Abstract
Background: Cancer and heart failure (HF) are significant causes of morbidity and mortality worldwide. Moreover, there is increasing evidence of a relationship between HF and cancer. Although oncology has experienced significant advancements in cancer therapies, patients with a combination of these conditions represent an important clinical challenge due to varying outcomes among different demographic populations. Therefore, understanding these trends is crucial for targeted interventions.
Aims: This study analyzed two decades of mortality data to examine the trends, patterns, and disparities in cancer-related and cancer with HF-related deaths across the United States (US).
Methods: Mortality data from 1999 to 2020 were obtained using CDC WONDER, identifying cancer and cancer with HF-related deaths in adults age ≥25 years via ICD-10 codes. Demographic and regional distributions of mortality were analyzed utilizing statistical methods. Joinpoint regression analysis was used to determine trends in age-adjusted mortality rates (AAMR) and annual percentage changes (APC).
Results: Between 1999 and 2020, there were 13,880,876 cancer-related deaths in the US, including 567,657 with HF listed as a cause of death. The AAMR for cancer-related deaths decreased from 343.7 to 252.4 per 100,000 (APC: −1.61% [95% CI: −1.70, −1.57] from 1999 to 2018, then −0.62% to 2020). Cancer with HF-related deaths initially declined (AAMR: 15.0 to 10.2 from 1999–2013) but increased from 2013 to 2020 (APC: +6.03%). Males had higher mortality rates than females for both conditions. Cancer-related mortality was highest among non-Hispanic (NH) Whites and Hispanics, while cancer with HF-related mortality was highest among NH Whites and NH American Indians/Alaska Natives. Geographically, the South had the most cancer-related deaths (37.3%), while the Midwest led in cancer with HF-related deaths (4.5%).
Conclusions: Cancer-related mortality has declined overall, whereas mortality for cancer with co-existing heart failure has risen since 2013 after an initial decline. Disparities persist, with the highest burden in NH Whites, males, and those in rural or underserved areas. The findings underscore the need for focused interventions aimed at reducing mortality related to cancer and cancer with heart failure, particularly among the vulnerable population.
Despite rapidly growing advancements in treatment, the clinical prognosis for patients with heart failure (HF) remains relatively poor, exposing high morbidity and mortality rates. This health concern imposes a significant impact on healthcare operating costs and burden on patients worldwide.1,2 Over recent years, various clinical studies established the presence of a complex bidirectional relationship between cancer and HF, where each condition may have an adverse effect on the other.3 Cancer treatment modalities, including chemotherapy or radiation, are known to contribute to cardiotoxicity, which might cause HF. Conversely, HF-related inflammation, oxidative stress processes, and systemic hemodynamic changes are known to be associated with an increased risk of developing cancer.3,4
Although there is growing evidence for this bidirectional relationship, the pathophysiological mechanisms connecting these two conditions remain relatively unclear, necessitating further advancement to better characterize this relationship as well as its impact on patient outcomes.4 The clinical trends in the United States (US) show a significant decline in cancer-related mortality over the last two decades. These trends can be mainly attributed to advancements in faster diagnosis, patient-oriented strategies, and improved treatment options.5,6 However, with the alarming growth rate of HF as a comorbidity among patients with cancer, additional complexities in treatment are introduced, influencing morbidity and mortality patterns, which are not yet fully understood. Current literature focuses mainly on HF or cancer as independent conditions; however, there is a gap in understanding both conditions as correlated. Moreover, disparities are present in cancer-related and HF-related outcomes across various demographic and geographic groups in the US. Factors including race, ethnicity, sex, socioeconomic status, and rural-urban residence contribute to unequal access to care, available treatment strategies, and patient outcomes.
This study aimed to investigate these gaps in the literature through an examination of two decades (1999–2020) of US mortality data. Long-term trends in cancer-related and cancer with HF-related mortality was analyzed to observe disparities in mortality rates based on sex, race/ethnicity, and geographic region. By performing such an analysis, we aimed to provide valuable insights into the relative burden of co-existing diseases and their impact on mortality in the US.
Methods
Study Design
This study analyzed mortality rate data from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER) platform. Data from 1999 to 2020 were extracted from multiple cause-of-death files. We identified cancer-related deaths using the International Classification of Diseases, 10th Revision (ICD-10) codes C00–C97, while deaths involving cancer with heart failure (HF) were identified using both C00–C97 and I50 codes.
The analyzed dataset included cause-of-death information extracted from death certificates from all 50 states and the District of Columbia. We defined cancer with HF-related deaths when both conditions were recorded on the death certificate, either as underlying causes or contributing factors. We restricted our analysis to patients aged 25 years and older at the time of death. This was done to minimize confounding from the pediatric population.
Institutional Review Board (IRB) approval was not required for this study, because it used publicly available, de-identified data from government sources. The study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines to ensure transparency in reporting.
Data Extraction
We extracted data on variables including population size, year of occurrence, geographic region, and socio-demographic characteristics. The socio-demographic variables analyzed included sex, age group, and racial and ethnic composition. Race and ethnicity were categorized as non-Hispanic (NH) White, NH Black or African American, NH American Indian or Alaska Native, NH Asian or Pacific Islander, and Hispanic or Latino.
Geographical stratifications included regional delineations (Northeast, Midwest, South, and West, as defined by the US Census Bureau) and urban-rural classifications. Urban-rural categorizations were based on the 2013 National Center for Health Statistics Urban-Rural Classification Scheme, which classifies areas into metropolitan (large central, large fringe, medium, and small metropolitan) and nonmetropolitan (micropolitan and noncore) categories.7 Additionally, healthcare settings, such as deaths occurring in medical facilities (emergency rooms, inpatient, or outpatient), nursing homes, hospice care, or at home, were considered in the analysis.
Statistical Analysis
To analyze national trends in mortality, crude mortality rates per 100,000 population were calculated by dividing the total number of deaths attributed to cancer and cancer with HF by the total population size in the specified year. These rates were used to investigate patterns of mortality concerning age groups, with a 95% confidence interval (CI) used for statistical analysis. Age-adjusted mortality rates (AAMRs) were calculated using the direct method, applying age-specific mortality rates to the 2000 US standard population distribution. This adjustment enabled equitable comparisons across populations and periods.
AAMRs were analyzed overall and stratified by demographic factors (sex, race/ethnicity), geographic regions (Northeast, Midwest, South, and West), and urban-rural categories. Trends in AAMRs were assessed using Joinpoint regression analysis (version 5.0.2, developed by the Statistical Research and Applications Branch of the National Cancer Institute). This software was employed to compute Annual Percentage Changes (APCs) in AAMR, along with 95% CIs. This methodology enabled the identification of temporal variations in AAMR by fitting log-linear regression models.
Joinpoint models begin with the simplest structure allowed by the data and progressively add join points up to a user-specified maximum. The APCs were categorized as either increasing or decreasing if the slope representing the mortality change significantly deviated from zero, as determined by two-tailed t-testing. Statistical significance was defined as a P value of < 0.05.
Results
Overall
Between 1999 and 2020, a total of 13,880,876 cancer-related deaths occurred among individuals aged 25 and older in the US. Of these recorded fatalities, 567,657 (4.09%) were associated with cancer and HF. The AAMR Cancer-related deaths decreased from 343.7 to 252.4 per 100,000 from 1999 to 2020. AAMR experienced a constant decline from 1999 to 2018 (APC −1.61, 95% CI −1.70 to −1.57), which gradually decreased in steepness from 2018 to 2020 (APC −0.62, 95% CI −1.52 to −0.21). Comparatively, AAMR for mortality associated with cancer and HF decreased from 15.0 to 13.1. The AAMR saw a steep decline from 1999 to 2005 (APC −2.19, 95% CI −2.76 to −1.46), which became steeper in the following years 2005 to 2008 (APC −4.56, 95% CI −5.32 to −1.99); however, it became more gradual from 2008 to 2013 (APC −2.34, 95% CI −3.72 to −0.15), reaching the lowest AAMR (10.2). From 2013 to 2017 (APC 1.97, 95% CI −0.42 to 3.68), it began to increase, achieving its steepest slope from 2017 to 2020 (APC 6.03, 95% CI 4.69 to 8.20). During the same period, cancer-related mortality without HF experienced a more substantial decline (AAMR reduction of 27.2%) compared to cancer with HF-related mortality (AAMR reduction of 12.7%) (Figure 1A, 1B).
(A) Overall cancer-related AAMRs per 100,000 in the United States, 1999 to 2020. (B) Percentage Drop of Age-Adjusted Mortality Rate (1999-2020) in Cancer with and without HF
Sex Differences
Cancer-related deaths occurred in 7,314,564 (52.7%) men and 6,566,312 (47.3%) women. Within these mortalities, HF and cancer were attributed to 311,742 (4.57% of 7,314,564 and 54.9% of 567,657) men and 255,915 (4.23% of 6,566,312 and 45.1% of 567,657) women. Cancer-related and cancer and HF-related mortality were higher in males than in females. For cancer mortality, AAMRs in females decreased from 282.1 to 214.2 between 1999 and 2020, with a single dominant period of decline from 2001 to 2018 (APC −1.48, 95% CI −1.93 to −1.45). Similarly, the change in cancer- and HF-related mortality went from 11.5 to 9.6 from 1999-2020, with the graph in agreement the overall trend-steepest decline from 2005 to 2008 (APC −5.24, 95% CI −6.11 to −1.61) and steepest increase from 2017 to 2020 (APC 5.83, 95% CI 4.19 to 8.31). On the other hand, cancer-related mortality AAMRs in males dropped from 440.2 to 304.0 following a similar overall trend of decrease—1999 to 2020 (AAPC −1.78, 95% CI −1.85 to −1.73), while cancer- and HF-related mortality AAMR decreased from 21.2 to 18.1 with decline till 2013 and steepest increase from 2017 to 2020 (APC 6.03, 95% CI 4.66 to 8.04) (Figure 2A, 2B).
(A) Sex-stratified cancer-related AAMRs per 100,000 in the United States, 1999 to 2020. (B) Sex-stratified cancer with heart failure-related AAMRs per 100,000 in the United States, 1999 to 2020.
Racial and Ethnic Disparities
Cancer-related mortality stratified by race showed: 734,202 (5.3%) were Hispanic; 11,166,420 (80.4%) were White; 1,560,272 (11.2%) were Black; 326,585 (2.4%) were Asian or Pacific Islander; and 64,041 (0.46%) were American Indian or Alaska Native from 1999-2020. AAMRs for cancer-related mortality declined in all cohorts from 1999-2020. AAMRs exhibited a similar trend in all ethnic groups, except for the American Indian cohort, which showed an initial rise from 1999 to 2008 (APC 0.19, 95% CI −0.50 to 2.18) before decreasing. The Black group had the most significant decrease in AAMRs in all ethnic groups, with a decline from 437.0 to 294.4. The most tremendous AAMR change was also observed in the Black cohort from 1999 to 2018 (APC −2.06, 95% CI −2.13 to −2.01).
From 1999-2020, cancer- and HF-related mortality stratified by race shows: 21,909 (3.0% of 734,202) were Hispanic; 479,227 From 1999-2020, cancer- and HF-related mortality stratified by race shows: 21,909 (3.0% of 734,202) were Hispanic; 479,227 (4.3% of 11,166,420) were White; 54,311 (3.5% of 1,560,272) were Black; 8,732 (2.7% of 326,585) were Asian or Pacific Islander; and 2,463 (3.8% of 64,401) were American Indian or Alaska Native. AAMRs decreased in all ethnic groups. The trend followed was generally the same, with a decline until 2013-2014 and then a statistically significant increase. The most remarkable AAMR surge was observed in the Black cohort from 2017 to 2020 (APC 7.59, 95% CI 5.64-11.05) (Figures 3A, 3B, 3C).
(A) Cancer-related Age-adjusted mortality rate per 100,000 deaths for each race (Hispanics, American Indians, Whites, Asians, and Blacks) in the United States, 1999 to 2020. (B) Cancer with heart failure related Age-adjusted mortality rate per 100,000 deaths for each race (Hispanics, American Indians, Whites, Asians, and Blacks) in the United States, 1999 to 2020. (C) Overall cancer with heart failure related AAMRs per 100,000 in the United States, 1999 to 2020.
Geographical Differences
Between 1999 and 2020, there were 2,699,771 (19.5%) cancer-related deaths that occurred in the Northeast Census Region; 3,257,803 (23.5%) cancer-related deaths in the Midwest; 5,179,683 (37.3%) cancer-related deaths in the South; and 2,743,619 (19.8%) cancer-related deaths in the West. AAMRs followed the overall trend and declined in all regions, specifically the South (from 347.4 to 258.2 from 1999 to 2020), Northeast (from 349.6 to 245.1 from 1999 to 2020), West (from 320.7 to 232.1 from 1999 to 2020), and Midwest (from 352.6 to 269.5 from 1999 to 2020).
Cancer and HF-related deaths accounted for: 107,018 (4.0% of 2,699,771) in the Northeast Census Region; 146,169 (4.5% of 3,257,803) deaths in the Midwest; 194,278 (3.8% of 5,179,683) deaths in the South; and 120,192 (4.4% of 2,743,619) deaths in the West. The overall trend did showcase a decline in the AAMR from 1999 to 2020; however, in concordance with other variables, the AAMR started increasing in the 2010s. The Midwest had the highest AAMR, even after a decline from 17.1 to 15.1 from 1999 to 2020 (with the lowest value in 2013 at 10.8) (Figures 4a and 4b).
(A) Cancer-related AAMRs per 100,000 Stratified by Regions in the United States, 1999 to 2020. (B) Cancer with heart failure related AAMRs per 100,000 Stratified by Regions in the United States, 1999 to 2020.
Urban-Rural Differences
AAMRs for cancer-related mortality in metropolitan areas and nonmetropolitan areas declined from 1999 to 2020; metropolitan mortality rates dropped from 342.6 to 245.8, and nonmetropolitan mortality rates from 349.5 to 287.6. AAMRs for cancer- and HF-related mortality showed a similar trend in both areas, with the metropolitan rate decreasing from 14.2 to 12.3 (lowest value in 2013-14 – 9.7), while the nonmetropolitan rates decreased from 18.6 to 16.8 (lowest value in 2012-13 – 12.5).
Comparative Regional differences in cancer-related and cancer HF-related mortality were observed, with states in the upper 90th percentile having a significantly higher mortality burden compared to those in the bottom 10th percentile. The top five states by percentile of the AAMRs for both rates show only Mississippi and Oklahoma overlapped. On the other hand, the bottom five states had Hawaii and New Mexico as the states that appeared in both, reflecting that cancer and HF-related mortality is not necessarily high/low in areas with high/low cancer mortality rates. (Mortality adjusted to age, sex, and region is further explained in the Supplementary Data file: Supplemental Figures 1, 2, 3, and supplemental Tables 1A, 1B, 2, 3A, 3B, 4-8, 9A, and 9B.)
Discussion
In this longitudinal retrospective examination spanning two decades analyzing mortality data sourced from the Centers for Disease Control and Prevention, we report several key findings on mortality trends and disparities in cancer-related and cancer with HF-related deaths in the US. Data reveal key findings, including the overall decline in cancer-related mortality, contrasting with the increasing mortality trends for cancer with HF in recent years. These findings underscore the evolving burden of these conditions and highlight disparities across demographic, geographic, and socioeconomic contexts.
The steady decline in cancer-related mortality rates from 1999 to 2020 reflects advancements in cancer management, including early detection through screening programs, improved diagnostic technologies, and the development of targeted and immune-based therapies.8-10 Improved screening programs have facilitated the early identification of cancer, enabling timely intervention and a better prognosis.9 Furthermore, advances in targeted therapies and immune-based treatments have revolutionized cancer therapy, resulting in improved outcomes and decreased mortality rates.10 These interventions have enhanced patient survival and reduced mortality across most demographic groups.
However, the rising mortality rates for cancer with HF since 2013, particularly during 2017–2020, indicate an urgent need to address this growing challenge. The recent rise in mortality rates linked to cancer and HF necessitates thorough examination due to various potential factors, such as shifts in population characteristics, changes in the prevalence of diseases, and disparities in healthcare access.11 The increasing prevalence of comorbid conditions such as diabetes, obesity, and hypertension, combined with an aging population, likely contribute to this trend.12 Moreover, advancements in cancer therapies, while effective as evidenced by a decrease in cancer-related mortality, may introduce cardiotoxicity, further complicating management for cancer patients.4 Structural changes because of chemotherapeutic agents like anthracyclines and alkylating agents can cause dose-dependent HF, with significant left ventricular dysfunction reported in up to 7%–26% of patients.13-15 Similarly, targeted molecular therapies including HER2, VEGF pathway, and Bcr-Abl inhibitors are associated with increased HF incidence.16,17 These specific protein kinase inhibitors target kinases often expressed in both cancer and normal cell types, leading to unintended effects on cardiac cells.18,19 Additionally, immune checkpoint inhibitors (ICIs) have become a mainstay in cancer therapeutics since the mid-2010s and have been linked to adverse cardiovascular events including myocarditis and HF, with some studies reporting left ventricular dysfunction in up to 49%–79% of affected patients exhibiting LV dysfunction.7,20,21 These patterns suggest treatment-related cardiotoxicity may be a key contributing factor to the increase in cancer-related HF mortality. Early detection of HF in cancer patients, enabled by modern technology, may also contribute to higher reporting of HF-related deaths.
Similarly, gender demonstrates minor variations in mortality trends. Although both men and women experienced decreases in cancer-related death rates over time, males consistently exhibited higher rates than females.22 Additionally, the observed patterns were comparable when analyzing changes in cancer-related death rates within the general population.23 Interestingly, a similar trend was noted regarding mortality related to HF. It is essential to examine gender-specific factors that influence cancer outcomes as well as explore disparities based on sex. Biological differences, such as hormone levels or genetic predispositions, may contribute to variations in the incidence and death rates between males and females.24 Furthermore, socioeconomic variables also play a significant role in influencing an individual’s healthcare-seeking behaviors and their ability to receive preventive treatments, which may impact differing mortality outcomes.25 Notably, inequities in access to high-quality medical services in remote areas may worsen outcomes for individuals with complex medical conditions such as cancer and HF, leading to an increase in mortality numbers.26
Clear disparities in mortality rates exist among various racial groups, with different trends observed for specific ethnicities. While cancer-related death rates have decreased across all ethnic groups, the Black population has seen the most significant decline.27 Nevertheless, discrepancies persist in death rates linked to cancer and HF, with certain racial groups displaying conflicting patterns.28 Notably, the American Indian or Alaska Native group stands out, as they have witnessed a recent upsurge in death rates. The presence of unequal death rates highlights systemic disparities in healthcare access, quality, and results among different racial groups. Marginalized populations are disproportionately affected by structural factors such as poverty, racism, and insufficient access to healthcare services that contribute to divergent cancer outcomes. Effectively addressing these inequalities requires a comprehensive approach that considers the social determinants influencing health outcomes and implements targeted interventions aimed at promoting fairness in healthcare.29
Geographical patterns indicate variations in mortality rates across different census regions.30 Although the incidence of cancer-related deaths declined uniformly, the Midwest consistently exhibited the highest rates even after this decrease. Similarly, mortality rates associated with HF followed a similar pattern, with higher rates persistently seen in the Midwest compared to other areas.31 These disparities could be due to differences in healthcare infrastructure, resource allocation, and population demographics. Rural areas, which have limited access to healthcare facilities and specialized services, may encounter challenges in effectively managing complex medical conditions such as cancer and HF.32 Policy measures addressing healthcare accessibility and staff shortages in underserved regions are essential for mitigating these disparities in death rates. Analyzing cancer-related death rates in urban and rural areas reveals similar declining trends over time; however, when considering both cancer- and HF-related death rates together, urban settings demonstrate lower mortality rates compared to nonmetropolitan areas.33 The comparison of states based on percentiles shows how mortality from cancer and HF is related. States with high cancer-related death rates may not always have correspondingly high rates of deaths from cancer and HF, indicating the factors influencing mortality for each condition may differ.11
In summary, despite significant progress in reducing cancer-related deaths over the past 20 years, the current increase in mortality rates for cancer and HF requires further investigation. Understanding the underlying factors contributing to these patterns within specific demographic, ethnic, and geographical contexts is crucial for directing focused efforts toward decreasing death rates and addressing inequalities in cancer treatment.34 Analyzing combined patterns of cancer-related death rates with those from cancer and HF emphasizes the need for a comprehensive strategy to improve outcomes. Closing gaps in healthcare access, promoting early diagnosis and prevention initiatives, as well as advancing innovative treatments are essential steps to reduce death rates among patients with both conditions. Progress also depends on collaborative efforts among healthcare, public health, and policy-making sectors.35
Limitations
The study encountered several limitations that require attention. Firstly, it relied on the CDC WONDER database for primary data, which records death certificates but may have inaccuracies or omissions. Secondly, the study focused solely on individuals aged 25 and above, potentially overlooking variations in younger age groups. Interpretation of trends may have been influenced by unaccounted factors, introducing biases in the conclusions. Thirdly, the use of ICD-10 codes may have also caused misclassification bias. Moreover, the lack of clinical data, such as specific biomarkers, treatment methods, lab results, or therapeutic approaches, made it challenging to comprehend the increase in fatalities. The absence of detailed subgroup analyses for varying occurrences of renal complications of diabetes resulted in a knowledge gap, hindering the identification of underlying causes for the rise in death rates. Lastly, the study did not consider socioeconomic factors, which significantly influence health outcomes, and failed to provide information on medical treatments.
Conclusions
Mortality related to cancer continues to decline, whereas mortality associated with cancer with heart failure has increased since 2013 after an initial decrease. The highest age-adjusted mortality rates for cancer-related deaths were observed among the NH White population and men, as well as individuals residing in the Southern and metropolitan areas of the US. Conversely, fatalities from cancer combined with HF were most prevalent in the NH White population, men, and those living in the Midwest and nonmetropolitan regions. These results highlight the need for integrating cardio-oncology approaches into cancer care to mitigate the long-term cardiovascular risks in cancer survivors, especially within vulnerable populations.
- Received March 14, 2025.
- Revision received July 2, 2025.
- Accepted August 12, 2025.
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