Tumor histologic subtypes and stage impact the risk of cardiovascular diseases death in lung cancer patients after chemotherapy or radiotherapy: a population-based study

Abstract

Background

Traditional cardiovascular diseases (CVDs) risk factors have been the focus of previous research in lung cancer patients treated with chemotherapy (CT) or radiotherapy (RT). However, the role of tumor characteristics in CVD death risk remains unclear. Therefore, we explored this association in CT/RT-treated lung cancer patients.

Methods

The study enrolled CT/RT-treated lung cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database [2002–2017]. The CVD death risk was estimated using Fine-Gray competing risk model. To adjust for potential confounders, we conducted sensitivity analyses. Subgroup analyses and interaction tests were performed to assess the robustness of the findings. A nomogram was constructed to visually demonstrate the influence of tumor characteristics on CVD death risk.

Results

The study cohort comprised 59,726 patients, followed for an average of 36.7 months. Non-small cell lung cancer (NSCLC) [adjusted hazard ratio (HR) =1.652, 95% confidence interval (CI): 1.359 to 2.008, P<0.001], localized stage (adjusted HR =3.273, 95% CI: 2.924 to 3.663, P<0.001), and regional stage (adjusted HR =2.177, 95% CI: 1.939 to 2.443, P<0.001) were significantly associated with higher risk of CVD death in CT/RT-treated lung cancer patients. The associations remained consistent across subgroup analyses. The nomogram demonstrated moderate discrimination and good calibration. Significant differences were observed across risk groups (P<0.001).

Conclusions

NSCLC, localized and regional stages were associated with higher risk of CVD death in CT/RT-treated lung cancer patients. Targeted strategies for CVD management are needed for these patients.

Highlight box.

Key findings

• Non-small cell lung cancer (NSCLC), localized and regional stage were associated with higher risk of cardiovascular diseases (CVDs) death in lung cancer patients with chemotherapy (CT) or radiotherapy (RT).

What is known and what is new?

• Prior studies on CVD risk in lung cancer patients mainly focused on direct cardiotoxicity of anticancer treatments and shared risk factors, without considering the potential role of tumor characteristics.

• Our study comprehensively analyzed the association between tumor characteristics and the risk of CVD death among CT/RT-treated lung cancer patients.

What is the implication, and what should change now?

• Management strategies based on tumor characteristics may improve care quality and prognosis in CT/RT-treated lung cancer patients.

• The prognosis of lung cancer patients varies across histologic subtypes and tumor stages. Patients with NSCLC or those with localized or regional stage lung cancer should undergo regular monitoring of CVD risk and receive personalized treatment.

Introduction

Lung cancer is the leading cause of cancer death worldwide (1), accounting for about 1 in 5 of all cancer deaths (2). Early detection and technological advances in screening and treatment for lung cancer have improved cancer survival rates (3,4). However, cardiovascular diseases (CVDs) in lung cancer patients have become a significant problem (5).

Previous studies on CVD risk in lung cancer patients have predominantly centered on anticancer treatments like chemotherapy (CT) (6,7) and radiotherapy (RT) (7,8), as well as shared risk factors such as smoking, advanced age, and obesity (9,10). However, emerging evidence suggests that cancer itself may contribute to CVD through systemic biological mechanisms (11).

In lung cancer, cross-talk between tumor cells and inflammatory cells may induce the release of pro-inflammatory cytokines (12), which are linked to neutrophil activation (13). Neutrophils can amplify vascular inflammation and injury through interactions with endothelial cells, platelets, and other immune cells, as well as through the formation of neutrophil extracellular traps (NETs) (11). In addition, neutrophils and NETs have been implicated in multiple stages of atherosclerosis, including endothelial dysfunction, thrombosis, and plaque progression (11,14). These findings suggest that tumor-associated inflammation may represent a potential mechanistic link between cancer progression and CVD.

Such tumor-associated inflammatory processes may vary across tumor types and may be reflected in clinical tumor characteristics. Tumor size, grade, and stage have been shown to be associated with the risk of CVD death in CT/RT-treated breast cancer patients (15), while tumor laterality, primary site and histologic subtypes have been identified as risk factors for CVD death in non-small cell lung cancer (NSCLC) patients (16,17). However, whether tumor characteristics independently influence CVD death among CT/RT-treated lung cancer patients remains unclear.

Thus, we undertook a comprehensive analysis based on Surveillance, Epidemiology, and End Results (SEER), a large population-based database to explore the association between tumor characteristics and CVD death risk among CT/RT-treated lung cancer patients. Our study aims to provide scientific evidence to inform routine CVD risk surveillance and support personalized management in this population. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0294/rc).

Methods

Study population and design

We identified patients diagnosed with lung cancer who received CT or RT from the SEER database [2002–2017]. The inclusion criteria were: (I) histologically confirmed primary lung cancer; (II) patients with a single primary tumor; (III) receipt of CT or RT; (IV) diagnosed between 2002 and 2017; (V) active follow-up records. Exclusion criteria comprised: (I) unknown race, sex, marital status, region and income; (II) unknown tumor stage, grade, histologic subtypes and laterality; (III) unknown surgical status (Figure 1). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Since the SEER is a public database comprising anonymized and de-identified data, neither Institutional Review Board approval nor explicit consent was necessary.

Figure 1.

Flowchart of participant selection. CT, chemotherapy; RT, radiotherapy; SEER, Surveillance, Epidemiology, and End Results.

Participant variables and outcomes

Baseline characteristics included age at diagnosis (<60 years, ≥60 years), race (White, Black, other), sex (male, female), marital status (married, unmarried), region (rural, urban), income (categorized as $0–44,999, $45,000–59,999, $60,000–75,000, or $75,000+), histologic subtypes [NSCLC, small cell lung cancer (SCLC), others], grade (low, high), stage (localized, regional, distant), laterality (right side, left side, unilateral, bilateral), and surgical status (yes, no). The histopathological classification was according to the International Classification of Diseases for Oncology, 3^rd Revision (ICD-O-3) codes (18).

The primary outcome was CVD death, defined according to the International Classification of Diseases, 10^th Revision (ICD-10) codes, including I00-I13, I20-I51 and I60-I78 (Table S1) (19,20). Non-CVD death was considered a competing risk. Follow-up duration was calculated from the date of initial lung cancer diagnosis to death or the last follow-up (December 31, 2017).

Statistical analysis

We used the Chi-squared test to compare the baseline categorical variables. The cause of death was analyzed by the proportions of deaths (21). To internally validate the robustness of the findings, participants were assigned to training and validation cohort through random allocation. The ratio was 7:3. For the initial variable screening in the training cohort, we performed a univariate competitive risk analysis (15). With significant differences from this screening, we constructed three progressively adjusted multivariate models: Model 1 adjusted for tumor stage and histologic subtypes; Model 2 further adjusted for age, sex, marital status, grade, and laterality; and Model 3, the fully adjusted model, additionally incorporated surgical status. Subgroup analyses were stratified by age (<60 years, ≥60 years), sex (male, female) and race (White, Black, other), with interaction tests performed to assess potential effect modification across subgroups (22). Based on the independent prognostic factors identified after multivariable and robustness analyses, a prognostic nomogram was further established and validated (Appendix 1).

All statistical analyses were performed using R software (version 4.4.1; R Core Team, Vienna, Austria) for chi-square tests, Cox regression analysis and the Fine-Gray competing risk analysis. Sensitivity analyses and subgroup analyses were used to validate the robustness of the results. A two-sided P<0.05 was considered statistically significant.

Results

Baseline characteristics

A total of 59,726 CT/RT-treated lung cancer patients were identified from 2002 to 2017. They were followed for an average of 36.7 months [standard error (SE) 0.2 months]. Among the 59,726 patients included, most were 60+ years old (76.3%), male (53.1%), White (80.5%), married (54.7%) and lived in urban areas (86.6%). Income distribution showed 4.11% earned $0–44,999, 22.4% earned $45,000–59,999, 35.1% earned $60,000–75,000, and 38.4% earned $75,000+. NSCLC (83.2%) was more common than SCLC (9.81%). For the laterality, 40.5% were left side and 57.4% was right side; for the grade, 40.4% were low-grade and 59.6% high-grade; for the stage, 24.6% were localized, 31.0% regional, and 44.4% distant. Surgery was performed in 38.4% of cases (Table 1).

Table 1. Baseline characteristics of lung cancer patients with CT or RT.

Characteristics	Patients (N=59,726)
	Number	Proportion
Age (years)
<60	14,172	23.7
≥60	45,554	76.3
Race
White	48,087	80.5
Black	6,406	10.7
†Other	5,233	8.76
Sex
Female	27,996	46.9
Male	31,730	53.1
Grade
Low	24,159	40.4
High	35,567	59.6
Histologic subtypes
Non-small cell lung cancer	49,664	83.2
Small cell lung cancer	5,857	9.81
‡Others	4,205	7.04
SEER stage
Distant	26,491	44.4
Regional	18,533	31.0
Localized	14,702	24.6
Surgery
No	36,811	61.6
Yes	22,915	38.4
Marital status
Married	32,668	54.7
Unmarried	27,058	45.3
Region
Rural	7,980	13.4
Urban	51,746	86.6
Income
$0–44,999	2,453	4.11
$45,000–59,999	13,395	22.4
$60,000–75,000	20,954	35.1
$75,000+	22,924	38.4
Laterality
Right side	34,296	57.4
Left side	24,194	40.5
Unilateral	185	0.31
Bilateral	1,051	1.76

^†, Other includes American Indian/AK Native, Asian/Pacific Islander. ^‡, Others include lung cancer cases classified as NOS. CT, chemotherapy; NOS, not otherwise specified; RT, radiotherapy; SEER, Surveillance, Epidemiology, and End Results.

Cause-specific mortality

Among 49,129 CT/RT-treated lung cancer patients who died, 46,115 (93.87%) deaths were attributed to cancer-related or unknown causes, while the remaining 3,014 (6.13%) were attributed to CVD. Among CVD deaths, diseases of the heart accounted for the majority of CVD deaths (78.70%) (Figure 2).

Figure 2.

Cause of death distribution in lung cancer patients receiving CT or RT. Cardiovascular deaths include diseases of the heart, cerebrovascular diseases, hypertension without heart disease, aortic dissection, atherosclerosis, and other diseases of arteries, arterioles, and capillaries. Others include deaths from specific cancer, deaths from other cancers, and other unknown causes. CT, chemotherapy; RT, radiotherapy.

Variable screening

Univariate competitive risk analysis showed that age ≥60 years, male sex, localized or regional stage, low grade, surgical intervention, NSCLC histology, and unmarried status were significantly associated with higher risk of CVD death among CT/RT-treated lung cancer patients (all P≤0.001) (Table S2).

Particularly, NSCLC [crude hazard ratio (HR) =2.039, 95% confidence interval (CI): 1.677 to 2.479; P<0.001], localized stage (crude HR =3.355, 95% CI: 3.000 to 3.753; P<0.001) and regional stage (crude HR =2.232, 95% CI: 1.988 to 2.505; P<0.001) were associated with higher CVD death risk in CT/RT-treated lung cancer patients (Figure 3A, Table S3).

Figure 3.

Competing risk regression for associations between tumor characteristics and CVD death. (A) Crude HRs from univariate analysis in training cohort. (B) HRs adjusted for tumor stage and histologic subtypes. (C) HRs further adjusted for age, sex, marital status, grade, and laterality. (D) HRs fully adjusted, additionally incorporated surgical status. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; Ref, reference; SEER, Surveillance, Epidemiology, and End Results.

Sensitivity analyses

To adjust for potential confounders and better characterize the impact of tumor characteristics (such as histologic subtypes and stage) on the risk of CVD death, three progressively adjusted Fine-Gray competing risk models were constructed. In Model 1 (adjusted for stage and histologic subtypes), NSCLC (adjusted HR =1.652, 95% CI: 1.359 to 2.008; P<0.001), localized stage (adjusted HR =3.273, 95% CI: 2.924 to 3.663; P<0.001), and regional stage (adjusted HR =2.177, 95% CI: 1.939 to 2.443; P<0.001) remained significantly associated with higher risk of CVD death (Figure 3B); in Model 2 (further adjusted for age, sex, marital status, grade, and laterality), the association remained stable for NSCLC (adjusted HR =1.611, 95% CI: 1.322 to 1.962; P<0.001) while maintaining strong associations for localized stage (adjusted HR =3.235, 95% CI: 2.876 to 3.640, P<0.001) and regional stage (adjusted HR =2.181, 95% CI: 1.939 to 2.453, P<0.001) (Figure 3C); and in Model 3 (fully adjusted for surgery), all associations persisted though attenuated for NSCLC (adjusted HR =1.576, 95% CI: 1.293 to 1.920; P<0.001), localized stage (adjusted HR =2.866, 95% CI: 2.506 to 3.277; P<0.001), and regional stage (adjusted HR =1.994, 95% CI: 1.757 to 2.264; P<0.001) (Figure 3D).

Subgroup analyses

In subgroup analyses stratified by age, sex, and race, the associations of NSCLC, localized stage, and regional stage with higher CVD death risk were generally consistent. Compared with SCLC, NSCLC was associated with higher CVD death risk, with no apparent differences across age and sex subgroups while more evident among White patients (Figure 4). Compared with distant stage, the association for localized stage appeared stronger in patients aged ≥60 years, whereas that for regional stage was more evident in male patients (Figure 5).

Figure 4.

Subgroup analyses of the association between tumor histologic subtypes and CVD death by age, sex and race. “Others” include lung cancer cases classified as NOS. “Other” includes American Indian/AK Native, Asian/Pacific Islander. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; NOS, not otherwise specified; NSCLC, non-small cell lung cancer; Ref, reference; SCLC, small cell lung cancer.

Figure 5.

Subgroup analyses of the association between tumor stage and CVD death by age, sex and race. “Other” includes American Indian/AK Native, Asian/Pacific Islander. CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; Ref, reference.

Nomogram integrating tumor histologic subtypes and stage for predicting CVD survival

The model was constructed using a training cohort and was validated in a validation cohort, with no significant differences in baseline characteristics between two cohorts (Table S4). Age, sex, histologic subtypes, stage, marital status, and surgery were identified as independent prognostic factors for CVD death risk and incorporated into the nomogram model (Figure S1). Stage was given a maximum rating, followed by age, histologic subtypes, sex, marital status and surgery (Table S5). A patient’s total score determines the predicted probabilities of CVD-specific survival over the next 5, 7.5 and 10 years. The nomogram demonstrated moderate discriminative performance, with C-index values of 0.670 in internal validation and 0.647 in external validation. Calibration curves demonstrated close agreement between nomogrampredicted and actual CVD-specific survival probabilities (Figure S2). Risk stratification based on nomogram-predicted total scores further identified significant differences in CVD survival among low-, intermediate-, and high-risk groups (P<0.001) (Figure S3).

Discussion

The present study is the first population-based analysis to comprehensively explore the association between tumor characteristics and the risk of CVD death among CT/RT-treated lung cancer patients. Our findings demonstrated that tumor histologic subtypes and stage were significantly associated with the risk of CVD death in this population.

Our study suggested that, among CT/RT-treated lung cancer patients, NSCLC was associated with higher risk of CVD death than SCLC. This finding differs from prior studies reporting higher CVD mortality in SCLC patients (23), which may be explained by treatment heterogeneity across histologic subtypes. For example, NSCLC is often managed with surgery and long-term systemic therapies, including targeted agents and immune checkpoint inhibitors (24), whereas SCLC, a highly aggressive malignancy (25,26), is typically treated with intensive, stage-specific regimens characterized by relatively short-course platinum-based CT in combination with RT and immunotherapy (27). As cancer therapies can exert direct cardiotoxicity (28,29), differences in treatment patterns may confound the association between histologic subtypes and CVD death risk. Notably, after restricting the analyses to CT/RT-treated patients, the higher CVD death risk in NSCLC became apparent. This suggests that factors beyond treatment exposure, including tumor-intrinsic biological differences, may contribute to the observed difference in CVD death risk.

Previous studies have reported distinct tumor microenvironment traits across lung cancer subtypes (30-32). NSCLC is often characterized by pronounced neutrophil-driven inflammatory microenvironment (33). Neutrophils can promote a hypercoagulable state and form NETs (11), which can induce endothelial dysfunction (ED) (34,35). ED is a well-established contributor to CVD (34), thereby providing a plausible mechanistic link between tumor progression and CVD and may partly explain the higher CVD death risk observed in NSCLC patients.

Our study further demonstrated that, among CT/RT-treated lung cancer patients, those with localized or regional stage were associated with higher CVD death risk than those with distant stage. Although tumor stage has been shown to be associated with CVD risk (36,37), this finding should be interpreted cautiously due to the potential impact of competing events (38). Patients with distant-stage lung cancer often experience rapid disease progression and are more likely to die from cancer before CVD-related death can occur or be recorded as the underlying cause (39). In contrast, patients with localized or regional tumor generally survive longer (40,41), providing a longer follow-up period during which CVD death driven by shared risk factors between lung cancer and CVD becomes clinically apparent (21). Overall, these findings suggest that patients with localized or regional stage may represent a high-risk population for CVD death and could benefit from intensified CVD risk assessment, long-term surveillance, and early, preventive interventions.

It remains unclear whether tumor laterality affects CVD death risk among CT/RT-treated lung cancer patients. Prior research found no significant impact of tumor laterality on CVD risk and mortality in CT/RT-treated breast cancer patients (15,42). A similar trend was observed for lung cancer in our study. Although one prior study suggested the right-sided laterality was associated with lower risk of CVD death in lung cancer patients, it did not account for treatment heterogeneity (16). Further investigation is therefore needed to clarify the influence of laterality on CVD mortality in lung cancer patients treated with CT or RT.

With increasing evidence that cancer survivors face an elevated risk of CVD death (43), cardio-oncology has rapidly developed to mitigate cardiovascular risk in cancer patients. Multidisciplinary collaboration between oncology and cardiology has been associated with better prognosis and clinical outcomes (44). The 2022 ESC Guidelines on cardio-oncology provided tools for baseline cardiovascular risk assessment and monitoring (45,46). Our results underscore the critical role of tumor characteristics, particularly histologic subtypes and disease stage, in assessing CVD death risk among CT/RT-treated lung cancer patients. Consequently, management strategies based on tumor characteristics may improve care quality and prognosis in CT/RT-treated lung cancer patients.

It is important to note that the nomogram was intended to visually demonstrate the influence of tumor characteristics on CVD death risk, and development of a predictive model was not the central focus of the present study.

Strengths and limitations

Primary strengths of this study include the large population and long-term follow-up period. To our knowledge, it is among the largest population-based studies and the first to evaluate the association between tumor characteristics and CVD death risk among CT/RT-treated lung cancer patients.

Nevertheless, several limitations warrant acknowledgment. First, although SEER database is comprehensive, it lacks data on types and doses of initial CT (47) and fields, doses and techniques of initial RT (48), and subsequent treatments (47,48). While we restricted the analysis to CT/RT-treated lung cancer patients to partially reduce treatment heterogeneity, variations in treatment intensity, regimens, and sequencing could not be fully captured. Consequently, residual confounding from unmeasured treatment heterogeneity is unavoidable and may have influenced our findings. Second, the prolonged accrual period may have inflated estimates of mortality risk due to denominator attrition (49). Third, some potential confounding factors, including cardiovascular comorbidities are shared risk factors, are not available in the SEER dataset, so we could not describe the risk of CVD death in these subgroups (20).

Conclusions

NSCLC, localized and regional stage were associated with higher CVD death risk in CT/RT-treated lung cancer patients. The management of CVD risk in CT/RT-treated lung cancer patients should extend beyond traditional CVD risk factors to tumor characteristics, particularly tumor histologic subtypes and stage. This study provides population-based evidence for reducing CVD death risk and optimizing the clinical management of CT/RT-treated lung cancer patients.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.