Demystifying the results of RTOG 0617: Identification of dose sensitive cardiac sub-regions associated with overall survival

Abstract

Introduction: The RTOG 0617 trial presented worse survival for patients with lung cancer treated in the high-dose (74Gy) arm. In multivariable models, radiation level and whole heart volumetric dose parameters were associated with survival. In this work, we consider heart sub-regions to explain the observed survival difference between radiation levels. Methods: Voxel-based analysis identified anatomical regions where dose was associated with survival. Bootstrapping clinical and dosimetric variables into an elastic-net model selected variables associated with survival. Multivariable Cox regression survival models assessed significance of dose to the heart sub-region, compared to whole heart v5 and v30. Finally, trial outcome was assessed following propensity score matching of patients on lung dose, heart sub-region dose, and tumour volume. Results: 458 patients were eligible for voxel-based analysis. A significance region (p<0.001) was identified in the base of the heart. Bootstrapping selected mean lung dose, radiation level, log tumour volume, and heart region dose. Multivariable Cox model showed dose to the heart region (p=0.02), and tumour volume (p=0.03) significantly associated with survival, radiation level was not significant (p=0.07). Models showed whole heart v5 and v30 were not associated with survival, with radiation level significant (p<0.05). In the matched cohort, no significant survival difference was seen between radiation levels. Conclusion: Dose to the base of the heart is associated with overall survival, partly removing the radiation level effect, and explaining that worse survival in the high dose arm is due in part to heart subregion dose. By defining a heart avoidance region, future dose escalation trials may be feasible