Novel methodology to investigate the impact of radiation dose to heart sub-structures on overall survival

Abstract

Introduction: For lung cancer patients treated with radiotherapy, dose to the heart is associated with excess mortality. However, it is often not feasible to spare the whole heart. Therefore, our aim is to define cardiac sub-structure(s) and dose thresholds which optimally reduce early mortality.

Method: 14 cardiac sub-structures were delineated on 5 template patients with representative anatomies. 1,161 non-small cell lung cancer patients were non-rigidly registered to these 5 template anatomies, mapping their radiotherapy dose. Mean and maximum dose to each sub-structure were extracted and the means evaluated as input to prediction models. The cohort was bootstrapped into two variable reduction techniques: elastic-net LASSO and random forest survival model. Each was optimised to extract variables contributing most to overall survival, model coefficients were evaluated to select these sub-structures. The most important variables, common to both models, were selected and evaluated in multivariable cox-proportional hazard models. A threshold dose was defined and Kaplan-Meier survival curves plotted.

Results: 978 patients remained after visual QA of the registration. Ranking the model coefficients across the bootstraps selected the maximum dose to the right atrium, right coronary artery and ascending aorta as the most important factors associated with survival. The maximum dose to the combined cardiac region showed significance in the multivariable model, hazard ratio 1.01Gy-1, p=0.03 after accounting for tumour volume (p<0.001), N-stage (p<0.01) and performance status (p=0.01). The optimal threshold for the maximum dose, equivalent dose in 2Gy fractions, was 23Gy. Kaplan-Meier survival curves showed a significant split, log-rank p=0.008.

Conclusion: The max dose to the combined cardiac region encompassing the right atrium, right coronary artery and ascending aorta was found to have the greatest impact on patient survival. A maximum EQD2 dose of 23Gy was identified and should be considered as a dose limit in future studies.

Keywords: Lung cancer; Radiotherapy; cardiac toxicity; dose response; survival.