Global Incidence of Pancreatic Cancer
Pancreatic cancer is the 12th deadliest form of cancer, with a 5-year survival rate of just 10%, with more than half of the cases being diagnosed at an advanced stage. A total of 495773 (262865 male and 232908 female) new cases and 466003 (246840 male and 219163 female) deaths from pancreatic cancer were reported worldwide in 2020. In both sexes, most of the new cases (191348; 38.6% of the total) and deaths (182074; 39.1% of the total) occurred in the Western Pacific Region. In both sexes, the highest ASRs were found in the European Region, while the lowest rates were reported in the South-East Asia Region. The general pattern of rising pancreatic cancer incidence and mortality was seen across countries worldwide in observed period. Out of all countries with an increase in pancreatic cancer incidence, females in France and India showed the most marked rise in incidence rates (AAPC = +3.9% and AAPC = +3.7%, respectively). Decreasing incidence trends for pancreatic cancer were observed in some countries, but without significance. Out of all countries with an increase in pancreatic cancer mortality rates, Turkmenistan showed the most marked rise both in males (AAPC = +10.0%, 95%CI: 7.4–12.5) and females (AAPC = +6.4%, 95%CI: 3.5–9.5). The mortality trends of pancreatic cancer decreased in both sexes only in Canada and Mexico.
World Health Organization (WHO) estimated pancreatic cancer as the third leading cancer-related cause of death in people of all ages for both sexes in the USA, Germany, Italy, Austria, Czechia, Finland, Hungary, Malta, Spain, and Switzerland in 2020.In four countries (Finland, Qatar, Benin and Guadeloupe), pancreatic cancer was the second leading cause of death of all cancers in 2020 in females aged ≥ 70 years.
The most significant increase in pancreatic cancer incidence was noted in people aged ≥ 70 years in France in both males (by +4.2% per year) and females (by +4.9%). An increase was observed in most of the countries in both sexes for persons aged ≥ 50 years. A decreasing trend in the incidence of pancreatic cancer was recorded only in females aged ≥ 70 years in Canada (by 0.3% per year). Also, a decreasing trend in pancreatic cancer incidence in males aged ≥ 70 years was noted only in Canada (by 0.4% per year). In males aged 30–49 years, incidence rates decreased mainly in transitional countries (Czechia by 1.9%, Estonia 2.1%, Latvia 2.2%, Lithuania 2.2% and Slovakia 1.5%). In almost all countries, a significantly increasing trend in mortality of pancreatic cancer was recorded both in males and females aged ≥ 70 years.
To date, the causes of pancreatic carcinoma are still insufficiently known. However, certain risk factors have been identified, such as tobacco smoking, diabetes mellitus, obesity, dietary factors, alcohol abuse, age, ethnicity, family history and genetic factors, Helicobacter pylori infection, non-O blood group and chronic pancreatitis. In the general population, screening of large groups is not considered useful to detect the disease at its early stage, although newer techniques and the screening of tightly targeted groups (especially of those with family history), are being evaluated. Primary prevention is considered of utmost importance.
Although the cause of pancreatic cancer is complex and multifactorial, cigarette smoking [3] and family history are dominant [4]. Pancreatic cancer is mainly divided into two types of pancreatic cancer: pancreatic adenocarcinoma, which is the most common (85% of cases) arising in exocrine glands of the pancreas, and pancreatic neuroendocrine tumor (PanNET), which is less common (less than 5%) and occurs in the endocrine tissue of the pancreas [5]. Pancreatic adenocarcinoma has a very poor prognosis, typically after diagnosis, only 24% of people survive 1 year, and 9% live for 5 years [6].
Based on the clinical stage of the tumor, pancreatic cancer is classified into four types: I (no spread or resectable), the cancer is limited to the pancreas and has grown 2 cm (IA) or greater than 2 cm but less than 4 cm (IB); II (local spread or borderline resectable), the cancer is > 4 cm and is limited to the pancreas, or there is spread locally to the nearby lymph nodes; III (wider spread or unresectable), cancer may have expanded to the nearby blood vessels or nerves, but has not metastasized to distant sites; IV (metastatic), cancer has spread to distant organs. Because pancreatic adenocarcinoma and the other less common exocrine cancers are typically diagnosed at a late stage (III or IV), it has a very poor prognosis compared to PanNET. At its early stages, pancreatic cancer usually lacks symptoms [7]. Upon progression of the tumor, it manifests as a gradual onset of non-specific symptoms including jaundice, weight loss, light-colored stools, abdominal pain, and fatigue [8].
Alcohol
Based on many studies, the risk of pancreatic cancer is undoubtedly increased by high alcohol consumption (more than three drinks per day), whereas there was no association found with low-to-moderate alcohol intake [52-54]. A large case-control study in 2010 showed increased risk even at the consumption of 60 g/day or more of liquor (spirits) but found no association with beer or wine [55].
A recent study found that heavy alcohol consumption was associated with a significant increase in pancreatic cancer risk among current smokers (age-adjusted odds ratio (OR) = 4.04, 95% CI: 1.58 – 10.37), whereas it was not observed among non-smokers (age-adjusted OR = 2.01, 95% CI: 0.50 – 8.18). Furthermore, low-to-moderate alcohol intake was associated with increased pancreas cancer risk among current smokers [56], suggesting that smoking can modify the alcohol-cancer relationship. However, the association between alcohol and smoking is very close. Therefore, it may be challenging to implicate alcohol as an independent risk factor for pancreatic cancer.
Obesity
Obesity is associated with an increased risk for several types of cancer including pancreatic cancer [57]. Some studies found that obesity increases the incidence and mortality of pancreatic cancer [58, 59]. A study by Li et al [60] found that being overweight (body mass index (BMI): 25.0 – 29.9 kg/m2) or obese (BMI ≥ 30 kg/m2) during early adulthood is associated with a higher risk of pancreatic cancer. Furthermore, obesity at an older age (30 – 79 years) was associated with lower overall survival.
According to an American Cancer Society (ACR) study, in both sexes, the risk of pancreatic cancer among obese was higher (RR = 2.08) compared to people of healthy BMI (18.5 – 24.9 kg/m2) [59]. A recent meta-analysis has confirmed the hypothesis that both general and abdominal fatness is associated with increased pancreatic cancer risk [61]. Besides, physical inactivity (which can contribute to fat accumulation and overweight) has been linked to an increased risk of pancreatic cancer.
Dietary factors
It seems reasonable that diet would affect the risk of different digestive diseases and cancers, including those of the pancreas. Dietary factors impact up to 30-50% of pancreatic cancer, and there is evidence that certain foods are associated with higher risk, while others are even protective [42, 62, 63].
Consumption of red meats (especially when cooked at high temperature), processed meats, cholesterol, fried foods, and other foods containing nitrosamines may increase the risk of pancreatic cancer [64, 65]. It is possible that carcinogens in meat and nitrite or N-nitroso compounds that are used for preserving processed meats are involved in pancreatic cancer [66]. The results of a meta-analysis that included 11 case-control studies showed that red meat intake increased the pancreatic cancer risk by about 48% (95% CI: 1.25 – 1.76). On the other hand, a high intake of vegetables and fruits, especially those enriched in citrus and antioxidants, has a protective action, decreasing the risk by 38% (95% CI: 0.54 – 0.73) and 29% (95% CI: 0.59 – 0.84), respectively [67].
Also, another meta-analysis of 11 prospective studies found a positive association between pancreatic cancer incidence and high consumption of red (120 g/day) or processed meat (50 g/day) (RR = 1.13 and RR = 1.19 respectively) [68]. However, some studies have not supported these findings [69], or have provided support for the association among men only [70]. For example, the EPIC study found no association between pancreatic cancer risk and intake of red and processed meat, while poultry consumption was associated with an increased risk [71]. Interestingly, two studies reported that frequent nut consumption significantly lowers the risk of pancreatic cancer in women [72, 73]. Additionally, in a large UK cohort study in 2016, mortality for pancreatic cancer was lower for low meat-eaters (about 30-45% lower mortality), as well as vegetarians and vegans (about 50% lower mortality) compared with regular meat-eaters [74].
Occupational exposures
The etiological fraction of pancreatic cancer due to occupational exposures (involving exposure to metalworking and pesticides) within a population was estimated at 12%.
A meta-analysis of occupational exposures and pancreatic cancer reported an increased risk with nickel exposure [75]. However, in occupational settings, nickel may be associated with high concentrations of polychlorinated biphenyls, and the latter compounds could account for the observed increased risk [76, 77]. Carcinogenic mechanisms of nickel may include increasing DNA methylation, inhibiting DNA repair, and inducing apoptosis through the generation of reactive oxygen species [78–82].
Additionally, few studies have found a link between exposure to cadmium and arsenic and pancreatic cancer risk. Cadmium is a non-essential metal that is known to accumulate in the human pancreas increasing the risk and mortality of pancreatic cancer [83, 84]. Cadmium is a well-established carcinogen that acts on different steps of carcinogenesis, inhibiting DNA repair and causing genomic instability [85–87]. Furthermore, it causes transdifferentiation of pancreatic cells, inhibits DNA repair and induces or regulates the activity of several oncogenes or tumor-suppressor proteins that are expressed in human pancreatic cancer [83, 88, 89]. Arsenic exposure has been associated with increased cancer risk [90], but regarding its association with pancreatic cancer, little has been published. A potential link between childhood exposure to milk powder contaminated with arsenic and an almost two-fold excess mortality due to pancreatic cancer was recently reported [91, 92]. Inorganic arsenic is a highly toxic and carcinogenic metalloid, which can induce oxidative stress leading to inhibition of DNA repair [90, 93, 94] and DNA strand breaks as well as DNA adducts [95]. Moreover, alterations in the methylation status of oncogenes and tumor-suppressor genes, mediated by arsenic, may also play a role in carcinogenesis [96].
As opposite, selenium, which is an essential micronutrient [97, 98], has been inversely associated with several cancers including pancreatic [99–103], while only a small study published in 1989 showed an increased risk of pancreatic cancer due to high selenium levels [104]; however, no replication studies have been published. Aberrant expression patterns of some selenoproteins suggest that they are relevant in scavenging reactive oxygen species and diminishing oxidative damage [105, 106]. Also, selenium may boost p53 activity, leading to either DNA repair or apoptosis [107]. Selenium also seems to play a role as the antagonist of arsenic, cadmium, and lead, decreasing the oxidative stress caused by exposure to these elements [108, 109].
Pancreatic cancer is mostly diagnosed in an advanced stage, and 80-90% of patients have unresectable tumors at the moment of diagnosis. There are several reasons because this occurs.
First, early-stage pancreatic cancer is usually clinically silent, and most people who present with symptoms attributable to pancreatic cancer have advanced disease. Symptoms are non-specific and include abdominal pain, jaundice, pruritus, dark urine, and acholic stools, which may be presenting symptoms as a result of an obstruction within the biliary tree [195]. Furthermore, anorexia, weight loss (which can arise from anorexia), early satiety, dyspepsia, and nausea occur too [196], while less common manifestations include panniculitis and depression. Given the wide range of non-specific symptoms, there are a broad number of diseases that need to be differentiated [7], which include but are not limited to: cholangitis, cholecystitis, cholelithiasis, choledocholithiasis, choledochal cysts, duodenal or gastric ulcers, gastritis, pancreatitis, abdominal aortic aneurysm, lymphomas, and primary or secondary cancers of the biliary tree, liver, pancreas, stomach or intestine. Therefore, diagnosis can be delayed or missed, which makes pancreatic cancer the most common tumor detected at the autopsy studies [17, 24]. To date, there are several diagnostic tools available, such as abdominal ultrasonography, tri-phasic pancreatic-protocol CT (which is the standard for diagnosis and staging [197, 198]), magnetic resonance imaging (MRI) [7, 138] and endoscopic ultrasound-guided fine-needle aspiration for cytological diagnosis [7] (which sensitivity is reported to be about 80% [199]). Additionally, in symptomatic patients, measurement of blood levels of cancer antigen 19-9 can help to confirm the diagnosis and predict prognosis and recurrence after resection [200]; however, it cannot stand as an individual screening tool for asymptomatic patients because it is not tumor-specific [201]
Besides cigarette smoking, alcohol abuse, high saturated fat consumption, and reduced physical activity may also influence pancreatic cancer mortality. Interestingly, the fact that in underdeveloped countries like Africa, there will be a dramatic increase in pancreatic cancer incidence and mortality suggests that socioeconomic disparities have a significant impact on the trends, as improved diagnostic tools and access to therapies may be very limited.
Smoking
Over one thousand million people practice smoking of tobacco worldwide, and it represents the most important environmental factor for pancreatic cancer in the world. The International Agency for Research on Cancer has confirmed that smoking is causally associated with pancreatic cancer [13, 43]. The risk of pancreatic cancer increases with the duration of smoking and the number of cigarettes smoked daily. The risk is nearly two times higher in smokers than in non-smokers [44–46]; additionally, a recent meta-analysis of 82 studies found that the relative risk (RR) of pancreatic cancer was RR = 1.74 for current and RR = 1.2 for former smokers and the risk persists for at least 10 years after smoking cessation [47–49].
In 2012, the European Prospective Investigation into Cancer (EPIC) study showed that the risk of pancreatic cancer increases for every five cigarettes smoked per day, and also, passive smoking can increase the risk of pancreatic cancer by 50% [49, 50]. While smoking prevalence has declined in many developed countries, it remains high in others and is increasing among women and in developing countries. For example, in 2011, a study estimated that around 26.2% of pancreatic cancers in men and 31.0% in women were linked to tobacco smoking in the UK [20], while in the world’s two most populous nations, India and China, smoker users are home to more smokers than the entire population of Europe [51].
The risk of pancreatic cancer associated with smoking remains elevated after allowing for potential confounding factors such as alcohol consumption.
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