Association Between Cardiovascular Substructure Dose and Death Without Progression after Chemoradiation for Locally Advanced Non-Small Cell Lung Cancer

Abstract

<h3>Purpose/Objective(s)</h3> Prior work has focused on associations between radiotherapy dose to cardiovascular (CV) substructures and either overall survival (OS) or cardiac events. Death without progression (DWP) is a potentially more specific endpoint than OS for understanding radiation toxicity and easier to record than cardiac events. We assessed associations of CV substructure dose with DWP and OS after chemoradiation (CRT) for locally advanced NSCLC (LA-NSCLC). <h3>Materials/Methods</h3> We retrospectively reviewed records of 187 patients with LA-NSCLC who received definitive CRT (median 66.6 Gy) from 2008-2016 at a single institution. CV substructures, including both atria (BA), right atrium, left atrium (LA), both ventricles (BV), right ventricle (RV), left ventricle, pericardium, aorta, superior vena cava, and pulmonary artery, were defined on radiation simulation scans using a deep learning auto-segmentation model. Dose-volume histogram (DVH) metrics to CV substructures (mean dose, volume receiving ≥5 Gy [V5], V30, V50), whole heart, lung, and esophagus were extracted. DWP was modelled with Fine-Gray method; disease progression was a competing event. OS was modelled with Cox regression. For each CV substructure, associations between each DVH metric and DWP and OS were assessed, and the candidate DVH metric with the lowest p value was promoted to multivariable analysis. Multivariable models with the same baseline covariates but different DVH metrics were generated and ranked by Akaike information criterion (AIC) to select "best" models. Cutpoint analyses were done with Contal and O'Quigley method. <h3>Results</h3> 98 patients (52%) received proton therapy and 89 (48%) received photon therapy (68/89 intensity-modulated radiation therapy). At median follow-up of 28.8 months, 143 (76%) patients had died; overall, 25 (13%) experienced DWP. Causes of DWP included respiratory failure due to heart failure, COPD, pneumonia, or aspiration (n=10), out-of-hospital cardiopulmonary arrest (n=4), undifferentiated sepsis (n=2), probable radiation pneumonitis (n=1), esophagopleural fistula (n=1), and unknown (n=7). On multivariable analysis for DWP, best model included RV mean dose (AIC 222); 2^nd best included BV V5 (AIC 231). 3-year cumulative incidence of DWP was 21.3% vs 5.6% for RV mean dose ≥5.5 Gy vs <5.5 Gy (p=0.001). On multivariable analysis for OS, best model included LA V5 (AIC 1277.8); 2^nd best included BA V5 (AIC 1278.5). 3-year OS was 25.6% vs 46.3% for LA V5 ≥74.5% vs <74.5% (p=0.002). Associations were stronger among and driven by the photon subgroup. Proton therapy delivered lower dose to multiple CV substructures (e.g., RV mean dose, median 0.03 Gy vs 7.7 Gy; and LA V5, median 46.1% vs 78.1%; both p<0.0001). <h3>Conclusion</h3> Radiation dose to CV substructures showed different associations with DWP and OS. These results suggest DWP may be a meaningful endpoint for understanding CRT toxicity in LA-NSCLC.