Association of Cardiac Dose with Cardiac Events and Survival for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC) Treated with Concurrent Chemoradiotherapy (cCRT) in the Era of Immune Checkpoint Inhibitor (ICI) Consolidation

Abstract

To assess the association of cardiac dose with post-cCRT cardiac events and survival among patients (pts) with LA-NSCLC after adoption of ICI consolidation, modern radiotherapy (RT) techniques, and data-driven cardiac constraints. This single-institution, multi-site retrospective study included 335 pts with LA-NSCLC treated with definitive cCRT (60-70 Gy) from October 2017 to December 2021. Pts were evaluated for ICI consolidation. Cardiac dose constraints included heart volume receiving ≥50 Gy (V50) <25% and mean heart dose (MHD) <20 Gy. Heart, left anterior descending artery (LAD), and left ventricle were autocontoured, manually reviewed, and edited. 21 dosimetric parameters (mean dose, max dose, and min dose to the hottest x% volume [Dx%(Gy); x from 5-95 in 5% intervals]) for each were extracted, as well as LAD V15. Baseline cardiovascular disease (bCVD) was defined as heart failure (HF), coronary artery disease, peripheral vascular disease, or cerebrovascular disease. Primary endpoint was post-cCRT major adverse cardiac events (MACE), defined as acute coronary syndrome, HF hospitalization/urgent visit, coronary revascularization, or cardiac death. Secondary endpoints were grade ≥3 cardiac events (CTCAE v5.0), overall survival (OS), cancer specific mortality (CSM), and other cause mortality (OCM). Competing risk regression was used for MACE and grade ≥3 cardiac events, and Cox regression for OS, CSM, and OCM. Median age was 68 years, 139 (41%) had bCVD, and 225 (67%) received consolidation ICI. Proton therapy was used in 117 (35%), intensity-modulated RT in 199 (59%), and 3D conformal RT in 19 (6%). Median MHD was 8.7 Gy (IQR 4.6-14.4) and median LAD V15 1.4% (IQR 0-22). Median follow-up was 39.5 months. 35 MACE events occurred; 1- and 2-year cumulative incidence (CI) were 4.2% and 9.5%. No cardiac dosimetric parameter associated with MACE after adjusting for bCVD and age (e.g., MHD sHR 0.98/Gy, 95% CI 0.93-1.03, p = 0.43) or within the following 3 subgroups: no bCVD, photon therapy, and ICI consolidation. 87 grade ≥3 cardiac events occurred; 1- and 2- year CI were 12.6% and 20.4%. Heart dose was not associated with grade ≥3 cardiac events after adjusting for bCVD, ECOG, and BMI (e.g., MHD sHR 1.00/Gy, 95% CI 0.97-1.03, p = 0.85) or within the 3 aforesaid subgroups. 183 OS events occurred, including 125 CSM and 58 OCM events. Multiple cardiac dosimetric parameters associated with worse OS on multivariable analysis (e.g., LAD V15 HR 1.01/%, 95% CI 1.00-1.02, p = 0.003), driven by associations with CSM (LAD V15 HR 1.02/%, p<0.001) but not OCM (LAD V15 HR 1.00/%, p = 0.73). Median OS was worse for LAD V15 ≥10% (22.2 vs 35.1 months, p = 0.004). Among pts with LA-NSCLC treated with cCRT after adoption of ICI consolidation, modern RT techniques, and cardiac constraints, post-cCRT cardiac events were common but showed no association with cardiac dose. Cardiac dose associated with OS, driven by an association with CSM and not OCM, which may not reflect cardiac toxicity.