Aug 2026· European Heart Journal, Supplement· Vol 28· 0 citations
TL;DR
High-dose ventricular cardiac exposure during definitive radiotherapy for lung cancer is associated with subclinical myocardial dysfunction as measured by GLS, with a disproportionately greater impact among patients with hypertension, which supports ventricular dose optimization and hypertension-informed cardiac surveillance strategies in lung cancer radiotherapy.
Abstract
Radiation-induced cardiac injury is an important late effect of definitive radiotherapy for lung cancer (1). Global longitudinal strain (GLS) is a sensitive marker of subclinical myocardial dysfunction; however, its relationship with detailed cardiac dosimetry remains incompletely defined (2).
To evaluate associations between cardiac dose–volume parameters and GLS deterioration after definitive radiotherapy for non-metastatic lung cancer, and to assess effect modification by hypertension.
Patients with non-metastatic lung cancer treated with definitive radiotherapy or concurrent chemoradiotherapy were identified from a prospective registry with protocol-driven echocardiographic follow-up. Cardiac dose–volume parameters for the whole heart and cardiac substructures were derived using a standardized cardiac atlas. GLS change from baseline to follow-up was analyzed using multivariable linear regression adjusted for baseline GLS and established cardiovascular risk factors, with interaction analyses for hypertension.
Ninety-eight patients with paired baseline and follow-up echocardiography were included. Median GLS significantly deteriorated from −16.17 at baseline to −14.11 at follow-up, corresponding to a median increase of 1.82% (95% CI, 1.40–2.25; p < 0.001) (Figure 1).
In adjusted analyses, higher total prescribed dose was significantly associated with GLS deterioration (β = 0.009 per 10 Gy increase, 95% CI 0.001–0.017, p = 0.032). Among cardiac substructures, ventricular high-dose exposure demonstrated the strongest associations with GLS change. Specifically, both left ventricular (LV) and right ventricular (RV) V45 (percentage volume receiving ≥45 Gy) were significantly associated with GLS deterioration (LV V45: β = 0.351 per 10% increase, 95% CI 0.044–0.658, p = 0.026; RV V45: β = 0.840, 95% CI 0.240–1.439, p = 0.007). In contrast, atrial dose parameters were not associated with GLS change.
Hypertension significantly modified the association between LV V45 and GLS deterioration. GLS change per 10% increase in LV V45 was modest among patients without hypertension but markedly greater among patients with hypertension, with a significant interaction (p for interaction = 0.027) (Figure 2).
During follow-up, 8 patients (8.2%) experienced CVD events, including arrhythmia, heart failure, and pulmonary thromboembolism.
High-dose ventricular cardiac exposure during definitive radiotherapy for lung cancer is associated with subclinical myocardial dysfunction as measured by GLS, with a disproportionately greater impact among patients with hypertension. These findings support ventricular dose optimization and hypertension-informed cardiac surveillance strategies in lung cancer radiotherapy.Paired change in GLS Association between V45 and GLS
PURPOSE
Relationships between radiation therapy (RT) dose to cardiac substructures and patient-reported outcomes, as assessed by health-related quality of life (HRQOL), remain unknown. We sought to: (1) compare RT dose to cardiac substructures in patients treated with proton versus photon RT on the Radiotherapy Comparative Effectiveness (RadComp) pragmatic randomized clinical trial, which compared proton versus photon RT in breast cancer; (2) evaluate whether there were changes in HRQOL outcomes from baseline to 6 months following RT; and (3) determine the potential associations between radiation dose-volume histogram (DVH) parameters and changes in cardiac-related HRQOL.
METHODS AND MATERIALS
This analysis included 1160 RadComp participants with available radiation DVH metrics for all cardiac substructures who completed baseline and ≥1 follow-up HRQOL over the 6 months post-RT. Cardiac substructures included the whole heart, left ventricle, right ventricle, left atrium, right atrium, and left anterior descending artery; exposures of interest included dose to 0.03 cm3, maximum dose, mean dose, and percent volume receiving a specified dose. HRQOL measures that we hypothesized could provide some insights into cardiac symptoms included Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) shortness of breath and chest pain, chest tightness, and angina.
RESULTS
The mean dose to the whole heart was lower with protons, 0.89 Gy(relative biological effectiveness (RBE)) (Q1-Q3, 0.49-1.39), compared with photons 2.99 Gy (Q1-Q3, 1.60-4.61) (P< .001), as was the mean dose to the left ventricle, left atrium, and left anterior descending artery (P < .001). PRO-CTCAE measures were favorable at all time points with only modest changes observed, and grade ≥3 toxicity was uncommon (≤5.5%) for all measures. No DVH metrics were significantly associated with any cardiac-related HRQOL outcomes over the 6 months post-RT when evaluated by treatment arm or laterality.
CONCLUSIONS
Proton RT generally conferred significantly lower doses to the heart and cardiac substructures compared with photon RT. PRO-CTCAE measures were favorable overall. No cardiac DVH parameters were associated with early HRQOL outcomes.
Jean L Wright, K. Ko, W. Kenworthy et al.· International Journal of Rad...· 0 citations
Purpose To evaluate the spatial dosimetric relationships between cardiac substructures and hyper-acute subclinical myocardial strain alterations after thoracic intensity-modulated radiotherapy (IMRT). Methods Forty patients with thoracic malignancies were prospectively enrolled. Two-dimensional speckle-tracking echocardiography (2D-STE) was performed at baseline and 1–2 days post-radiotherapy to assess left ventricular global longitudinal strain (LVGLS) and right ventricular free wall longitudinal strain (RVFWLS). Cardiac substructures, including the atrioventricular node (AVN), sinoatrial node (SAN), and right coronary artery (RCA), were contoured standardized. Acute subclinical strain alteration was defined as a ≥ 15% relative reduction from baseline. Optimal dosimetric cutoffs were determined via Maxstat analysis, and independent predictors were identified using multivariable logistic regression. Results Immediately post-radiotherapy, the incidence of hyper-acute subclinical strain alterations was 65% (26/40) for the right ventricle and 40% (16/40) for the left ventricle, captured by 2D-STE prior to any conventional LVEF decline. Multivariable analysis identified AVN Dmean ≥ 6.83 Gy as an independent predictor of acute LV strain alterations (OR = 4.49, 95%CI: 3.46–5.82, P < 0.001). For the right ventricle, RCA V5 ≥ 77.56% (OR = 6.0, 95%CI: 4.26–8.53, P < 0.001), SAN D max ≥ 33.36 Gy (OR = 3.07, 95%CI: 2.11–4.44, P < 0.001) were independent predictors. Conclusion Hyper-acute subclinical strain alterations are highly prevalent immediately after thoracic radiotherapy, with right-sided structures exhibiting enhanced radiosensitivity. Dosimetric metrics of the AVN, SAN, and RCA serve as independent predictors. Although these data-driven cutoffs are exploratory and hypothesis-generating, they suggest that independent sparing of the conduction system and coronary vasculature should be considered in precision radiotherapy, warranting validation in future large-scale, multicenter trials.
Yan-Jun Zhang, Xiaochen Han, Fei-Fei Wang et al.· Frontiers in Cardiovascular...· 0 citations
Radiotherapy (RT) for early breast cancer (eBC) has been associated with increased long-term cardiovascular morbidity, primarily due to cardiac irradiation. Although advances in RT planning have substantially reduced mean heart dose (MHD), evidence suggests that dose to specific cardiac substructures may be more relevant for radiation-induced cardiotoxicity. Understanding contemporary cardiac and substructure dose exposure, as well as temporal trends, is essential for optimizing cardiac risk among cancer patients.
The purpose is to quantify radiation dose to the heart and cardiac substructures in eBC patients treated with adjuvant RT and to evaluate changes in cardiac dose exposure over time in a real-world clinical cohort.
All eBC patients receiving adjuvant RT at a single institution between 2009 and 2020 were included. Planning CT scans were retrieved, and the heart and nine cardiac substructures were automatically delineated using the open-source AI-based tool PlatiPy. A random 10% of delineations underwent manual validation and were accepted without modification. Dose metrics were extracted from the treatment planning system and reported as EQD2 (α/β = 2 Gy). Temporal changes in cardiac and substructure dose exposure were assessed using Wilcoxon tests.
In total, 6926 patients were included (3562 left-sided eBC patients and 3364 right-sided eBC patients). RT planning and delivery varied over time; deep inspiration breath-hold was available throughout the study period, and 3D-conformal RT was the predominant technique.
Figure 1 shows mean dose to the heart and 9 cardiac substructures. Changes in median mean doses over time are illustrated in Figure 2.
Median MHD for the entire cohort was 0.57 Gy (IQR: 0.29–0.99). For left-sided locoregional RT, MHD increased significantly over time (p < 0.001), whereas a significant decrease was observed for right-sided breast-only RT (p < 0.0001).
Dose exposure to cardiac substructures was generally low. The highest median doses were observed for the left anterior descending coronary artery (LAD) during left-sided locoregional RT (2.70 Gy, IQR: 2.12–4.77) and for the right coronary artery (RCA) during right-sided locoregional RT (1.45 Gy, IQR: 1.16–2.00). Median LAD dose increased significantly over time for left-sided locoregional RT (p < 0.01), but not for left-sided breast-only RT (p = 0.19).
These results likely reflect multiple factors, including the DBCG IMN study [2], which increased IMN-cover-age prioritization from 2015 and a shift toward a MHD rather than a LAD dose guidance in 2017.
Contemporary adjuvant RT for eBC results in very low cardiac and substructure doses for most patients. However, a significant increase in MHD and LAD dose over time was observed for left-sided locoregional RT due to changes in planning priorities. Further investigations include linkage of dosimetry data to cardiotoxicity outcomes.Boxplot with whiskers at 10% and 90% Median mean dose over time
B. Boegh Irankunda, N. Forbes, F. V. Carstensen et al.· European Heart Journal, Supp...· 0 citations
LV GLS appears to be a sensitive and clinically useful echocardiographic marker for the early detection of anthracycline-induced cardiotoxicity in adult breast cancer patients and may improve identification of subclinical cardiac dysfunction before a measurable decline in left ventricular ejection fraction occurs.
T. Mainka, Emil Sergejuk, W. Kotlarski et al.· International Journal of Inn...· 0 citations
Radical radiotherapy is delivered with curative intent in approximately 40% of patients with lung cancer. The RTOG 0617 trial and subsequent studies demonstrated that higher cardiac radiation exposure is associated with increased mortality. As clinical equipoise precludes randomisation to different cardiac dose limits, estimation of the causal effect of cardiac radiation dose on survival must rely on observational data. Traditional analyses have relied on multivariable regression models incorporating heart dose parameters and cardiac risk factors, but failure to consider causal structure may induce confounding bias. Targeted maximum likelihood estimation (TMLE) integrates machine learning to estimate outcome and treatment assignment models, approximating a randomised comparison within observational data and providing reliable effect estimates even if one model is misspecified.
Previous work has identified radiation dose to the base of the heart as being associated with increased mortality. However, the causal effect of radiation dose to the base of the heart on overall survival remains unclear. We therefore aimed to estimate this effect using a target trial emulation framework with TMLE.
The study included 1,051 patients with lung cancer treated with radiotherapy at a tertiary cancer centre between 2010 and 2013, with time zero defined as radiotherapy initiation. Radiation dose to the base of the heart was categorized as low (0–11.26 Gy), medium (11.26–23.34 Gy), or high (23.34–48.85 Gy). Overall survival was defined from radiotherapy initiation to death or censoring at last follow-up. The causal estimand was defined as time-specific differences in survival probability between dose groups. A directed acyclic graph (DAG) identified the minimal adjustment set. TMLE was applied to compare overall survival across dose groups over a 2-year follow-up.
After dose categorization, 367 patients were included per group, with approximately 300 retained per group in complete-case analyses. The DAG identified age, tumor volume, tumor location, T stage, M stage, and radiotherapy modality as the minimal adjustment set. No meaningful survival difference was observed between the low- and medium-dose groups. In the high- versus low-dose comparison, survival differences emerged early and became consistent after approximately 5 months, peaking during mid follow-up and remaining evident through the end of follow-up. In the high- versus medium-dose comparison, survival differences showed transient mid follow-up significance and did not become consistently significant until approximately 15 months.
Under causal assumptions within regions of sufficient overlap, higher radiation dose to the base of the heart was associated with distinct time-varying survival differences. Further studies should explore dose–response patterns across cardiac substructures within a causal analysis framework.High–low survival difference (TMLE) High–medium survival difference (TMLE)
B. Jiang, M. Summers, E. Osorio et al.· European Heart Journal, Supp...· 0 citations
It is suggested that RV strain assessment provides information complementary to conventional LV–based cardiotoxicity criteria and may occur in the absence of concurrent changes in conventional LV cardiotoxicity parameters as currently defined.
Z. Tlegenova, A. Amanova, S. Balmagambetova et al.· European Heart Journal, Supp...· 0 citations
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