Trends in Pancreatic Cancer Related Mortality in the United States from 1999-2020

Background : Pancreatic cancer related mortality trends in the U.S. population have not been explored recently and the availability of the CDC WONDER


Introduction
Across the globe, the prevalence of pancreatic cancer is on the rise and has surged by over two-fold in the last three decades [1].In 2018, pancreatic cancer ranked as the seventh leading contributor to cancerrelated deaths worldwide [2].However, Pancreatic ductal adenocarcinoma (PDAC) ranks as the third main contributor to cancer-related mortality in the United States, and it is associated with a mere 10% survival rate over a five-year period [3].Pancreatic adenocarcinoma is responsible for approximately 90% of all Pancreatic Cancers [4].The estimated new cases of Pancreatic cancer in 2023 as of Sep23' are 64,050 which is 3.3% of all new cancer cases in this period and the estimated deaths from from pancreatic cancer in 2023 as of Sep23' are 50,550 which is 8.3% of all cancer deaths in this period [5].In a crosssectional cancer projection study conducted by Rahib et al. in 2021, it was shown that by the year 2040, lung, prostate, liver, and pancreas were expected to be the leading sources of cancer-related fatalities among men.Likewise, for women, the principal contributors to cancer-related mortality in 2040 were projected to be lung, breast, pancreas, and uterine cancer [6].Awareness of the demographic and regional patterns in relation to Pancreatic Cancer mortality can aid in the identification of populations at highest risk so that timely interventions can be offered.Therefore, we sought to evaluate these differences in Pancreatic Malignancy associated AAMRs from 1999 to 2020.

Study Setting and Population
In this study, death certificate data were retrieved from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database (7)

Data Abstraction
Data for population, year, geographical region and states were abstracted.Demographics including sex, age, and race/ethnicity were isolated.Race/ethnicity was classified as Hispanic or Latino, non-Hispanic (NH) White, NH Black or African American, NH American Indian or Alaskan Native and NH Asian or Pacific Islander.This information has been extracted from reported data on death certificates and has previously been used in the analyses of mortality trends pertaining to several causal factors of death from the CDC WONDER database [8,9].Regions were classified into Northeast, Midwest, South, and West according to the U.S. Census Bureau definitions [10].

Statistical Analysis
To examine national trends in Pancreatic Cancer related mortality, we calculated crude and ageadjusted mortality rates (AAMRs) per 100,000 population from 1999 to 2020 by year, sex, race/ethnicity and state with 95% CIs.Crude mortality rates were analyzed when comparing the AAMRs with respect to different age groups and were determined by dividing the number of Pancreatic Cancer related deaths by the corresponding U.S. population of that year.AAMRs were calculated by standardizing Pancreatic Cancer related deaths to the year 2000 U.S. population.To quantify annual AAMR trends, the Joinpoint Regression Program (Version 5.0.2;National Cancer Institute) was used to determine the annual percent change (APC) with 95% CI in AAMR [11].This approach detects noteworthy fluctuations in AAMR (Age-Adjusted Mortality Rate) over a period by employing log-linear regression models in cases where there is temporal variation.APCs (Annual Percent Changes) were categorized as rising or falling if the slope representing the mortality change was significantly distinct from zero through a two-tailed t-test.A significance level of P < 0.05 was considered statistically significant.

Results
A total of 847,589 Pancreatic Cancer related deaths occurred among the overall U.S. National population between 1999 and 2020.Of these, 703,360 deaths occurred in the adult population aged 45-84 years old.Crude death rates could not be calculated for 85+ years old population because total population data for this age group was not available [12] and the extracted death rates are flagged as unreliable for ages 1-14 as the rate is calculated with a numerator of 20 or less [13).In addition, distinctly higher death tolls could be appreciated with the population entering middle and older ages age as shown in figure 1.Therefore, we shall be analyzing the overall population data recruited from the CDC WONDER database and simultaneously doing a sensitivity analysis of the age category 45-84 years.

Trends in pancreatic cancer related mortality for overall population (all age groups)
Similar trends in similar general trajectories were appreciated as displayed in Figures 7 and 8.

Discussion
In our examination of mortality data spanning two decades, we present a few noteworthy findings.First and foremost, it's crucial to highlight that there has been no overall decline in Pancreatic cancer related mortality rates from 1999-2020.Pancreatic cancer has consistently remained one of the prominent diseases leading to mortality in the United States, and over a span of 22 years, we have observed a rise in AAMRs for both men and women.One possible explanation for these statistics could be that majority of patients do not display noticeable symptoms through disease progression to advanced metastatic cancer, where tumor cells exhibit significant invasiveness.Detecting the cancer at an early stage poses a considerable challenge [14].In addition, majority of patients ultimately experience a recurrence, even following an aggressive treatment approach, resulting in only 12.5% survival rate over a five-year period (2013-2019) [5].Mortality rate data for both sexes exhibited an upward trend and men had consistently higher AAMRs than women over the course of 22 years.The difference in mortality rates might be attempted to be clarified by the global variation in the incidence of Pancreatic cancer between the sexes, incidence in men being higher than women [15,16].One potential explanation could be that women tend to have higher levels of certain hormones, which could have a protective effect against pancreatic cancer [17).This was supported by Sadr-Azodi et al.'s paired cohort study, which found that women who received menopausal hormone therapy had a 23% lower prevalence of pancreatic cancer compared to those who did not receive MHT.Additionally, MHT for 1-2 years reduced the prevalence by 35%, while MHT for over 3 years led to a 60% reduction in prevalence [18).Previous, more dated research data supports our conclusions about the Black or African American population having the highest AAMRs among the five racial groups [19,20].At present, there is a shortage of studies addressing this racial disparity, making it a critical research gap area that needs our focus to curtail the number of deaths from pancreatic cancer.Efforts to comprehend the causes behind this inequality have proposed that when it comes to men, the well-established risk factors, primarily cigarette smoking and diabetes mellitus, account for nearly all of the difference in pancreatic cancer rates between black and white individuals.On the other hand, among women, it seems that additional factors play a role, particularly substantial alcohol consumption and high body mass index [21].The incidence of pancreatic cancer among Black individuals residing in Africa seems to be notably lower when contrasted with the rates observed among African-Americans [22].Notably, among all the population subsets examined, the only one to show a decline in mortality from Pancreatic cancer was the Black or African American community.To our understanding, there has been relatively little investigation into this specific aspect of Pancreatic cancer, which provides additional rationale for conducting a more thorough analysis of the statistics related to pancreatic cancer within the Black or African American population in the United States.The geographic variation in AAMRs, with District of Columbia having the highest and Utah having the lowest AAMRs; albeit both displaying a rising trend over the years, bears resemblance to a study by Hao Y et al. discussing the geographic patterns of cancer related mortality in the U.S. by congressional districts, in which, the following was brought to light: In the case of men, death rates (per 100,000 person-years) range from 186.3 in Utah's congressional district #3 to 343.7 in the District of Columbia.Similarly, for women, the rates span from 123.4 in Utah's congressional district #1 to 217.4 in Pennsylvania's congressional district #2 [23].This data underscores how death rate patterns vary by area and warrants further county wise analysis to delve deeper into resolving any district specific barriers to the provision of healthcare services.

Study Limitations
Firstly, due to reliance on ICD codes and death certificates, there is a chance for inaccurate reporting or the omission of cases.Secondly, the database lacks details on clinical factors that could be helpful in the characterization of pancreatic cancer.Thirdly, information regarding pancreatic cancer management is absent.Lastly, data related to socioeconomic factors influencing health, which can impact access to healthcare, is also unavailable.
and investigated from 1999 to 2020 for Pancreatic cancerrelated mortality in the overall population and separately in adults aged 45 -84 years using codes from the International Statistical Classification of Diseases and Related Health Problems-10th Revi-sion (ICD-10) as follows: C25.0 (Head of pancreas -Malignant neoplasms); C25.1 (Body of pancreas -Malignant neoplasms); C25.2 (Tail of pancreas -Malignant neoplasms); C25.3 (Pancreatic duct -Malignant neoplasms); C25.4 (Endocrine pancreas -Malignant neoplasms); C25.7 (Other parts of pancreas -Malignant neoplasms); C25.8 (Overlapping lesion of pancreas -Malignant neoplasms); C25.9 (Pancreas, unspecified -Malignant neoplasms).The Multiple Cause-of-Death Public Use record death certificates were examined to select Pancreatic Neoplasia-related deaths, identified as those with Pancreatic Cancer reported anywhere on the death certification either as a contributing or underlying cause of death.A sensitivity analysis was also conducted following the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting.