Aortic radiation dose was associated with increased CAD risk (HR 1.59 per 5 Gy; 95% CI 1.14–2.21), while LAD dose was associated with CAD and CHF in childhood cancer survivors.
Cohort (n=25,481)
Does cardiac substructure-specific radiation dose predict late cardiovascular events in childhood cancer survivors?
Specific cardiac substructure radiation doses, particularly to the LAD and aorta, are strong predictors of late cardiovascular events in childhood cancer survivors, enabling targeted 20-year risk thresholds for survivorship surveillance.
Effect estimate: HR 1.59 (95% CI 1.14-2.21)
12123 Background: Radiation-associated cardiovascular disease (CVD) remains a major late toxicity in childhood cancer survivors. Whole-heart dose may mask heterogeneous substructure exposure, limiting precision in survivorship surveillance and modern radiotherapy planning. Methods: Using the Childhood Cancer Survivor Study (CCSS) open-access cardiac substructure dosimetry dataset (12 mean-dose structures; Gy), we modeled time from cancer diagnosis to CAD, CHF, valvular disease, and arrhythmia with elastic-net Cox (α=0.5; 10-fold CV). Bootstrap stability selection (200 resamples) quantified reproducible substructure predictors; “core” structures were defined by selection frequency ≥0.80. Parsimonious Cox models were fit using core structures (dose scaled per 5 Gy) and adjusted for sex, race, age at diagnosis, anthropometric category, and smoking. Model discrimination was assessed using the concordance index (C-index). Model-based predicted 20-year absolute risks were used to estimate dose thresholds for clinically interpretable risk targets (reference profile: median covariates; modal factor levels). Results: Among 25,481 survivors, events occurred for CAD (n=475), CHF (n=544), valvular disease (n=131), and arrhythmia (n=181). LAD and aorta emerged as reproducible, endpoint-specific predictors: LAD was core across CAD/CHF/valvular outcomes; aorta and LMCA were core for CAD/valvular; pericardium was core for CAD/CHF. In adjusted core models, aortic dose was associated with CAD (HR 1.59 per 5 Gy; 95% CI 1.14–2.21; C-index 0.796) and valvular disease (HR 1.96; 95% CI 1.15–3.32; C-index 0.773). LAD dose was associated with CAD (HR 1.26; 95% CI 1.05–1.53; C-index 0.796) and CHF (HR 1.23; 95% CI 1.02–1.47; C-index 0.818). Absolute risk translation identified interpretable thresholds: predicted 20-year CAD risk crossed ~1% at 13 Gy mean aortic dose and ~2% at 20 Gy; CAD risk crossed ~1% at 24 Gy mean LAD dose. Predicted 20-year CHF risk crossed ~0.5% at 21 Gy mean LAD dose. Predicted 20-year valvular risk crossed ~1% at 23 Gy mean aortic dose. Conclusions: Substructure-specific dosimetry yields reproducible radiation “signatures,” with LAD and aorta dose consistently linked to late CVD. These dose–risk thresholds provide actionable benchmarks for risk-stratified survivorship surveillance and may inform substructure-sparing dose constraints in contemporary radiotherapy planning moving beyond whole-heart dose to endpoint-specific substructure constraints. Substructure-specific dose thresholds for 20-year cardiovascular risk. Outcome Core Substructure HR per 5 Gy (95% CI) 20-Year Risk Target Dose Threshold (Gy) CAD Aorta 1.59 (1.14–2.21) 1% 13 CAD Aorta 1.59 (1.14–2.21) 2% 20 CAD LAD 1.26 (1.05–1.53) 1% 24 CHF LAD 1.23 (1.02–1.47) 0.5% 21 Valvular Aorta 1.96 (1.15–3.32) 1% 23
Pamreddy et al. (Wed,) conducted a cohort in Childhood cancer survivors (n=25,481). Cardiac substructure radiation dose was evaluated on Time from cancer diagnosis to CAD, CHF, valvular disease, and arrhythmia (HR 1.59, 95% CI 1.14-2.21). Aortic radiation dose was associated with increased CAD risk (HR 1.59 per 5 Gy; 95% CI 1.14–2.21), while LAD dose was associated with CAD and CHF in childhood cancer survivors.