Epidemiology and prospects for prevention of pancreatic cancer | ПРЕЦИЗИОННАЯ ОНКОЛОГИЯ

Epidemiology and prospects for prevention of pancreatic cancer


Worldwide, pancreatic cancer is the 13th most common type of cancer. Its poor prognosis makes it the eighth major form of cancer-related death causing more than 227,000 deaths annually. Age-adjusted incidence rates range from 10–15 per 100,000 people in parts of Northern, Central, and Eastern Europe to less than 1 per 100,000 in areas of Africa and Asia. The highest incidence rates were observed among African American in the United States and New Zealand Maoris; the lowest rates were reported for India and Thailand. Pancreatic cancer incidence and mortality statistics are similar throughout the world. In the United States, based on cases diagnosed in 2001–2005 from 17 Surveillance Epidemiology and End Results (SEER) geographic areas, the age-adjusted incidence rate for all races was 13.0 per 100,000 men and 10.3 per 100,000 women. Based on patients died in 2001–2005, the ageadjusted death rate per 100,000 for pancreatic cancer was 12.2 for men, 9.3 for women, 15.4 for black men, 12.4 for black women, 12.1 for white men, and 9.0 for white women. Worldwide, pancreatic cancer occurs slightly more frequently in men than in women and in urban areas more than in rural regions. In the United States, while the incidence in women has increased slightly over the past two decades, the incidence in men has dropped slightly. Now the incidence is about the same for both sexes, probably as a result of the increased use of tobacco by women. The reasons for the regional and ethnic differences in the incidence of pancreatic cancer are unknown. The higher incidence in most developed countries probably reflects diagnostic capacity rather than etiology. The fact that the rates in African Americans are considerably higher than in native Africans suggests an environmental influence. Among men, the established risk factors (mainly cigarette smoking and diabetes mellitus) explain almost the entire black/white disparity in incidence. Among women, moderate/heavy alcohol consumption and elevated body mass index appear to contribute to the racial disparity.

Established risk factors


Age is the most established predictor of pancreatic cancer incidence and death. The risk of pancreatic cancer is low in the first three to four decades of life but increases sharply after age 50 years, with most patients between the ages of 60 and 80 years and the median age at diagnosis of 72 years (Table I–11 (http://seer.cancer.gov/csr/1975_2005/results_single/ sect_01_table.11_2pgs.pdf )). Approximately 0.0% was diagnosed under age 20; 0.4% between 20 and 34; 2.4% between 35 and 44; 9.6% between 45 and 54; 18.9% between 55 and 64; 26.6% between 65 and 74; 29.5% between 75 and 84; and 12.5% 85+ years of age.

Hereditary risk factors

Inherited pancreatic cancers represent approximately 5–10% of all pancreatic cancers. Pancreatic cancer may be inherited as part of a known cancer syndrome or in association with hereditary pancreatitis or cystic fibrosis.

Hereditary breast-ovarian cancer syndrome is associated with mutations in BRCA1 or BRCA2. BRCA2 is a tumor suppressor gene on chromosome 13q12 and its protein product is involved in the repair of DNA strand breaks. Deleterious germline mutations in the BRCA2 gene have been found in 17% of patients with familial pancreatic cancer and in 7% of patients thought to have sporadic pancreatic cancer. Such germline BRCA2 mutations represent the most common inherited predisposition to pancreatic cancer and are associated with an up to 10 times greater risk of pancreatic cancer than exists in the general population.

The familial atypical multiple-mole melanoma (FAMMM) syndrome is a rare autosomal dominant genetic disorder with incomplete penetrance caused by germline mutations in the CDKN2A (p16) tumor suppressor gene on chromosome 9p21 and is associated with the development of multiple nevi, including malignant melanoma. Among 159 families collected in the Creighton University registry of familial pancreatic cancer, 19 (12%) showed FAMMM and 8 with ascertained mutations within CDKN2A. Both early-onset and lateonset pancreatic cancer have been seen in the affected families.

Peutz-Jeghers syndrome is rare and inherited as an autosomal dominant genetic disorder characterized by the presence of multiple hamartomatous gastrointestinal polyps and mucocutaneous pigmentation and is associated with an increased risk of several gastrointestinal cancers. It is often caused by mutations in the LKB1/STK11 tumor suppressor gene on chromosome 19p13. Although patients with Peutz-Jeghers syndrome are at significant higher risk of pancreatic cancer, the exact magnitude of the risk is unclear. One study showed relative risk (RR) is 132 (95% confidence interval (CI), 44–261) with a cumulative lifetime risk of 36%.

Interestingly, biallelic inactivation of the LKB1/STK11 gene was also found in 4% of patients with resected sporadic pancreatic cancers. Lim et al. analyzed the incidence of cancer in 240 individuals with Peutz-Jeghers syndrome possessing germline mutations in STK11. All pancreatic cancers were diagnosed between age 34 and 49 years. The risk of developing pancreatic cancer was 5% at age 40, increasing to 8% at age 60 years.

Li-Fraumeni syndrome occurs among carriers of mutations within TP53 gene. TP53 is an extensively studied tumor suppressor protein with a critical role in controlling cell-cycle arrest and apoptosis. Germline mutation of p53 is known to be the underlying genetic defect in the Li-Fraumeni syndrome of childhood malignancies, bone and soft-tissue sarcomas, premenopausal breast carcinoma, brain tumors, adrenocortical carcinoma, and leukemias. Pancreatic adenocarcinoma is the only adult epithelial malignancy that has been proven to be associated with Li-Fraumeni syndrome, other than breast cancer.

Hereditary nonpolyposis colon cancer (HNPCC), also known as Lynch syndrome, is an autosomal dominant genetic disorder caused by germline mutations in mismatch repair genes resulting in an increased risk of colorectal cancer and other cancers, including cancer of the breast, endometrium, and ovary. Patients with HNPCC may also have an increased risk of pancreatic cancer. However, the magnitude of the increased risk is not clear because the numbers of cases often are not adequate for an appropriate assessment of the risk.

Familial adenomatous polyposis (FAP) is the most common adenomatous polyposis syndrome. It is an autosomal dominant inherited disorder characterized by the early onset of hundreds to thousands of adenomatous polyps throughout the colon. The genetic defect in FAP is a germline mutation in the adenomatous polyposis coli (APC) tumor suppressor gene, located on chromosome 5q21. APC encodes a multi-domain protein that plays a major role as a tumor suppressor by antagonizing the wingless-type (Wnt) signaling pathway. A study of 197 FAP pedigrees found a RR of 4.46 (95% CI, 1.2–11.4).

Hereditary pancreatitis is a rare form of pancreatitis. It has an autosomal dominant pattern of transmission with 80% penetrate. It is characterized by the development of recurrent episodes of severe chronic pancreatitis starting at an early age. The symptoms usually arise by age 40 years, but can occur before age 5 years. In approximately one-third of all cases, no etiologic factor can be found, and these patients are classified as having idiopathic disease. Mutations in the cationic trypsinogen gene (PRSS1) on chromosome 7q35 have been identified in patients with hereditary or idiopathic chronic pancreatitis. Lowenfels and colleagues obtained data on 246 patients with hereditary pancreatitis from pancreatologists in 10 countries. They found that the estimated cumulative risk of pancreatic cancer developing by age 70 was approximately 40% in this patient population. The mean age at the diagnosis of pancreatic cancer was 57 years. Idiopathic pancreatitis has been found to be associated with mutations in the cystic fibrosis gene (CFTR). Compared with the background population, the risk of pancreatic cancer is approximately 50 to 60 times greater than expected.

Familial pancreatic cancer kindreds have also been identified that are not affected by an inherited cancer syndrome. At-risk patients for familial pancreatic cancer include those with a minimum of two first-degree relatives with pancreatic cancer. A meta-analysis identified

7 case-control and 2 cohort studies involving 6,568 pancreatic cancer cases. This analysis found a significant increase in risk associated with having an affected relative, with a summary RR of 1.80 (95% CI, 1.48–2.12). Individuals with a family history of pancreatic cancer have nearly a two-fold increased risk of pancreatic cancer compared with those without such a history. The study suggested that families with two or more pancreatic cancer cases might benefit from comprehensive risk assessment that involves collection of detailed information on family history and environmental exposure, especially smoking history. Previous studies of a well-known family of familial pancreatic cancer suggested that the susceptibility locus for autosomal dominant pancreatic cancer is on chromosome 4q32–34 and Palladin might be the responsible gene. However, two later studies failed to confirm these findings in other study populations [30,31].

More details on this topic can be found in the Chapter ‘‘Genetic susceptibility – High risk groups, chronic and hereditary pancreatitis, familial pancreatic cancer syndromes’’ of this book.

Cigarette smoking

The risk factor most firmly associated with pancreatic cancer is cigarette smoking. A metaanalysis of 82 independent studies published between 1950 and 2007 containing epidemiologic information on smoking and pancreatic cancer across four continents. This analysis found the overall risk of pancreatic cancer estimated from the combined results for current and former smokers was, respectively, 1.74 (95% CI, 1.61–1.87) and 1.20 (95% CI, 1.11–1.29), compared with never smokers. For former cigarette smokers, the risk remains elevated for a minimum of 10 years after cessation and long-term smoking cessation (>10 years) reduces the risk by approximately 30% relative to the risk in current smokers. It is currently estimated that approximately 25% of cases of pancreatic cancer are due to cigarette smoking.

In animals, pancreatic malignancies can be induced through the long-term administration of tobacco-specific N-nitrosamines or the parenteral administration of other N-nitroso compounds. These carcinogens are metabolized to electrophiles that readily react with DNA, leading to the miscoding and activation of oncogenes. Indeed, the detections of carcinogen-DNA adducts in human pancreas tissues and tobacco-specific compounds in pancreatic juice further support the link between cigarette smoking and pancreatic cancer [33–35]. Recent molecular epidemiological studies have also shown that individual genetic variability in carcinogen metabolism and DNA repair may partially determine the susceptibility to smoking-related pancreatic cancer [36–40]. Previous studies have also shown an association of K-ras mutation in pancreatic tumors with cigarette smoking [41,42]. Information generated from such studies may facilitate the development of strategies in identifying high-risk individuals for the primary prevention of pancreatic cancer.

Noncigarette tobacco use has been increasing in the United States. Several previous studies have reported significant associations between use of pipe, smokeless tobacco, or cigar [43,46–48] and risk for pancreatic cancer. Compared with never smokers, the risk of pancreatic cancer for current and former pipe and/or cigar smokers was respectively 1.47 (95% CI, 1.17–1.83) and 1.29 (95% CI, 0.68–2.45) in the recent meta-analysis report.

Few studies have investigated the relation of passive smoking or environmental tobacco smoke (ETS) with risk of pancreatic cancer. A Canadian population-based cases control study including 583 pancreatic cancer cases and 4,813 controls first reported a statistically nonsignificant moderate increased risk of developing pancreatic cancer (odds ratio [OR], 1.21; 95% CI, 0.60–2.44) when childhood and adult exposure to ETS compared to non-exposure among never smokers. A hospital-based case-control study conducted at the University of Texas M. D. Anderson Cancer Center included 808 cases and 808 controls found passive smoking was significantly associated with risk of pancreatic cancer among ever smokers (OR, 1.7; 95% CI, 1.0–2.6) but not among never smokers (OR, 1.1; 95% CI, 0.8–1.6).

Similarly, one study, including two prospective cohorts, did not observe an association between passive smoking and risk among never smokers [50]. Overall these data do not support a significant role of passive smoking in pancreatic cancer.


The positive association between obesity, as measured by high body mass index (BMI), and risk for pancreatic cancer has been observed in at least 16 out of the 27 prospective studies and 3 meta-analyses [51–53]. The first meta-analysis identified 6 case–control and 8 cohort studies involving 6,391 cases of pancreatic cancer from 1966 to 2003. The summary RR per unit increase in body mass index was 1.02 (95% CI, 1.01–1.03). The second meta-analysis of 21 independent prospective studies involving 3,495,981 individuals and 8,062 pancreatic cancer patients showed that the RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.16 (95% CI, 1.06–1.17) in men, and 1.10 (95% CI, 1.02–1.19) in women. The latest meta-analysis includes 16 prospective studies involving 3,338,001 individuals and 4,443 cases. The RR of pancreatic cancer per 5 kg/m2 increase in BMI was 1.07 (95% CI, 0.93–1.23) in men, and 1.12 (95% CI, 1.03–1.23) in women. It has been estimated that the population attributable fraction of obesity-associated pancreatic cancer is 26.9% for the U.S. population. In 2007, the World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) concluded that the evidence that greater body fatness is a cause of pancreatic cancer is convincing.

Abdominal fatness is probably also a cause of pancreatic cancer. Central adiposity is associated with glucose intolerance and is a risk factor for diabetes; hence concomitantly increased insulin levels may be the mechanism through which central adiposity increases pancreatic cancer risk. A few studies have investigated central adiposity in association with risk of pancreatic cancer [55–59]. In the American Cancer Society Cancer Prevention Study II Nutrition Cohort, men and women who reported ‘‘central’’ weight gain had a RR of pancreatic cancer of 1.45 (95% CI, 1.02–2.07) compared with men and women who reported peripheral weight gain, independent of BMI. Central weight gain was defined as reported weight gain in chest and shoulders or waist, and peripheral weight gain was defined as reported weight gain in hips and thighs or equally all over. In the European Prospective Investigation into Cancer and Nutrition study (EPIC), 324 incident cases of pancreatic cancer were diagnosed in the cohort over an average of 6 years of follow-up. Larger waist-to-hip ratio and waist circumference were both associated with an increased risk of pancreatic cancer (RR per 0.1, 1.24; 95% CI, 1.04–1.48; and RR per 10 cm, 1.13; 95% CI, 1.01–1.26, respectively). In the NIH-AARP Diet and Health study, 654 pancreatic cancer cases were identified in 495,035 AARP cohort members during an average of 5 years of follow-up. Waist circumference was positively associated with pancreatic cancer (fourth против first quartile: RR, 2.53; 95% CI, 1.135.65) in women but not men. In the Women’s Health Initiative study, women in the highest quintile of waist-to -hip ratio after adjusting for potential confounders had 70% (95% CI, 10–160%) excess risk compared with women in the lowest quintile. When waist-tohip ratio was analyzed as a continuous variable, risk increased by 27% (95% CI, 7–50%) per 0.1 increase. This observation was made on the basis of 251 cases after following up 138,503 women for average of 7.7 years. In a pooled analysis of 30 cohort studies involving 519,643 Asian-Pacific participants and 324 deaths from pancreatic cancer, the RR (95% CI) was 1.08 (1.02–1.14) for every 2-cm increase in waist circumference.

Physical activity has been associated with improved glucose metabolism, increased insulin sensitivity, and decreased insulin, independent of its effects on weight. Increased physical activity may confer a reduced risk for pancreatic cancer. However, a recent systematic review found total physical activity (occupational and leisure time) was not significantly associated with risk for pancreatic cancer (4 prospective studies; summary RR, 0.76; 95% CI, 0.53–1.09). A decreased risk for pancreatic cancer was observed for occupational physical activity (3 prospective studies; RR, 0.75; 95% CI, 0.58–0.96) but not for leisure-time physical activity (14 prospective studies; RR, 0.94; 95% CI, 0.83–1.05). Measurement of physical activity is subjected to error, and the non-differential misclassification would bias the risk estimate towards the null.

Diabetes mellitus

In addition to cigarette smoking and obesity, type II diabetes is likely to be a third modifiable risk factor for pancreatic cancer. Diabetes mellitus has been implicated both as an early manifestation of pancreatic cancer and as a predisposing factor [63,64]. Related to this is the observation that pancreatic adenocarcinoma of duct cell origin can induce peripheral insulin resistance. In addition, a putative cancer-associated diabetogenic factor has been isolated from the conditioned medium of pancreatic cancer cell lines and from patient serum. From the standpoint of clinical observations, a cohort study showed that patients were at increased risk of pancreatic cancer after an initial hospitalization for diabetes, and this risk persisted for more than a decade. Two meta-analyses have investigated the risk of pancreatic cancer in relation to diabetes. The first meta-analysis conducted in 1995 and identified 20 of a total of 30 case-control and cohort studies. The second meta-analysis was conducted in 2005 that included 17 case-control and 19 cohorts or nested case-control studies published from 1996 to 2005. The summary OR (95% CI) of pancreatic cancer for diabetics relative to nondiabetics was 2.1 (1.6–2.8) and 1.82 (1.66–1.89) in the first and second meta-analysis, respectively. The first meta-analysis found requiring diabetes duration of at least 5 years resulted in an RR of 2.0 (95% CI, 1.2–3.2). The authors concluded that pancreatic cancer occurs with increased frequency among persons with long-standing diabetes. The second meta-analysis found that individuals in whom diabetes had only recently been diagnosed (<4 years) had a 50% greater risk of pancreatic cancer compared with individuals who had diabetes for 5 years (OR, 2.1 против 1.5; P = 0.005). These results support a modest causal association between type II diabetes and pancreatic cancer.

It has been estimated that approximately 1% of diabetics aged 50 years will be diagnosed with pancreatic cancer within 3 years of first meeting criteria for diabetes. Pancreatic cancer-induced hyperglycemia occurs up to 24 months prior to the diagnosis of pancreatic cancer. Therefore, it has been suggested that diabetes itself may act as a biomarker of early pancreatic cancer. Identifying the patients with cancer-associated diabetes at their diabetes onset would offer an opportunity for early detection of pancreatic cancer.

The studies on type I diabetes and risk of pancreatic cancer are rare. A systematic review and meta-analysis conducted in 2007 identified 3 cohort studies and 6 case-control studies. Based on 39 cases, the summary RR for pancreatic cancer in young-onset or type I diabetes versus no diabetes was 2.00 (95% CI, 1.37–3.01). Since this study indicates a similarly elevated risk in type I as in type II diabetes, this weighs against the involvement of b-cell activity in the etiology of pancreatic cancer in diabetes.

The causal relationship between diabetes and risk of pancreatic cancer is supported by findings from biomarker studies. Prediagnostic elevations in post-load plasma glucose, serum and plasma glucose, insulin, and plasma C-peptide levels have been associated with greater risk of pancreatic cancer. These observations suggest that insulin plays an important role in pancreatic carcinogenesis. High insulin concentrations in the microenvironment of the pancreatic duct cell may contribute to malignant transformation. In addition, the insulin-like growth factors (IGFs) may also play a role in promoting pancreatic tumor development. The prediagnostic biomarkers of IGF axis have been investigated in association with pancreatic cancer in a few prospective cohort studies. A study of 93 pancreatic cancer cases and 400 randomly selected cohort controls from the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study found no association between IGF-I, or IGF binding protein-3 (IGFBP-3), or IGF-1:IGFBP-3 molar ratio and the risk of pancreatic cancer in male smokers. In a Japanese nested case-control study including 69 cases and 207 controls, there was a positive, but statistically insignificant association between serum levels of IGF-I and risk of death from pancreatic cancer. In a pooled nested case-control study in the United States, plasma levels of IGF-1, IGF-2, or IGFBP-3 were not associated with risk of pancreatic cancer among 212 incident cases and 635 matched controls. In the same study setting including 144 pancreatic cancer cases that occurred 4 years after plasma collection and in 429 controls, lower plasma IGFBP-1 level was significantly associated with an increased risk of pancreatic cancer in never smokers (RR, 2.07; 95% CI, 1.26–3.39). The strength of the association was not substantially attenuated by the inclusion of plasma IGF-I, C-peptide, and IGFBP-3 in the multivariate models, suggesting an independent effect for IGFBP-1 on pancreatic cancer risk.

Suspected risk factors


Alcohol consumption is an established risk factor for pancreatitis and type II diabetes mellitus, both of which are associated with increased risk of pancreatic cancer. However, only a few studies have shown significant increased risk in association with total alcohol intake more than 30 g per day among more than 60 analytic studies [84–87]. In 2007, a panel sponsored by the WCRF and AICR concluded that the current data on the relationship between alcohol intake and pancreatic cancer risk were too inconsistent to reach a judgment on the association between alcohol intake and risk of pancreatic cancer. A recent pooled analysis of the primary data from 14 prospective cohort studies has shown a slight positive association of pancreatic cancer risk with alcohol intake (summary multivariate RR, 1.22; 95% CI, 1.03–1.45 comparing >30–0 grams/day). This association was statistically significant among women only. A recent EPIC study of 555 non-endocrine pancreatic cancer cases showed that high lifetime ethanol intake from spirits/liquor at recruitment tended to be associated with a higher risk (RR, 1.40; 95% CI, 0.93–2.10 comparing 10+ g/day против 0.1–4.9 g/day), but no associations were observed for wine and beer consumption. In the NIH-AARP Diet and Health Study, the authors identified 1,149 eligible exocrine pancreatic cancer cases among 470,681 participants during average 7.3 years of follow-up, the RR of pancreatic cancer was 1.45 (95% CI, 1.17–1.80) for heavy total alcohol use ( 3 drinks/day, 40 g alcohol/day) and 1.62 (95% CI, 1.24–2.10) for heavy liquor use, compared to the light alcohol use (<1 drink per day among ever drinkers). The increased risk was not statistically significant in women due to the fact that women tended to drink less. However, the confounding effect of smoking cannot be excluded because heavy alcohol users were more likely to be smokers. Additional large studies or meta-analysis of pooled data from existing studies are required to demonstrate the association of alcohol consumption and risk independent of smoking. Overall, moderate alcohol consumption is not a risk factor of pancreatic cancer. Heavy alcohol use, in particular heavy drink of liquor, may play a role in pancreatic cancer development. Alcohol consumption may sensitize the pancreas to inflammatory, immune, and fibrosing responses induced by genetic and environmental predisposing factors and functions as a co-factor in the development of pancreatic disease.


Alcohol is the dominant identified cause for chronic pancreatitis, although a significant number of individuals may have chronic pancreatitis of idiopathic origin. As pancreatic cancer may obstruct pancreatic enzyme flow, pancreatitis may be a consequence of pancreatic cancer. Even after exclusion of individuals diagnosed with pancreatitis in close proximity to pancreatic cancer, some have reported a continued association between a remote history of pancreatitis and/or chronic pancreatitis and pancreatic cancer, whereas others have not. For example, in a cohort study of 2,015 patients with chronic pancreatitis from six countries, Lowenfels et al. reported an increased risk of pancreatic cancer in patients with chronic pancreatitis, with the cumulative incidence of pancreatic cancer increasing with the longer duration of follow-up. Talamini and colleagues made similar observations in a study of 715 patients with chronic pancreatitis and found a 13to 18-fold increase in the incidence of pancreatic cancer. They also observed that patients with a short duration between pancreatitis and pancreatic cancer diagnosis were older, had a lower percentage of men, infrequently used tobacco and alcohol, and were more likely to be noninsulin-dependent diabetics compared to patients without pancreatic cancer or patients in whom pancreatic cancer developed late after the diagnosis of chronic pancreatitis. The authors therefore hypothesized that the cancer causes pancreatitis in some cases (as may be the case with hyperglycemia) and emphasized that, for this reason, cancer should be strongly considered in a patient diagnosed with idiopathic chronic pancreatitis without a history of significant alcohol or tobacco use, especially in the context of hyperglycemia. Somewhat in contrast, however, were the findings of Karlson and colleagues, who identified 230 patients with pancreatic cancer among 29,530 patients in the Swedish national  registry discharged 1 year or more after a hospital admission for pancreatitis. Although they found that the standardized incidence ratio (observed/expected) for pancreatic cancer increased in patients with pancreatitis (2.8; 95% CI, 2.5–3.2), after 10 years or more, the excess risk declined and was of borderline significance. The authors concluded that their data thus did not support a causal association between pancreatitis and pancreatic cancer; instead, alcohol consumption and smoking were thought to contribute significantly to the increased cancer risk associated with chronic pancreatitis. As inflammation has been implicated in the causal pathway of many other malignancies, a causal relationship between pancreatitis and pancreatic cancer is plausible, possibly through increased cell-proliferation due to chronic inflammation in the presence of growth factors. Additional studies are required to clarify the association between pancreatitis and pancreatic cancer.

Dietary factors

Various dietary factors have been examined in association with pancreatic cancer. According to the 2007 report by WCRF and AICR, there is suggestive evidence supporting associations of intakes of total energy, total fat, red meat consumption, animal protein, or fruit intake with risk of pancreatic cancer. The evidence on the role of dietary fiber, vegetables, carbohydrate and sugar, soy products, dairy products, and vitamin C supplement is limited and inconclusive; and coffee consumption is unlikely to have a substantial effect on risk of pancreatic cancer.


There is a general consensus that a higher intake of meat and animal product is associated with increased risk of pancreatic cancer. For example, the Multiethnic cohort study including 482 incident pancreatic cancers found a significant association with processed meat; those in the fifth quintile of daily intake had a 68% increased risk compared with those in the lowest quintile (RR, 1.68; 95% CI, 1.35–2.07). The authors also found that intake of total and saturated fat from meat was associated with statistically significant increases in pancreatic cancer risk but that from dairy products was not. Recent studies suggested that the method of meat preparation and subsequent intake of food mutagens might contribute to the development of pancreatic cancer [96–98]. It is known that cooking meat at high temperature, e.g., deep fry, grill or barbeque, could produce potential carcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons. In a hospital-based case-control study conducted at the University of Texas M. D. Anderson Cancer Center including 626 cases and 530 noncancer controls, Li et al. investigated the dietary exposure to food mutagens and risk of pancreatic cancer. They found that a significantly greater portion of the cases than controls showed a preference to well-done pork, bacon, grilled chicken, and pan-fried chicken. The daily intakes of 2-amino-3,4,8-trimethylimidazo[4,5-f ]quinoxaline and benzo(a)pyrene, as well as the mutagenic activity, were the significant predictors for pancreatic cancer with adjustment of other confounders. The NIH-AARP Diet and Health Study including 836 patients with exocrine pancreatic cancer found total, red, and high-temperature cooked meat intake was positively associated with pancreatic cancer among men but not women. Men showed significant 50% increased risks for the highest tertile of grilled/barbecued and broiled meat intake and significant doubling of risk for the highest quintile of overall meat-mutagenic activity. The fifth quintile of the heterocyclic amine, 2-amino-3,4,8-trimethylimidazo[4,5-f ] quinoxaline intake showed a significant 29% (P trend = 0.006) increased risk in men and women combined. Interestingly, the M.D. Anderson case-control study reported a significant interaction between NAT1 (N-acetyltransferase 1) genotype and dietary mutagen intake on modifying the risk of pancreatic cancer among men but not women . The OR (95% CI) was 2.23 (1.33–3.72) and 2.54 (1.51–4.25) for men having the NAT1*10 and a higher intake of 2-amino-1-methyl-6 phenylimidazo[4,5-b]pyridine and benzo[a]pyrene, respectively, compared with individuals having no NAT1*10 or a lower intake of these dietary mutagens. These studies support the hypothesis that meat intake, particularly meat cooked at high temperatures and associated mutagens, may play a role in pancreatic cancer development.

Fruits and vegetables

Many case-control studies have suggested that higher consumption of fruits and vegetables is associated with a lower risk of pancreatic cancer, whereas cohort studies do not support such an association. A Swedish cohort study with 135 cases and a recent EPIC study with 555 cases did not find an association of overall fruit and vegetable intake, subgroups of vegetables and fruits, and pancreatic cancer risk. The Multiethnic Cohort Study including 526 cases did not find an association between total or specific vegetable intake and risk of pancreatic cancer but high intake of dark green vegetables may exert protective effect among current smokers. The consumption of cruciferous vegetables and pancreatic cancer risk warrants further investigation. In a systematic review including 4 casecontrol studies and 5 cohort studies, the authors showed that an inverse association in risk of pancreatic caner with intake of citrus fruits. The results varied substantially across studies, and the apparent effect was restricted to case-control studies. In a population-based case-control study in San Francisco Bay area including 532 cases and 1,701 ageand sexmatched controls, inverse associations were found between risk of pancreatic cancer and consumption of total or specific vegetables and fruits such as dark leafy, cruciferous and yellow vegetables, carrots, beans, onions and garlic, and citrus fruits and juice. Compared with less than five servings per day of total vegetables and fruits combined, the risk of pancreatic cancer was 0.49 (95% CI, 0.36–0.68) for more than nine servings per day.

Flavonoinds, folate, lycopene

Fruit and vegetables contain many chemicals with potential anti-cancer properties including carotenoids, vitamins C and E, flavonoids, folate, selenium and plant sterols. Flavonoids, which are found in certain plant foods, are thought to lower cancer risk through their antioxidant, antiestrogenic and antiproliferative properties. In the Multiethnic Cohort Study, baseline exposure data were collected in Hawaii and California in 1993–1996. Intake of total flavonols was associated with a reduced pancreatic cancer risk (RR for the highest против lowest quintile, 0.77; 95% Cl, 0.58–1.03). Of the three individual flavonols, kaempferol was associated with the largest risk reduction (RR, 0.78; 95% CI, 0.58–1.05). Total flavonols, quercetin, kaempferol, and myricetin were all associated with a significant inverse trend among current smokers but not among never or former smokers. In the ATBC Cancer Prevention Study, the authors found flavonoid-rich diet may decrease pancreatic cancer risk in male smokers not taking supplemental alpha-tocopherol and/or beta-carotene. These two studies provide evidence for a preventive effect of flavonols on pancreatic cancer, particularly for current smokers.

Folate plays an important role in DNA synthesis and repair. A meta-analysis of 1 casecontrol study and 4 prospective cohort studies found the summary RR for the highest versus the lowest category of dietary folate intake were 0.49 (95% CI, 0.35–0.67) for pancreatic cancer. A Swedish prospective cohort study found increased intake of folate from food sources, but not from supplements, may be associated with a reduced risk of pancreatic cancer. In the ATBC Cancer Prevention Study, serum folate and pyridoxal-50 -phosphate (PLP) concentrations showed statistically significant inverse dose-response relationships with pancreatic cancer risk. In a pooled nested case control analysis, baseline serum concentrations of folate, PLP, vitamin B12, or homocysteine were not associated with risk of pancreatic cancer in general, but a modest inverse trend was observed when the analysis was restricted to nonusers of multivitamins. However, the association of folate intake and risk of pancreatic cancer was not observed in two large studies conducted in the United States [111,112]. The inconsistent observations on the association between folate intake and risk of pancreatic cancer may suggest that the influence of folate consumption may be restricted to populations that are relatively folate deficient, e.g., heavy smokers or heavy alcohol drinkers.

A Canadian case-control study of 462 histologically-confirmed pancreatic cancer cases and 4721 population-based controls found lycopene, provided mainly by tomatoes, was associated with a 31% reduction in pancreatic cancer risk among men. However, the Food and Drug Administration review found very limited evidence to support an association between tomato or lycopene consumption and reduced risk of pancreatic cancer. A meta-analysis on clinical trials could not find evidence that antioxidant supplements can prevent gastrointestinal cancers, including pancreatic cancer.

Carbohydrate, glycemic index/load

A multicenter, population-based case control study of pancreatic cancer showed an increased risk of pancreatic cancer associated with a higher intake of carbohydrate, but not all the associations were statistically significant [116,117]. Some types of carbohydrate increase the level of serum glucose and insulin more than others. Glycemic index and glycemic load are measures designed to take into consideration of these differences. The glycemic index represents the postprandial glucose response of individual food items compared with a reference food. Refined grains, such as white bread or white rice, produce a larger increase in postprandial glucose levels than foods such as whole grain foods. Glycemic load reflects both the quality (i.e., glycemic index) and the quantity of the carbohydrates that are consumed by individuals. A high dietary glycemic index/load could increase the risk of pancreatic cancer due to the adverse effect of high postprandial glucose level and resulting insulin demands. The associations of dietary carbohydrates, refined sugars, and glycemic index/load with pancreatic cancer have been investigated in many studies and the results are inconsistent. However, the seven large-scale prospective studies consistently showed null associations of carbohydrate, glycemic index and glycemic load with risk of pancreatic cancer [118–124]. Six of these studies stratified the analyses by BMI and/or physical activity subgroups, and most of these studies did not report any significant findings, with only one exception. A meta-analysis showed no significant associations between pancreatic cancer risk and either glycemic index or glycemic load in a comparison of the highest with the lowest category of intake. In line with these findings, a recent large cohort study did not show that consumption of added sugar or of sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.

Other factors

Infectious agents

Some data suggest an association between Helicobacter pylori or hepatitis B infection and pancreatic cancer [127–129]. H. pylori may result in sub-clinical pancreatitis and can increase gastrin levels, which have a trophic effect on the pancreas. In addition, given that the gastric carriage of H. pylori is a known risk factor for peptic ulcer formation and gastric cancer, this may explain the association between gastric resection and pancreatic cancer observed in some study but not in others. In a hospital-based case-control study in Austria, a serological analysis was performed among 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma and controls for the presence of IgG antibodies against H. pylori. In pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls, the OR (95% CI) was 2.1 (1.1–4.1). However, microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. In 2001, a nested case-control study of 121 exocrine pancreatic cancer cases and 226 cancer-free control subjects from a Finnish cohort of older male smokers found that 82% of cases were seropositive for H. pylori antibodies, compared with 73% of controls (OR, 1.87; 95% CI, 1.05–3.34). In this study, CagA+ strains were associated with slightly greater odds of pancreatic cancer than the CagA ones (OR, 2.01; 95% CI, 1.09–3.70 and OR, 1.65; 95% CI, 0.82–3.29, respectively). However, a study in Kaiser Permanente Medical Care Program found neither H. pylori (OR, 0.85; 95% CI, 0.49–1.48) nor its CagA protein (OR, 0.96; 95% CI, 0.48–1.92) was associated with subsequent development of pancreatic cancer. Similarly, a recent nested case-control study in a Swedish cohort did not find H. pylori seropositivity was associated with pancreatic cancer (OR, 1.25; 95% CI, 0.75–2.09). However, a statistically significant association was found in never smokers adjusted for alcohol consumption. These findings should be interpreted cautiously due to the limited number of cases in the subgroup analysis. The role of infection with H. pylori is the subject of ongoing research.

A recent case-control study in 476 patients with pathologically confirmed adenocarcinoma of the pancreas and 879 age-, sex-, and race-matched healthy controls found a possible association between past exposure to hepatitis B virus and risk of pancreatic cancer. In this study, anti-HBc was positive in 38 cases (8%) and 35 controls (0.9%). The estimated OR (95% CI) was 1.8 (0.9–3.1) for anti-HBc+/anti-HBs+ and 3.4 (1.3–9.1) for anti-HBc+/ anti-HBs . The proximity of the liver to the pancreas and the fact that the liver and pancreas share common blood vessels and ducts may make the pancreas a potential target organ for hepatitis viruses. In fact, hepatitis B surface antigen (HBsAg), a marker for chronic HBV infection, was detected in pure pancreatic juice and pure bile juice and there was evidence of HBV replication in pancreatic cells and concurrent damage to exocrine and endocrine epithelial cells with an inflammatory response [135,136]. The possibility that viral hepatitis can lead to pancreatic damage was further supported by findings of elevated pancreatic enzyme levels in a substantial percentage of patients with acute and chronic HBV and HCV infection [137,138]. However, de Gonzalez et al. reported in a study of 201,975 Koreans including 664 cases of pancreatic cancer, no association was found between hepatitis B HBsAg positivity and pancreatic cancer (RR, 1.13; 95% CI, 0.84–1.52). The association of hepatitis B infection and pancreatic cancer needs further investigation.


The role of occupational or industrial factors in pancreatic cancer has been investigated extensively. Increased risk of pancreatic cancer has been associated with exposures to some chemicals (e.g., organochlorines, chlorinated hydrocarbons, and formaldehyde), or some specific occupations (e.g., stone miners, cement workers, gardeners, and textile workers). However, the statistical power of most of these studies is quite low because of the rarity of pancreatic cancer. Many of these observations could be by chance alone. A meta-analysis [140,141] reviewed 261 studies published from 1969 through 1998 on pancreatic cancer and job titles including more than 3,799 observed pancreatic cancer cases. The results suggest that occupational exposures to chlorinated hydrocarbon compounds may increase the risk of pancreatic cancer; the summary RR was 2.21 (95% CI: 1.31–3.68). Suggestive weak excess was also found for exposure to insecticides. The summary RR was 1.95 (95% CI: 0.51–7.41). In spite of many investigations, there is no compelling evidence linking occupational exposure to substance to risk of pancreatic cancer. Large studies with refined exposure measurement are required to test the hypothesis generated from the previous studies. The possible interactions between occupational exposure, lifestyle factors, and genetic susceptibility remain to be elucidated.


A number of studies have examined the association of prior allergies with risk of pancreatic cancer. A meta-analysis of 14 population-based studies (4 cohort and 10 case-control studies) with a total of 3,040 pancreatic cancer cases found history of allergy was associated with a reduced risk of pancreatic cancer (RR, 0.82; 95% CI, 0.68–0.99). The risk reduction was stronger for allergies related to atopy (RR, 0.71; 95% CI, 0.64–0.80), but not for asthma (RR, 1.01; 95% CI, 0.77–1.31). There was no association between allergies related to food or drugs and pancreatic cancer (RR, 1.08; 95% CI, 0.74–1.58). In addition, two population-based case control studies based on direct interview consistently demonstrated a 20–30% reduced risk of pancreatic cancer among individuals with any prior history of allergy [143,144]. The hyperactive immune system of allergic individuals may, therefore, in some way lead to increased surveillance and protect against pancreatic cancer development.

Non-steroidal anti-inflammatory drugs

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have received considerable interest because these agents target cyclooxygenase enzymes, therefore may inhibit tumor growth by enhancing immune responses, modulating cellular proliferation, inhibiting prostaglandin synthesis, influencing apoptosis and tumorigenesis. The Iowa Women’s Health Study of 28,283 postmenopausal women including 80 pancreatic cancer cases found a significant lower RR of pancreatic cancer for aspirin user compared to non-user (RR, 0.57; 95% CI, 0.36–0.90). However, this finding was not confirmed in a later study. A moderate increased risk was reported for women with extended period of regular aspirin use in the Nurses’ Health Study including 161 cases. In the Women’s Health Initiative study, nearly 40,000 women were randomized to receive either 100 mg aspirin every other day or placebo. No statistically significant difference was noted between tested and placebo group after average 10.1 years of follow-up [148,149]. Larsson et al. reported a meta-analysis of 11 studies conducted from 1966 to October 2006 (3 case-control studies, 7 cohort studies, and 1 randomized trial), involving 6,386 pancreatic cancer cases. Neither use of aspirin, nonaspirin NSAIDs, nor overall NSAIDs were associated with pancreatic cancer risk. In 2007, Capurso et al. conducted a meta-analysis including 8 studies (4 cohort studies, 3 case-control studies, and 1 randomized controlled trial) of 6,301 patients enrolled 1971–2004 and no association was found between use of aspirin or NSAIDs and risk of pancreatic cancer. Whether the negative findings were related to the large baseline exposure in controls in North America needs to be clarified in future study.

Statins and metformin

Statins, competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, are a class of pharmacologic agents that reduce plasma cholesterol. Statins have been shown to have antitumor activity in various studies on pancreatic cancer cell lines. However, a meta-analysis till December 2007 including 12 studies (5 case–control studies, 4 cohort studies, and 3 randomized placebo-controlled trials) did not support a reduced risk of pancreatic cancer in association with low-dose intake of statins at the population level.


Pancreatic cancer remains a major cause of cancer-related death. Effective prevention measure depends on well-defined risk factors by epidemiological research. Unlike previous studies that universally impeded by small sample size, survivor bias, and use of proxy respondents for patients, more pooled studies and large prospective studies have emerged to provide epidemiologic evidence on risk factors of pancreatic cancer. Cigarette smoking is a well established risk factor. There is accumulating evidence supporting a role of obesity and diabetes as risk factors for this malignancy. More than 50% of the pancreatic cancer is probably preventable by adapting a healthy lifestyle. The associations of dietary factors, alcohol, pancreatitis, infectious agent, occupational and hormonal factors and risk of pancreatic cancer are inconclusive. The study findings on systematic reviews on exposure and risk of pancreatic cancer should be considered suggestive because there are great between-study heterogeneity due to different assessment tools and study populations. Publication bias is often a concern. Welldesigned large prospective studies and consortium studies are required to further define the environmental and host factors contributing to the development of pancreatic cancer. Further research on the genetic susceptibility factors and their interactions with the known risk factors for pancreatic cancer may help better understand the etiology of this disease and offer new tools for identifying high-risk individuals for preventive intervention.

Key research points

  • The percentage of pancreatic cancer cases attributable to the inherited pancreatic cancer syndromes is small. However, investigations on the molecular mechanisms underlying these inherited syndromes shed light on the pathophysiology of pancreatic tumorigenesis. These individuals may be benefited by close surveillance and screening with imaging modalities.
  • Cigarette smoking and obesity may each be responsible for causing as many as 25% of the cases of pancreatic cancer. Therefore, it is possible that as many as 50% of pancreatic cancer cases are preventable. Avoid smoking and maintaining a healthy body weight offer the best available strategy for reducing the incidence of this disease.
  • Diabetes could be the manifestation of pancreatic cancer, but long-standing type II diabetes mellitus has been implicated as a risk factor.
  • Other suspected risk factors for pancreatic cancer include heavy alcohol consumption and pancreatitis.
  • Consume of a well balanced diet with adequate amounts of fruits and vegetables, limited amounts of alcohol, and limited amounts of red meat, especially high fat or processed meat may also reduce the risk of pancreatic cancer.

Future scientific directions

  • Effective prevention measure depends on well-defined risk factors by epidemiological research.
  • The cause of pancreatic cancer involves multiple factors and complex etiology. Well-designed large prospective studies and consortium studies are required to generate sufficient amount of information on the role of environmental and host factors in pancreatic cancer development.
  • Further research on the genetic susceptibility factors and their interactions with the known risk factors for pancreatic cancer may help better understand the etiology of this disease and offer new tools for identifying high-risk individuals for monitoring and screening.
  • New molecular techniques, such as genome-wide association scan, microarray analysis of gene expression and proteomic approaches may ultimately help in discovering biomarkers for early diagnosis, which will have a major impact on reducing the mortality of pancreatic cancer.


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