expression of special AT-rich binding protein-2 (SATB2) (45). In an animal study that was conducted on mice, the mice were raised with two diets containing alcohol and without alcohol, and finally, continuous consumption of alcohol led to the production of cancer stem cells and pancreatic cancer (46). However, in a case-control study conducted in the United States, high alcohol consumption (≥22 drinks/week) increased the risk of pancreatic cancer only in men and in women it had no significant effect (22–35 drinks/week: OR =2.2, 95% CI: 1.1–4.0; >35 drinks/week: OR =2.6, 95% CI: 1.3–5.1) (24). Subsequently, a prospective study also reported that alcohol consumption (60 g/day or more) was a significant risk factor for pancreatic cancer only in men [hazard ratio (HR): 1.63, 95% CI: 1.16–2.2] (47). And a pooled study also confirmed this claim (consumption of 45 g/day or more in men: OR =2.23, 95% CI: 1.02–4.87; consumption of 30 g/day or more in women: OR =1.35, 95% CI: 0.63–2.87) (48). In contrast, two case-control studies designed and conducted in the United States reported high alcohol consumption (≥21 drinks/week) as a risk factor for pancreatic cancer only in black women (49,50). But unlike the review studies in most cohort and case-control studies, alcohol did not have a significant effect on pancreatic cancer. For example, a case-control study was designed by Norell et al. in Sweden, and alcohol consumption categorized the participants into three doses of 0–1, 2–9 and ≥10 g/day, and finally, the effect of each dose of alcohol consumption on pancreatic cancer was not significant (51). Another prospective study reported that alcohol consumption at any of the reported doses (<1, 1–2, and >2 drinks/day) had no effect on pancreatic cancer (52). Afsar et al.’s cohort study also reported the effect of alcohol on cancer as meaningless without reporting the dose (53). In addition, a review study also stated that there is no evidence that alcohol affects cancer (54). Other studies are reported in table available at https://cdn.amegroups.cn/static/public/apc-24-31-1.pdf.

Mechanisms

Although the metabolism of alcohol in the pancreas has not been fully identified, several mechanisms have been proposed for its effect on the pancreas (46). For example, ethanol can damage the pancreas by changing mucosal permeability and can also induce cytochrome P4502E1 and increase the production of reactive oxygen species (55). In addition, chronic alcohol administration in mice increased the contact of cathepsin B and inactive pancreatic enzymes, which ultimately led to premature activation of these enzymes and pancreatic damage (56). On the other hand, alcohol increased the number of mouse M2 macrophages. These macrophages lead to an increase in carcinogenesis by preventing the absorption of T cells in the tumor (7). Another effect of alcohol is to increase the expression of SATB2 in pancreatic cells through the increase of reactive oxygen species. SATB2 is a transcription factor that is normally required for fetal development, but its high expression in adults can lead to cancer (46). However, the most important effect of alcohol is related to acetaldehyde, which is mainly produced during the metabolite of ethanol and by alcohol dehydrogenase and is a strong carcinogen (16,55). Part of the mechanism of acetaldehyde effects is the formation of adducts with DNA and interference with DNA repair and methylation, disruption of antioxidant defense, and increased activity of pancreatic stellate cells (through the mitogen-activated protein kinase pathway). These cells lead to pancreatic fibrosis through increased collagen production (55,56). Under normal conditions, acetaldehyde is finally metabolized to acetate. This action is performed by acetaldehyde dehydrogenase (ALDH) (55). On the other hand, some people have ALDH2*2 allele. This allele leads to a decrease in the function of ALDH enzyme. As a result, alcohol consumption in these people is associated with a greater risk, and according to research, the number of these people is higher in East Asian countries, so that about 30% to 50% of the East Asian population has this allele (57). However, each alcoholic drink can contain its own carcinogenic substances (16).

Discussion

Key findings

The results of this systematic review show that heavy alcohol consumption (≥3 drinks/day) is significantly associated with an increased risk of pancreatic cancer, while low to moderate alcohol consumption is not. These findings are consistent with the results of some other studies, but at the same time, there are also differences with some previous research.

Comparison with similar research

A study by Lucenteforte et al. (36) reported in a study that heavy alcohol consumption (>3 drinks/day) is associated with an increased risk of pancreatic cancer. This finding is consistent with the results of this study and suggests that high doses of alcohol can be considered as an important risk factor for pancreatic cancer. Also, a study by Wang et al. (41) showed that alcohol consumption of more than 50 g/day significantly increases the risk of pancreatic cancer. These results confirm that the dose of alcohol consumption is a key factor in determining the risk of pancreatic cancer.

In terms of biological mechanisms, Apte et al. (58) showed that alcohol metabolites, such as acetaldehyde and oxygen free radicals, can damage the DNA of pancreatic cells and cause cancerous mutations. These mechanisms are consistent with the findings of this study that heavy alcohol consumption leads to increased oxidative stress and tissue damage in the pancreas.

However, some other studies have reported different results. For example, Genkinger et al. (59) showed in a large meta-analysis that alcohol consumption, even at high doses, was not significantly associated with an increased risk of pancreatic cancer. This discrepancy may be due to differences in the methods of measuring alcohol consumption, demographic differences, or length of follow-up across studies. For example, in the study by Genkinger et al., alcohol consumption was assessed overall without different doses, which could lead to inconsistent results.

Also, the study by Jiao et al. (60) reported that alcohol consumption was associated with an increased risk of pancreatic cancer only in smokers, while no such association was seen in nonsmokers. This finding suggests that the interaction between alcohol and other risk factors, such as smoking, may play an important role in the development of pancreatic cancer. This may partly explain the differences between the results of this study and other studies.

Explanations of findings

The reasons for the similarities between the results of this study and some other studies may be due to the use of similar methods of measuring alcohol consumption and examining specific doses. For example, studies that carefully segregated alcohol consumption, such as Lucenteforte et al. (37) and Wang et al. (41), have reported similar results to this study.

On the other hand, the differences may be due to confounding factors such as gender, race, and lifestyle differences. For example, Michaud et al. (48) found that heavy alcohol consumption was associated with an increased risk of pancreatic cancer only in men, while no such association was seen in women. This difference may be due to hormonal or metabolic differences between the sexes.

Implications and actions needed

Overall, this study is consistent with much previous research that has linked heavy alcohol consumption to an increased risk of pancreatic cancer. However, the differences in results between studies may be due to differences in the methods used to measure alcohol consumption, demographic differences, and confounding factors such as smoking and diet. Prospective studies with more carefully designed studies that take these factors into account could help clarify the relationship between alcohol consumption and pancreatic cancer.

Strengths and limitations

The present study had several strengths, including comprehensive data collection, dose-response analysis and reporting, and mechanistic insights. One of the major limitations of this study was the lack of access to the full text of some articles, which may affect the results of this study. Also, due to the high heterogeneity of the data collection methods and the results of the studied studies, it was not possible to quantitatively analyze the indicators and conduct a meta-analysis.

Conclusions

This systematic review examined the relationship between alcohol consumption and the risk of pancreatic cancer and analyzed the evidence from different studies. The results showed that heavy alcohol consumption (equivalent to 3 or more alcoholic drinks per day) was significantly associated with an increased risk of pancreatic cancer, especially in men. This finding is consistent with biological mechanisms such as the production of acetaldehyde (a carcinogen) and increased oxidative stress in the pancreas, which lead to tissue damage and cancer development. Animal and laboratory studies have also confirmed the effect of alcohol on the development of cancerous changes in pancreatic cells. However, low to moderate alcohol consumption (<3 drinks/day) was not significantly associated with an increased risk of pancreatic cancer. This may be due to differences in the metabolism of alcohol at lower doses or other protective factors. The discrepancies in the results of different studies may be due to differences in the methods of measuring alcohol consumption, gender, race, and geography, as well as the duration of alcohol consumption over the life span of individuals.

Overall, this study emphasizes that reducing alcohol consumption, especially at high doses, can be considered a preventive strategy to reduce the risk of pancreatic cancer. Given the global increase in alcohol consumption and its role in the development of various diseases, public education and health policies to reduce alcohol consumption are essential. Also, conducting prospective studies with a more careful design and considering confounding factors such as lifestyle, diet, and genetic factors can help to clarify this relationship. Finally, this study emphasizes the importance of lifestyle modification and reduction of modifiable risk factors such as alcohol consumption for the prevention of pancreatic cancer.

Recommendations

We suggest that other researchers in the world conduct a regional subgroup analysis, as this could yield interesting insights. Most studies have been conducted in Western populations, while data from East Asia or Africa are limited. Examining regional differences in alcohol consumption patterns, as well as genetic factors such as ALDH2 polymorphisms in East Asia, could highlight unique risk profiles and improve the global applicability of the findings. This analysis could also help to clarify how genetic or cultural variations influence the relationship between alcohol consumption and pancreatic cancer risk.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://apc.amegroups.com/article/view/10.21037/apc-24-31/rc

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-31/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-24-31/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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