Review
Pancreatic Cancer: A Review of the Evidence on Causation

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Pancreatic cancer kills more than 250,000 people each year worldwide and has a poor prognosis. The aim of this article is to critically review the epidemiologic evidence for exposures that may either increase or decrease the risk. A Medline search was performed for epidemiologic studies and reviews published up to April 2007. Consistent evidence of a positive association was found for family history and cigarette smoking. Many studies documented a positive association with diabetes mellitus and chronic pancreatitis, although the etiologic mechanisms are unclear. Other associations were detected, but the results were either inconsistent or from few studies. These included positive associations with red meat, sugar, fat, body mass index, gallstones, and Helicobacter pylori, and protective effects of increasing parity, dietary folate, aspirin, and statins. There was no evidence linking alcohol or coffee consumption with an increased risk of pancreatic cancer. The associations with many exposures need to be clarified from further epidemiologic work in which there is both precise measurement of risk factors, adjustment for potential confounders, and, for dietary studies, information recorded on the method of food preparation and pattern of consumption. Such work is important to reduce the incidence of this fatal disease.

Section snippets

Family History and Genetic Disorders

A family history of pancreatic cancer in a first-degree relative is associated with an increased risk of pancreatic cancer of between 2.5 to 5.3 times.2, 3, 4, 5, 6 The risk increases the more relatives are affected, with a risk of 6.4 (95% confidence interval [CI], 1.8–16.4) in those with 2 affected relatives, increasing to a risk of 32.0 (95% CI, 10.2–74.7) in those with 3 affected relatives.7 The increased risk in family members could be owing to genetic factors and/or lifestyle habits that

Occupational Exposures

The effect of occupational exposures was assessed in a comprehensive meta-analysis of data from 92 studies that reported effects for 23 agents.13 The results showed that chlorinated hydrocarbon solvents and related compounds had a meta-risk ratio of 1.4 (95% CI, 1.0–1.8), and for nickel and nickel compounds the meta-risk ratio was 1.9 (95% CI, 1.2–3.2). For other agents, small but nonsignificant risks were reported, including chromium compounds, polycyclic aromatic hydrocarbons, organochlorine

Hormonal Factors

Increasing parity may prevent pancreatic cancer by reducing insulin-like growth factor levels and body iron stores. Insulin-like growth factors are involved in the development of cancer and promote cellular proliferation and inhibit apoptosis.16, 17 Pregnancy can induce changes in the insulin-like growth factor axis and an analysis of plasma insulin-like growth factors showed a lower concentration in women with 4 or more births compared with nulliparous women (180 vs 212 ng/mL, P for trend =

Concomitant Illness

In patients with diabetes mellitus, a meta-analysis of 36 epidemiologic studies reported an odds ratio of 1.82 (95% CI, 1.66–1.89).30 The mechanism of the diabetes association needs to be studied, investigating possibilities that include a common causative agent, the metabolic consequences of diabetes, and, finally, residual confounding. A possible mechanism is that hyperglycemia promotes hyperinsulinemia and activation of insulin-like growth factor 1, which stimulates cell proliferation.31 A

H pylori Infection

There are several plausible biological mechanisms for how H pylori infection could increase the risk of pancreatic cancer. These are secondary to the H pylori–induced gastritis including a reduced absorption of anti-oxidants such as vitamin C,56 and hypergastrinemia, which stimulates pancreatic cancer cell growth.57 Also, increased secretin levels, as a consequence of decreased somatostatin production, have trophic effects on the pancreatic ductal epithelium.58 Three epidemiologic studies, 1

Cigarette Smoking

Smoking is reported consistently as an environmental risk factor for pancreatic cancer and accounts for approximately 25% of all pancreatic cancers.65 Carcinogens reach the pancreas via the blood steam or refluxed bile, and nitrosamines, present in cigarettes, induce pancreatic tumors in animal models.66 Cigarette smoking approximately doubles the risk of pancreatic cancer and the effect is related to its duration and intensity.67, 68, 69, 70, 71, 72, 73, 74, 75 The importance of these data

Total Energy Intake

The effect of total energy intake has been reported, to the best of our knowledge, in only 2 prospective cohort studies. One from Finland, in men, found an inverse trend (P = .05).77 However, a prospective investigation from Iowa, in women, found no association with total caloric intake.78 The relationship may be confounded by physical activity because there is a correlation between physical activity and energy intake, and physical activity itself may be protective against pancreatic cancer.79,

Meat

The hypothesis that meat increases risk is based on experimental data that cooking meat at high temperatures, particularly red meat, produces heterocyclic amines and polycyclic aromatic hydrocarbons, which are carcinogenic in animals.82 To date, 7 cohort studies specifically have investigated red meat consumption and pancreatic cancer, with 3 studies reporting a significant positive association,69, 83, 84 3 studies reporting no association,67, 77, 85 and 1 study reporting a reduced risk.86 In

Sugar Intake

A high dietary sugar intake leads to hyperinsulinemia, which may be carcinogenic by altering the cell cycle, inhibiting apoptosis, and down-regulating insulin-like growth factor binding protein 1. Prospective studies involving biomarkers have reported double the risk of pancreatic cancer in subjects with both higher fasting serum glucoses and fasting insulin concentrations.87, 88 However, cohort investigations using food-frequency data, have either found no association with total sucrose89 or

Dietary Fat

Dietary fat entering the duodenum initiates the release of cholecystokinin, which stimulates pancreatic hyperplasia, increasing its susceptibility to carcinogens.93 Fat intake has been investigated in 3 cohort studies with no consistent associations detected.77, 84, 85 In the Finnish male smokers study, energy-adjusted saturated fat intake was associated positively with pancreatic cancer (highest vs lowest quintile: hazard ratio, 1.60; 95% CI, 0.96–2.64; P trend = .02).77 No significant

Fruit and Vegetable Consumption

Fruits and vegetables contain anti-oxidants that have anticarcinogenic properties. Cohort studies have not reported any protective associations between pancreatic cancer and total fruit or vegetable intake,39, 67, 69, 77, 94, 95, 96 although, again, small associations could be undetected because of measurement error in the dietary assessment methods. However, in a Swedish cohort study a significant inverse association was observed with the cruciferous vegetable cabbage (≥1 serving/wk vs never

Beverages

Reviewing the studies on the potential carcinogenicity of alcohol and coffee, The International Agency for Research on Cancer concluded that there was little evidence to support casual associations.101, 102 Since these statements, similar data have been reported in the US Health Professionals Follow Up Study,103 The Nurses Health Study,103 The Japan Collaborative Cohort Study for Evaluation of Cancer Risk,104 and The Swedish Twin Registry Cohort Study.10 However, The Iowa Women’s Health Study,

Anthropometric Measurements and Physical Activity

Anthropometric measures including BMI, waist circumference, and waist-hip ratio are dependent on several factors including diet and physical activity. A meta-analysis of 6 case-control and 8 cohort studies of 6391 cases of pancreatic cancer reported an increased risk of 2% (95% CI, 1%–3%) for each unit increase in BMI.105 Since this meta-analysis in 2003, 8 prospective studies have been published with conflicting results. The European Prospective Investigation Into Cancer and Nutrition Study

Potential Effects of Drugs

Aspirin inhibits cyclooxygenase enzymes, which may prevent carcinogenesis by enhancing cellular immune responses, inhibiting prostaglandin synthesis, and influencing apoptosis, tumorigenesis, and angiogenesis.113 Aspirin also either could increase or decrease the risk of pancreatic cancer by its ability to influence different lipoxygenase enzymes, which can have either anticarcinogenic or procarcinogenic properties.114 The only trial that has assessed aspirin in the incidence of pancreatic

Conclusions

Smoking and family history are unequivocal risk factors for pancreatic cancer. The data are consistent for diabetes mellitus and chronic pancreatitis, but importantly the biological mechanisms are unknown and need further investigation. For most other exposures the evidence is either inconsistent or derived from relatively few studies. Clarification is required in which there is, first, accurate measurement of exposures, and, second, consideration adjustment for other risk factors. Such work is

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