Abstract
Background/Aims
Advances in gastric cancer treatment have improved survival rates, which has led to a growing interest in the risk of non-cancer-related conditions, particularly cardiovascular diseases. This study aimed to investigate the risk of heart failure in patients with gastric cancer according to their initial cancer stage.
Methods
We conducted a nationwide, population-based, retrospective cohort study using the Cancer Public Library Database of Korea. Patients diagnosed with gastric cancer between 2012 and 2019 were enrolled and followed until the end of 2020. Heart failure development was defined as a new diagnosis of heart failure that required hospitalization. Based on the Surveillance, Epidemiology, and End Results Program staging for gastric cancer, patients were classified into three groups localized, regional, and distant stages.
Results
Of the 202,347 patients in the study, 16,004 (7.9%) developed heart failure during a median follow-up period of 3.6 years. The cumulative incidence of heart failure significantly increased with worsening gastric cancer stage (log-rank, p<0.001). After adjusting for age, sex, diabetes status, hypertension status, dyslipidemia status, income, residential area, and initial treatment modality, with the localized stage as the reference group, the hazard ratio for heart failure was 1.52 (95% confidence interval [CI], 1.46 to 1.58) for patients in the regional stage group and 2.87 (95% CI, 2.69 to 3.07) for those in the distant stage group.
Conclusions
In patients with gastric cancer, the risk of heart failure requiring hospitalization increased with worsening cancer stage. Even in young patients and those without metabolic risk factors, close monitoring for heart failure development following cancer treatment is essential.
Keywords: Gastric cancer, Heart failure, SEER Program, Epidemiology, Risk factors
INTRODUCTION
Malignancy and heart failure are the leading causes of death worldwide.1-3 Although both diseases were previously considered independent and unrelated, recent studies suggest that each condition raises the risk of the other.4,5 Notably, a previous prospective cohort study reported that patients with cancer have a 52% higher risk of developing heart failure compared to the general population.4 This increased risk can be attributed to shared risk factors, including age, hypertension, diabetes, dyslipidemia, and lifestyle factors.6,7 Furthermore, recent studies have identified several pathogenic processes that are common to both heart failure and cancer, including inflammation, cellular proliferation, and neurohormonal stress.8,9 Additionally, several anticancer therapies have cardiotoxic effects that can induce heart failure in cancer patients after prolonged exposure.10,11 As cardiovascular disease is a significant cause of non-cancer-related death among patients with malignancies,12 effective management of these risk factors has become increasingly important, especially in cancers with high survival rates.
Gastric cancer remains a substantial health concern, ranking as the fifth most common malignancy and cause of cancer-related deaths globally.3 However, endoscopic screening for malignancy and advances in endoscopic treatments, surgery, and chemotherapy have significantly improved the survival rates of patients with gastric cancer.13,14 In Korea, the overall 5-year survival rate for gastric cancer has increased from 55.7% to 77.0% over the past 20 years, with approximately 340,000 prevalent cases reported by 2021.14,15 With the growing number of long-term gastric cancer survivors, concerns regarding the risk of other significant diseases are also increasing. Although several studies have investigated the risk of cardiovascular disease in gastric cancer patients,16,17 evidence regarding this risk according to cancer stage is limited.
Our study aimed to investigate the risk of heart failure in gastric cancer patients based on cancer stage using a nationwide cohort from Korea’s cancer registry database.
MATERIALS AND METHODS
1. Data source
We performed a retrospective cohort study using claims data from Korea-Clinical Data Utilization Network for Research Excellence (K-CURE) Cancer Public Library Database (CPLD), which was established by the National Cancer Data Center as part of the K-CURE project organized by the Ministry of Health and Welfare.18 This database comprises the entire patient population newly diagnosed with cancer between 2012 and 2019. The CPLD encodes diagnoses using the International Classification of Diseases, 10th Revision (ICD-10), and International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). It also provides information such as demographics, hospitalizations, treatments, procedures, and prescription drugs. For malignant cases, staging is based on the Surveillance, Epidemiology, and End Results (SEER) Program summary staging system. Mortality status and cause of death were collected from death certificates.18 The CPLD committee approved the use of information from the database. This study was approved by the Institutional Review Board of Seoul National University Hospital (IRB number: 2411-078-1587), which waived the requirement for written informed consent.
2. SEER summary stage
The SEER summary stage is a widely used cancer staging system, particularly in population-based cohort studies, that categorizes tumor extent at diagnosis into three stages: localized, regional, and distant.19,20 The localized stage refers to cancer confined to the organ of origin, the regional stage indicates spread to nearby lymph nodes or adjacent tissues, and the distant stage involves metastasis to distant organs. SEER staging is determined based on laboratory tests, imaging studies, pathology reports, and surgical findings performed within 4 months of diagnosis, provided there has been no disease progression.14
3. Study design and population
An overview of the population selection process is presented in Fig. 1. We included all Korean men and women diagnosed with gastric cancer between 2012 and 2019 from the CPLD (n=235,167). Gastric cancer was identified based on the presence of the ICD-O-3 code C16. Among these patients, those aged ≥30 were selected at the time of diagnosis (n=234,494). Individuals with insufficient SEER staging information or missing data were excluded. Additionally, patients with heart failure as a baseline comorbidity, identified by the ICD-10 code I50, were excluded to ensure that any heart failure events occurring during the study period represented de novo cases. As a result, 202,347 subjects were included and followed up. Finally, the study population was categorized into localized, regional, and distant groups based on SEER staging to compare heart failure risk by cancer stage. The index date was defined as the date when gastric cancer was registered in the CPLD.
Fig. 1.
Flowchart of study population selection. SEER, Surveillance, Epidemiology, and End Results.
4. Study outcome
Heart failure development was defined as a new diagnosis of heart failure, identified by the ICD-10 code I50 and requiring hospitalization. This definition is based on previous studies to avoid overestimation of diagnosis.21 The final follow-up date was December 31, 2020. The study population was followed up from the index date until the development of heart failure, death, or the end of the follow-up period.
5. Other variables
Age, sex, comorbidities, income, residential area, and initial treatment modality were included as additional variables of interest. Baseline comorbidities included diabetes, hypertension, and dyslipidemia, identified using the ICD-10 codes E11-E14, I10-13 and I15, and E78, respectively, along with prescriptions for the corresponding medications within the year of cancer diagnosis. Information on income status was collected from the insurance eligibility database and classified into three groups based on percentiles: (1) medical aid & <30th, (2) 30th to <90th, and (3) ≥90th percentiles. Residential areas were categorized as metropolitan or other. The metropolitan areas included Seoul and six other metropolitan cities with populations exceeding 1,000,000 people. The initial treatment modalities were performed within 4 months of cancer diagnosis and classified as operation (including both endoscopic and surgical treatments), chemotherapy, radiation therapy, and immunotherapy. Multiple treatments were accounted for by counting each treatment modality. For example, localized-stage patients who received surgery followed by adjuvant chemotherapy, or distant-stage patients who initially underwent surgery and were subsequently classified as distant stage requiring chemotherapy, were both counted for the treatments they received. This approach allowed for the adjustment of the impact of multiple treatments on patient survival, despite overlapping counts. Among chemotherapy, prescriptions of 5-fluorouracil, oxaliplatin, and trastuzumab were additionally identified to investigate the effect of cardiotoxic chemotherapy.
For an additional analysis, we investigated cardiac comorbidities, including atrial fibrillation, valvular heart disease, and ischemic heart disease, identified using the ICD-10 codes I48, I05 and Z95, and I20–I25, respectively. In a subset of patients with available health screening data, lifestyle factors including smoking, alcohol consumption, and body mass index were also incorporated. Smoking status was categorized into three groups: never smokers, ex-smokers, and current smokers. Alcohol consumption was classified into three groups: non-drinkers (0 g/day), mild to moderate drinkers (male: <30 g/day, female: <20 g/day), and heavy drinkers (male: ≥30 g/day, female: ≥20 g/day). Body mass index was treated as a continuous variable and included in the adjustment.
6. Statistical analysis
Data were expressed as numbers and frequencies for categorical variables and means±standard deviations for continuous variables. Chi-square tests and analysis of variance were used for group comparisons. Heart failure incidence was reported as events per 1,000 person-years, with cumulative incidence calculated using the Kaplan-Meier method and log-rank tests for differences based on SEER stage.
Cox proportional hazards models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the association between cancer stage and heart failure risk. Multivariate models were used to adjust for potential effect modifications by other variables: (1) Model 1, unadjusted; (2) Model 2, adjusted for sex and age; (3) Model 3, adjusted for sex, age, income, and residential area; (4) Model 4, adjusted for sex, age, income, residential area, and comorbidities; and (5) Model 5, adjusted for sex, age, income, residential area, comorbidities, and initial treatment modalities.
Subgroup analyses were performed after stratifying the patients according to age, sex, comorbidities, prescriptions of 5-fluorouracil or oxaliplatin, income, residential area and year of cancer diagnosis. Age was categorized as ≥65 years or <65 years, income as ≥30th percentile or <30th percentile, and the year of cancer diagnosis was grouped into 2-year intervals.
Two-sided p-values <0.05 were considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R software 4.4.1 for Windows (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
1. Baseline characteristics
Among a total of 202,347 patients in the study population, the mean age at baseline was 63.12±11.89 years, and 137,671 patients (68.0%) were male (Table 1). The SEER stages were classified as follows: 136,132 patients (67.3%) had a localized stage, 43,462 (21.5%) had a regional stage, and 22,753 (11.2%) had a distant stage. Patients with localized-stage gastric cancer were younger and more likely to be male than those with regional or distant stages. In addition, patients with localized-stage disease were less likely to have diabetes at baseline but more likely to have hypertension and dyslipidemia than patients with advanced disease. The median follow-up duration was 3.6 years, and 16,004 patients (7.9%) developed heart failure during the study period.
Table 1.
Baseline Characteristics of the Study Population
| Variable | Total (n=202,347) | SEER stage | p-value | ||
|---|---|---|---|---|---|
| Localized (n=136,132) | Regional (n=43,462) | Distant (n=22,753) | |||
| Age, mean±SD, yr | 63.12±11.89 | 62.9±11.43 | 63.71±12.51 | 63.33±13.26 | <0.001 |
| Sex, No. (%) | <0.001 | ||||
| Male | 137,671 (68.0) | 92,998 (68.3) | 29,280 (67.4) | 15,393 (67.6) | |
| Female | 64,676 (32.0) | 43,134 (31.7) | 14,182 (32.6) | 7,360 (32.3) | |
| Comorbidities, No. (%) | |||||
| Diabetes | 40,347 (20.0) | 26,831 (19.7) | 8,919 (20.5) | 4,597 (20.2) | <0.001 |
| Hypertension | 87,809 (43.4) | 59,569 (43.8) | 18,845 (43.4) | 9,395 (41.3) | <0.001 |
| Dyslipidemia | 52,013 (25.7) | 38,085 (28.0) | 9,669 (22.2) | 4,259 (18.7) | <0.001 |
| Income status, No. (%) | <0.001 | ||||
| Medical aid & <30th | 38,851 (19.2) | 24,801 (18.2) | 9,076 (20.9) | 4,974 (21.9) | |
| 30th to <90th | 101,861 (50.3) | 67,682 (49.7) | 22,420 (51.6) | 11,759 (51.7) | |
| ≥90th | 61,635 (30.5) | 43,649 (32.1) | 11,966 (27.5) | 6,020 (26.5) | |
| Residential area, metropolitan, No. (%) | 87,625 (43.3) | 59,315 (43.6) | 18,549 (42.7) | 9,761 (42.9) | 0.002 |
| Initial treatment modality, No. (%) | <0.001 | ||||
| Operation* | 167,939 (83.0) | 125,296 (92.0) | 37,198 (85.6) | 5,445 (23.9) | |
| Chemotherapy | 41,085 (20.3) | 6,790 (5.0) | 19,690 (45.3) | 14,605 (64.2) | |
| Radiotherapy | 1,570 (0.8) | 168 (0.1) | 585 (1.3) | 817 (3.6) | |
| Immunotherapy | 200 (0.1) | 66 (0.05) | 43 (0.1) | 91 (0.4) | |
| Year of diagnosis, No. (%) | <0.001 | ||||
| 2012–2013 | 53,129 (26.3) | 34,482 (25.3) | 12,478 (28.7) | 6,169 (27.1) | |
| 2014–2015 | 51,214 (25.3) | 34,080 (25.0) | 11,239 (25.9) | 5,895 (25.9) | |
| 2016–2017 | 50,936 (25.2) | 34,959 (25.7) | 10,360 (23.8) | 5,617 (24.7) | |
| 2018–2019 | 47,068 (23.3) | 32,611 (24.0) | 9,385 (21.6) | 5,072 (22.3) | |
| Heart failure development, No. (%) | 16,004 (7.9) | 9,957 (7.3) | 4,015 (9.2) | 2,032 (8.9) | <0.001 |
| Follow-up duration, median (IQR), yr | 3.62 (1.63–6.06) | 4.38 (2.47–6.52) | 2.94 (1.32–5.50) | 0.69 (0.27–1.37) | <0.001 |
SEER, Surveillance, Epidemiology, and End Results; IQR, interquartile range.
2. Risk of developing heart failure according to SEER stage in gastric cancer
The cumulative incidence of heart failure in the study population, according to the SEER stage of gastric cancer, is presented in Fig. 2. The incidence of heart failure increased significantly with the advancing SEER stage (log-rank test, p<0.001).
Fig. 2.
Cumulative incidence of heart failure in gastric cancer patients according to SEER stage. SEER, Surveillance, Epidemiology, and End Results.
Heart failure incidence rates (per 1,000 person-years) were 16.23 for the localized stage, 26.31 for the regional stage, and 80.01 for the distant stage, respectively (Table 2). In both the univariate and multivariate Cox proportional hazards models, the HR for heart failure increased progressively with the advancing cancer stage. In the unadjusted model, the HR for heart failure was 1.59 (95% CI, 1.53 to 1.64) for the regional stage and 3.98 (95% CI, 3.79 to 4.18) for the distant stage, compared to the localized stage. After adjusting for age, sex, income, residential area, comorbidities, and treatments, the HR for heart failure was 1.52 (95% CI, 1.46 to 1.58) for the regional stage and 2.87 (95% CI, 2.69 to 3.07) for the distant stage, compared to the localized stage. The results remained consistent across all other adjusted models.
Table 2.
Risk of Developing Heart Failure in Gastric Cancer Patients According to SEER Stage
| SEER stage |
No. | No. of events |
Duration, person-years | IR, 1,000 person-years | HR (95% CI) | ||||
|---|---|---|---|---|---|---|---|---|---|
| Model 1 | Model 2 | Model 3 | Model 4 | Model 5 | |||||
| Localized | 136,132 | 9,957 | 613,641.15 | 16.23 | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) | 1 (reference) |
| Regional | 43,462 | 4,015 | 152,585.89 | 26.31 | 1.59 (1.53–1.65) | 1.60 (1.54–1.66) | 1.59 (1.53–1.65) | 1.61 (1.56–1.67) | 1.52 (1.46–1.58) |
| Distant | 22,753 | 2,032 | 25,395.89 | 80.01 | 3.98 (3.79–4.18) | 4.17 (3.97–4.39) | 4.13 (3.93–4.35) | 4.24 (4.03–4.46) | 2.87 (2.69–3.07) |
SEER, Surveillance, Epidemiology, and End Results; IR, incidence rate; HR, hazard ratio; CI, confidence interval; Model 1, unadjusted; Model 2, adjusted for age and sex; Model 3, adjusted for age, sex, income and residential area; Model 4, adjusted for age, sex, income, residential area, diabetes, hypertension, and dyslipidemia; Model 5, adjusted for age, sex, income, residential area, diabetes, hypertension, dyslipidemia, and initial treatment modality.
Among patients who did not receive any treatment within 4 months after diagnosis, 9,347 patients in the localized stage had a heart failure incidence rate of 32.8, 4,167 patients in the regional stage had a rate of 63.9, and 5,810 patients in the distant stage had a rate of 113.2.
3. Subgroup analyses
After stratifying by age, sex, and comorbidities, all subgroups demonstrated an increased HR for heart failure with advancing gastric cancer stage, even after adjusting for age, sex, income, residential area, and initial treatment modality (Table 3). The interaction between heart failure risk and SEER stage was more pronounced in patients aged <65 years (HR: 1.79 vs 1.44 and 5.16 vs 2.04, p<0.001), female patients (HR: 1.49 vs 1.53 and 3.48 vs 2.64, p<0.001), and those without diabetes (HR: 1.57 vs 1.40 and 3.16 vs 2.21, p<0.001), hypertension (HR: 1.61 vs 1.47 and 3.75 vs 2.30, p<0.001), and dyslipidemia (HR: 1.52 vs 1.52 and 3.12 vs 2.28, p<0.001). This suggests an association between SEER stage and heart failure, independent of previously known predisposing factors for heart failure.
Table 3.
Risk of Developing Heart Failure According to the SEER Stage of Gastric Cancer Stratified by Age, Sex, and Comorbidities
| Subgroup | SEER stage | No. | No. of events |
Duration, person-years |
IR, 1,000 person-years |
HR (95% CI)* | p-value for interaction |
|---|---|---|---|---|---|---|---|
| Age | <0.001 | ||||||
| 30–64 yr | Localized | 73,296 | 2,958 | 350,773.25 | 8.43 | 1 (reference) | |
| Regional | 21,936 | 1,336 | 88,665.17 | 15.07 | 1.79 (1.67–1.91) | ||
| Distant | 11,877 | 1,039 | 15,775.87 | 65.86 | 5.16 (4.73–5.62) | ||
| ≥65 yr | Localized | 62,836 | 6,999 | 262,867.90 | 26.63 | 1 (reference) | |
| Regional | 21,526 | 2,679 | 63,920.72 | 41.91 | 1.44 (1.38–1.51) | ||
| Distant | 10,876 | 993 | 9,620.02 | 103.22 | 2.04 (1.89–2.21) | ||
| Sex | <0.001 | ||||||
| Male | Localized | 92,998 | 7,176 | 417,249.44 | 17.20 | 1 (reference) | |
| Regional | 29,280 | 2,870 | 101,890.67 | 28.17 | 1.53 (1.46–1.61) | ||
| Distant | 15,393 | 1,375 | 17,229.48 | 79.81 | 2.64 (2.45–2.84) | ||
| Female | Localized | 43,134 | 2,781 | 196,391.71 | 14.16 | 1 (reference) | |
| Regional | 14,182 | 1,145 | 50,695.23 | 22.59 | 1.49 (1.39–1.60) | ||
| Distant | 7,360 | 657 | 8,166.41 | 80.45 | 3.48 (3.17–3.82) | ||
| Diabetes | <0.001 | ||||||
| Present | Localized | 26,831 | 2,958 | 111,795.01 | 26.46 | 1 (reference) | |
| Regional | 8,919 | 1,112 | 27,624.16 | 40.26 | 1.40 (1.30–1.50) | ||
| Distant | 4,597 | 475 | 4,558.16 | 104.21 | 2.21 (1.99–2.46) | ||
| Absent | Localized | 109,301 | 6,999 | 501,846.14 | 13.95 | 1 (reference) | |
| Regional | 34,543 | 2,903 | 124,961.73 | 23.23 | 1.57 (1.50–1.65) | ||
| Distant | 18,156 | 1,557 | 20,837.74 | 74.72 | 3.16 (2.95–3.40) | ||
| Hypertension | <0.001 | ||||||
| Present | Localized | 59,569 | 6,191 | 257,267.55 | 24.06 | 1 (reference) | |
| Regional | 18,845 | 2,355 | 60,721.80 | 38.78 | 1.47 (1.40–1.55) | ||
| Distant | 9,395 | 958 | 9,447.19 | 101.41 | 2.30 (2.13–2.50) | ||
| Absent | Localized | 76,563 | 3,766 | 356,373.60 | 10.57 | 1 (reference) | |
| Regional | 24,617 | 1,660 | 91,864.09 | 18.07 | 1.61 (1.51–1.71) | ||
| Distant | 13,358 | 1,074 | 15,948.71 | 67.34 | 3.75 (3.46–4.07) | ||
| Dyslipidemia | <0.001 | ||||||
| Present | Localized | 38,085 | 3,631 | 157,680.04 | 23.03 | 1 (reference) | |
| Regional | 9,669 | 1,231 | 30,719.23 | 40.07 | 1.52 (1.42–1.63) | ||
| Distant | 4,259 | 461 | 4,584.16 | 100.56 | 2.28 (2.0 –2.53) | ||
| Absent | Localized | 98,047 | 6,326 | 455,961.11 | 13.87 | 1 (reference) | |
| Regional | 33,793 | 2,784 | 121,866.67 | 22.85 | 1.52 (1.45–1.60) | ||
| Distant | 18,494 | 1,571 | 20,811.73 | 75.49 | 3.12 (2.91–3.35) |
SEER, Surveillance, Epidemiology, and End Results; IR, incidence rate; HR, hazard ratio; CI, confidence interval.
*Adjusted for age, sex, income, residential area, diabetes, hypertension, dyslipidemia, and initial treatment modality.
Fig. 3 illustrates the HRs for developing heart failure based on age, sex, and comorbidities, stratified by SEER stage. This provides a detailed assessment of the impact of each factor using different references from those in Table 3. Interestingly, patients aged <65 years had a higher risk of heart failure compared to older patients in the distant stage, unlike those in other stages. Female sex was associated with a decreased risk of heart failure compared with male sex in the localized and regional stages. Diabetes, hypertension, and dyslipidemia were consistently linked to an increased risk of heart failure in the localized and regional stages. However, in the distant stages, patients with these conditions showed no significant differences from those without these comorbidities.
Fig. 3.
HRs for developing heart failure based on age, sex, and comorbidities, stratified by SEER stage of gastric cancer. All hazard ratios were calculated after adjustments for age, sex, income, residential area, diabetes, hypertension, dyslipidemia, and initial treatment modality. SEER, Surveillance, Epidemiology, and End Results; HR, hazard ratio; CI, confidence interval.
Heart failure risk significantly increased with SEER stage after stratifying by prescriptions of 5-fluorouracil or oxaliplatin and adjusting for other variables (Supplementary Table 1). When stratified by chemotherapy exposure within each SEER stage, the risk of heart failure increased stepwise with advancing stage among patients who did not receive chemotherapy. In contrast, for those treated with 5-fluorouracil or oxaliplatin, hazard ratios in the localized and regional stages were comparable, and a significant excess risk was observed in the distant stage. For trastuzumab, an elevated risk was already evident in the localized stage and remained similarly high in the regional and distant stages without significant differences across stages (Supplementary Table 2).
All subgroups stratified by income, residential area, and year of cancer diagnosis also showed an increased HR with advancing gastric cancer stage after adjustment (Supplementary Table 3). The association between heart failure risk and SEER stage was more prominent in patients with a more recent cancer diagnosis (p<0.001). However, income (p=0.209) and residential area (p=0.300) showed no significant interactions. In addition, low-income patients faced higher heart failure risks in localized and regional stages, while non-metropolitan residency and recent diagnoses were linked to increased risk across all stages (Supplementary Table 4).
4. Additional analyses
In the multivariable model adjusted for atrial fibrillation, valvular heart disease, and ischemic heart disease, as well as age, sex, hypertension, diabetes mellitus, dyslipidemia, income, residential area, and initial treatment, the risk of heart failure remained significantly higher in patients with advanced gastric cancer stages. Compared with the localized stage, the adjusted hazard ratios were 1.43 (95% CI, 1.38 to 1.50) for the regional stage and 2.86 (95% CI, 2.68 to 3.01) for the distant stage. In a separate analysis of 89,160 patients with available health screening data, the model was further adjusted for lifestyle factors including smoking status, alcohol consumption, and body mass index. The results consistently showed that the risk of heart failure remained significantly higher with advancing gastric cancer stage (Supplementary Table 5).
DISCUSSION
This large population-based cohort study demonstrated an increased risk of heart failure requiring hospitalization in patients with advanced-stage gastric cancer. We observed a significant stepwise increase in heart failure risk with the progression of gastric cancer stages, from localized to regional and distant. Acute decompensation of heart failure necessitating admission remains associated with poor clinical outcomes, including in-hospital mortality ranging from 4 to 6%, rehospitalization rates, and 1-year mortality ranging from 10% to 30%.22 Therefore, our findings highlight the need for meticulous management of risk factors and early detection of heart failure in patients with gastric cancer.
To the best of our knowledge, our study is the first to report the risk of heart failure in patients with gastric cancer according to cancer stage. The increased risk of heart failure observed in advanced cancer stages can be attributed to the cardiotoxicity of chemotherapy.23 Five-fluorouracil and oxaliplatin, which are widely used in both adjuvant and palliative chemotherapy for gastric cancer,24,25 have been reported to cause significant symptomatic cardiotoxicity in patients during treatment.26,27 The increase in the use of trastuzumab, a treatment for HER2-positive gastric cancer, may have contributed to the elevated risk of heart failure in recent years.28 The prominently increased risk of heart failure in younger (<65 years) patients with distant-stage gastric cancer can similarly be explained by their greater likelihood of receiving aggressive chemotherapy and surviving long enough for cardiotoxic effects to manifest.29,30 In addition, malnutrition and anemia, which are commonly observed in patients with advanced-stage gastric cancer due to poor oral intake and tumor bleeding, may further contribute to the aggravation of heart failure.31,32 Although these risk factors are well established in the development of heart failure, our findings highlight the importance of carefully managing these exacerbating factors and closely monitoring for heart failure in patients with advanced-stage gastric cancer. Additionally, the greater difference in heart failure risk observed in recent years may partly reflect the broader epidemiological shift of increasing heart failure hospitalizations,33,34 but it also underscores the continued importance of addressing this issue.
Several observational studies have suggested a decreased risk of cardiovascular disease in patients who underwent surgical treatment for gastric cancer compared with the general population.35,36 Weight loss and subsequent improvements in metabolic risk factors have been proposed as the main reasons for decreased risk.37 For instance, a nationwide cohort study reported improved glycemic control and a reduced prevalence of diabetes in patients who underwent radical gastrectomy.38 However, there are concerns that the beneficial effects of gastrectomy on glucose and lipid profiles can diminish over time,39,40 as symptoms impairing oral intake generally improve within 1 year after surgery.41 Additionally, another population-based study revealed that gastric cancer patients aged <40 years, who are expected to have long-term survival after surgery, have an increased risk of cardiovascular diseases, including heart failure, compared to non-cancer individuals.16 Therefore, the favorable effects on metabolic risk factors after gastrectomy may decrease, particularly in younger patients with longer expected survival times. This suggestion is supported by the pronounced association between heart failure risk and SEER stage observed among patients aged <65 years compared with older patients in our study. These findings underscore the importance of long-term management of heart failure risk factors in early-stage gastric cancer to support prolonged survival.
In summary, the underlying causes of heart failure likely differ by gastric cancer stage, requiring stage-specific management approaches. In early-stage patients, heart failure is linked to aging and preexisting comorbidities, while in advanced-stage patients, cardiotoxic agents, cancer progression, and overall poor clinical status are more prominent contributors. Consequently, long-term management of metabolic risk factors is critical for early-stage gastric cancer patients, while close monitoring and early detection are essential for advanced-stage patients exposed to a cardiotoxic environment.
The rising risk of heart failure with cancer progression, even after adjusting for other factors, highlights the impact of cancer on heart failure development. This link was particularly notable in patients without diabetes, hypertension, or dyslipidemia. This finding supports the hypothesis that there are common pathogenic mechanisms between cancer and heart failure, such as inflammation, oxidative stress, and neurohormonal activation, in addition to the traditional risk factors. Inflammation and oxidative stress are known drivers of cardiovascular diseases8 and have been reported to promote cancer initiation and progression.42 Regarding neurohormonal activation, previous studies have demonstrated that the use of renin-angiotensin system inhibitors is associated with improved overall survival in cancer patients,8 including those with advanced gastric cancer.43 Furthermore, a recent meta-analysis reported a significant correlation between using angiotensin receptor blockers and reduced gastric cancer progression.44 However, evidence on the association between gastric carcinogenesis and neurohormone activation remains limited. Future research on this topic may help elucidate the association between gastric cancer stage and heart failure risk.
In this study, male sex, diabetes, hypertension, dyslipidemia, low income, and non-metropolitan residency were associated with an increased risk of heart failure in patients with localized or regional stages, consistent with the findings of previous studies.17,3, However, in the distant stage, except for residential areas, heart failure risk did not significantly differ based on these risk factors. One possible explanation is that the factors above, including chemotherapy-induced cardiotoxicity, malnutrition, and anemia, play a more significant role at an advanced stage, in which overall survival is typically shorter, than that of traditional risk factors. Additionally, patients undergoing chemotherapy regularly visit hospitals for check-ups, enabling sooner detection and better management of modifiable risk factors of heart failure. This increased medical access may have attenuated the impact of preexisting risk factors on heart failure development. The importance of medical access is supported by the finding that non-metropolitan residency, which is linked to reduced healthcare accessibility, is associated with an increased risk of heart failure, even in the distant stage. In contrast, patients with localized or regional diseases usually receive curative treatments and are unlikely to undergo regular medical checkups after achieving a cure. Thus, in long-term survivors of early-stage gastric cancer, heart failure incidence related to metabolic risk factors increases over time. However, this explanation remains speculative due to limited study details.
This study has several limitations. First, this study has a retrospective design, may be subject to unmeasured confounding factors, and should be interpreted as showing associations rather than causal relationships. Adjustment for whether patients underwent screening endoscopy prior to gastric cancer diagnosis was not possible due to the limitations of the data. Differences in baseline screening behavior may have influenced both the stage at diagnosis and the subsequent risk of heart failure. Second, this study lacked information on the outcomes or complications of the treatments administered to patients, and we could not provide adjusted results based on subsequent treatments following the initial treatment modalities. In addition, detailed information on chemotherapy dosage and treatment duration was not available in the database, and therefore we were unable to account for their potential impact on heart failure risk. Third, the diagnosis of heart failure was identified using ICD codes, which could have led to an overestimation or underestimation of the actual incidence. Fourth, discrepancies between the SEER stage and the commonly used American Joint Committee on Cancer TNM staging system may have introduced misclassification bias, making it difficult to directly apply the findings of this study to the TNM system. Specifically, gastric cancer stages IB to IIB, according to the American Joint Committee on Cancer 8th edition, can be classified as either localized or regional according to the SEER staging.47 However, given the prominent differences in heart failure risks across the SEER stages, the overall trend is unlikely to be significantly affected by the TNM staging system. Finally, since our study was conducted in a Korean population, the generalizability of the results to Western populations is limited due to potential differences in the incidence of heart failure and risk factors. Nevertheless, this study underscores the importance of efforts to prevent the development of chronic diseases unrelated to cancer among long-term cancer survivors.
This population-based cohort study found that the risk of heart failure increases with the progression of gastric cancer. Effective management of metabolic risk factors is essential in early-stage gastric cancer to support prolonged survival. In advanced-stage gastric cancer, where cancer mortality is high, cardiovascular risks rise as well, emphasizing the need for close monitoring and early detection.
ACKNOWLEDGEMENTS
This research was supported by grants from the National Research Foundation of Korea (#NRF-RS-2025-00523468) and Seoul National University Hospital Research Fund (#03-2025-0140).
SUPPLEMENTARY MATERIALS
Supplementary materials can be accessed at https://doi.org/10.5009/gnl250209.
Footnotes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Study concept and design: S.L., Y.J.C., K.H., S.J.C. Data acquisition: K.H. Data analysis and interpretation: S.L., Y.J.C., K.H., S.J.C. Drafting of the manuscript: S.L., S.J.C. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: S.L., K.H. Approval of the final manuscript: all authors. S.J.C. and K.H. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
DATA AVAILABILITY STATEMENT
Data analyzed in this study are available from the corresponding author upon reasonable request.
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