An epidemiological review of pancreatic cancer with special reference to India

Incidence and mortality - global burden

Globally, based on GLOBOCAN (2018) estimates, 0.46 million new PC cases and 0.43 million deaths due to PC are reported annually [Table 1] and the incidence and mortality rates are 4.8 and 4.0, respectively. It is seen that the rates in high human development index (HDI) countries are three-fold compared to low HDI countries.^[1]

Regional variations, as shown in Table 1, indicate that incidence rates of PC in males were highest in Eastern Europe (9.9), followed by Western Europe (9.5), North America (8.7), and lowest in South Central Asia (1.1); among females, the rates were 7.2 in Western Europe, followed by Northern America (6.5), Northern Europe (6.4), and lowest in South Central Asia (1.0);^[1] In the future, it is projected that the deaths due to PC will be ranked third, breast cancer being ranked third as of now.^[6]

It is seen in Table 2 that in male population, incidence rates were higher in Republic of Moldova (15.3) and Hungary (12.9), while in female population, Hungary (9.1), and UAE (10.1) showed higher rates; the mortality rates among males in Republic of Moldova (12.3) and Hungary (11.2) showed the higher rates while in females, rates in UAE (10.0) and Hungary (7.9) were higher.^[1] In Table 2, it is observed that in all the countries, the incidence rates were higher than mortality rates in both the sexes, except in Russian Federation; it is observed that in Russian Federation, mortality rates were higher in both males and females than its incidence.^[1]

Differences in incidence rates between registries across the world

As per the CI5-XI,^[2] there are gender-specific variation in PC [Table 3]. The incidence rates differed among men; the incidence rates were higher in Italy- Sondrio (12.0), Czech Republic (11.8), and Slovakia (11.8), while it was lower in India-Dindigul (0.5), India-Tripura (0.6), and South Africa- Eastern Cape (0.7).^[2] Similarly among women, rates were higher in Italy-Sondrio (9.0), Czech Republic (8.0), Germany-Bremen (7.8)^[2] and lower in India-Tripura (0.3), India-Dindigul (0.3), and South Africa-Eastern Cape (0.4).^[2]

It is seen from Table 4, that the proportion of PC cases in Bhutan and China is more than two-fold than that seen in India, which is similar to that observed in the north-eastern regions of India.^[2]

Incidence and mortality in India

The rates are obtained from the Population-Based Cancer Registries (PBCR) in India. It is projected that the number of cases will escalate from 10969 in 2015 to 11655 in year 2020 though it is not included among the ten leading cancer sites in India.^[3] Mizoram has the highest age-adjusted incidence rates and northeastern region has significantly high number of PC cases as compared to any other regions across the country.

In Figure 1, it is seen that, among males, Mizoram (3 per 10⁵) showed highest rates followed by Mumbai (2.8) and Thiruvananthapuram (2.6), whereas in females, Mumbai (2.2 per 10⁵) showed highest rates followed by Delhi (1.7) and Thiruvananthapuram (1.5).^[3] Although Mumbai and Mizoram share similar incidence rate for males, it is not so in females.

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Figure 1:

Age-adjusted incidence rates (per 10⁵) of PC in Indian Population-Based Cancer Registries (2012-2014).

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Time trends across the globe and in India

Global trends

Cancer trends are an important indicator of the changing pattern of occurrence of cancer and provide insight into the possible reasons/factors that may have contributed to the phenomenon. The age standardized incidence rate data from year 1988 to 2012 for age (0–85+ years) showed some interesting trends in both the sexes, as reported in CI5-Vol XI.^[2] The incidence rates in males in USA, as shown in Figure 2, though with fluctuations did not show much change, over the period and China as well did not show any significant change in rates; however, France, Bas-Rhin had shown 30% increase, a 20% increase over the period in Japan, Miyagi, and two-fold increase in India, Chennai, and a 50% increase in rates in Italy, Parma.^[2]

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Figure 2:

Time-trends of pancreatic cancer in some selected countries across the globe –males.

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Similarly, among the females, as seen in Figure 3, China, Shanghai, France-Bas-rhin, and Italy, Parma showed about 50% increase over the period from 1988 to 2012, while registries as USA, India, and Japan did not show any appreciable change in incidence rates.^[2]

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Figure 3:

Time-trends of pancreatic cancer in some selected countries across the globe – females.

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Time trends in Indian PBCR

The comparison between four PBCR, Bengaluru, Chennai, Delhi, and Mumbai, as displayed in Figure 4, is based on data from a network of Indian cancer registries;^[4] it shows that the rates have increased more than two-fold. Mumbai had shown a steady increase in the AAR from 2.1 in 1982 to 2.8 in 2012, Bengaluru AAR has tripled from 0.6 in 1982 to 1.8 in 2012, Delhi showing increasing trends from 1990 to 2002 which after a decline, again peaked to 2.5 in 2012, and in Chennai it peaked in 1997 (2.0) followed by a decline in 2002 and eventually increased to 1.8 in 2012; this trend as seen in Indian registries indicated an inconsistent trend in the rates of PC over the years.^[3,4]

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Figure 4:

Trends in Indian population-Based Cancer registries: Age-adjusted incidence rates (per 10⁵) (1982–2012)– males.

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Hospital-based cancer registries (HBCR)

HBCR are important source for population registries, where a major proportion of cases is diagnosed. India has a large network of HBCRs. The frequency of PC cases seen in males (very few female cases) in different hospital registries across India, as Mumbai, Chennai, Bengaluru, Delhi, Mizoram, Thiruvananthapuram, and Silchar are shown in Figure 5 reveals that the highest number of cancer cases is seen in Thiruvananthapuram and Chandigarh in both the males and females.^[7]

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Figure 5:

Number of pancreatic cancer cases in HBCR across India (NCDIR, 2016).^[7]

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Trend of PC seen in the Tata Memorial Hospital (TMH)

TMH is a premier cancer hospital in India setup seven decades ago. Figure 6 showing 5-yearly interval data of PC cases which indicates an increasing trend in the proportion of PC cases in both the sexes over the years.^[8-14]

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Figure 6:

Distribution of pancreatic cancers seen over the years in Tata Memorial Hospital: 1987–2017.

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In TMH, it is seen from Figure 6 that there has been a sevenfold increase in the cases over the years from 1987 to 2012 in both sexes; however, from 2012 to 2017, there has been a two-fold increase in both sexes. This could probably be due to awareness of the cancer facility expertise in diagnosis and treatment in TMH that has shown the increase in registrations.

HDI

HDI has profound effect on the inequalities with respect to PC. Higher the HDI score, higher is the rates [Figure 7]. The incidence rates in High-HDI (4.6) are three-fold or six-fold in very high-HDI (7.2), when compared to low-HDI (1.2) countries; similarly, the mortality rates are also either threefold or six-fold in high-HDI or very high-HDI countries as compared to low-HDI countries [Figure 7].^[15]

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Figure 7:

Age-standardized rates (per 10⁵) of pancreatic cancer by human development index.

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Ethnic variations and migration impact

Incidence rates according to racial origin and migrant population are very well elucidated in Cancer Incidence in Five Continents Vol XI.^[2] The differences in incidence rates by racial origin and migration are shown in Figure 8.

It is observed that the incidence rate for PC, in general, is higher in American–Blacks (11.8) as compared to American–Whites (8.6) population. As per data from year 1973–2013 (SEER-9 registries), higher incidence rate is observed among American–Black males (11.2), American– Black females (9.4) than that seen in American–White males (9.1) and American–White females (6.4), indicating that there is a ethnic variations in PC occurrence in the population between the races.^[2]

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Figure 8:

Incidence rates (ASR) by racial origin and migration status.

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Similarly insight into the migration effect is shown in Figure 8. It reveals that among males, the rates observed in USA, San Francisco Bay Areas of Chinese (5.3), Japanese (7.9), and Filipino (5.6) are different than those observed in the host USA, San Francisco Bay Area (8.7) population. Similarly among females, the rates observed in USA, San Francisco Bay Area of Chinese (3.9), Japanese (7.9), and Filipino (5.5) are different than those observed in the host USA, San Francisco Bay Area (6.2) population. In both the sexes, it indicated clearly that migration has no significant effect on PC occurrence in the population, over the years.^[2]

The large variation in time for migrants to adopt the host population’s cancer risk suggests that risk factors have organ-specific effects, or operate at different times in life. The persistent difference in cancer incidence several generations after migration supports the idea that living in the host country is not, alone, sufficient to modify cancer risk for all cancer sites to the level of the host population. Although the migration effect, if any, can be partially explained by known etiologic factors, a large proportion of the changing risk remains.

Tobacco consumption

Smoking of tobacco is known to be one of the causative risk factor for PC. Cigarette smoking is the only established risk factor;^[29] those who smoked had a two-fold enhanced risk compared to those who never smoked, and about 20–30% of PCs were due to cigarette smoking.

Smoking is higher in males as compared to females and a major risk factor attributing to cancer cases in males.^[30] It is interesting to know that the risk of developing PC reduces after cessation of smoking; it is been projected that 25% of deaths due to PC in United States can be prevented with smoking cessation.^[31]

Diet

High consumption of grilled and processed meat, fried food, food rich in cholesterol, and nitrosamines is directly associated with increased risk of developing PC by 30–50%.^[34,35] A qualitative analysis of case–control studies revealed that high intake of vegetable and fruits was associated with decreasing the risk for the development of PC.^[36] However, there are inconsistent findings on red meat as a risk factor.^[37,38]

Obesity and physical inactivity

One of the earlier meta-analysis study reported a positive correlation between obesity, and increased BMI as a risk factor for PC in both sexes.^[39] In another meta-analysis study consisting of 21 independent prospective studies concluded that the RR for BMI was 1.16 in men and 1.10 in women.^[40] The strongest association observed was between BMI and PC mortality in racial disparity study arising due to smoking/ obesity in Black men.^[41]

It was reported that obese people were 20% more likely to develop PC and lack of physical activity might increase PC risk further.^[5]

Workplace exposure to certain chemicals

The American Cancer Society reported that heavy exposure at work to certain chemicals used in the dry cleaning and metal working industries might increase the risk of PC.^[5]

Age at diagnosis

It is known that risk for cancer increases with advancing age and PC is no exception.

Occurrence of PC is extremely rare in those below the age of 30 years, and is common in those above the age of 55 years, majority being in their seventh and eighth decades of life.^[42,43]

The age interval at which the incidence is highest differs between countries. In India, the incidence peaks in their sixth decade of life whereas in the United States, it is in the seventh decade of life.^[42]

Gender

The incidence of PC in men is higher than women and it is more pronounced while comparing highly developed and less developed countries, and it is seen in Indian population as well.^[15]

Studies on evaluating gender-specific hormonal risk factors causal role in susceptibility to the PC are reported in the literature;^[44,45] however, one of the studies negated association of reproductive factors in women.^[44] The study concluded that the findings indicated that there were other factors as environmental conditions or habits like smoking which till recent past were more common in males than females.^[42]

Race

Black-origin have been diagnosed with PC at 48% and died at a 37% higher rate than White-origin;^[46] it was concluded that there could be some other lifestyle risk factors that contributed to this outcome.

Family history

It has been estimated that the risk of developing PC in an individual with two affected family members to be 6.4-fold and 32-fold for three or more affected family members.^[47] The sporadic cases of PC in family do not appear to be a potential risk factor in the development of PC.^[48] Except for BRAC2, so far, no gene has been identified in majority of familial PC cases.^[49]

Inherited genetic syndromes

As per the report by the American Cancer Society, some of the inherited gene (mutations) can be transmitted from parent to child who might cause 10% of PCs. Sometimes these changes result in syndromes that include increased risks of other cancers/other health problems.^[5]

Diabetes mellitus

Diabetes has direct association with the risk of development of PC. Both, Type-1 and Type-2 diabetes has risk of developing PC.^[5] Study on Italian population had shown that diabetes is believed to be cause for approximately 10% of PC.^[50] Several other studies in various populations had also provided evidence that PC and diabetes are strongly linked with respect to onset of PC.^[51-54]

Elaborate study of association between diabetes and PC is very much required and will help to use condition of diabetes as a marker of disease and to identify the population at risk for screening.^[55]

Chronic pancreatitis

As per the American Cancer Society reports, chronic pancreatitis, a long-term inflammation of the pancreas, though increased risk for smokers, may never develop PC; they attribute this risk to an inherited gene mutation.^[5]