Evaluation of Observer Variation as Natural Experiment to Detect Sensitive Heart Subregions

Abstract

There is growing evidence associating dose to the base of the heart to reduced survival of lung cancer patients (McWilliam EJC 2017). However, randomized evidence on the benefits of sparing the base of the heart is missing. In this study we investigate variability in the shape between patients of heart contours used in planning as a natural experiment to evaluate selective heart sparing. The core assumption is that regions that are not included in the heart delineation will not be spared. Data was collected for 1705 lung cancer patients treated in one center between 2010 and 2016 with IMRT/VMAT (55-66Gy in 20-33#) or SABR (54-60Gy in 3-8#), planned using manual heart contours, called delineation 1. Consistent reference heart contours were obtained using a commercial autocontouring software, called delineation 2. Heart shapes were mapped to spherical coordinates (φ, Φ, r) and the difference in radius Δr = r1 - r2 for each set of angles φ, Φ was calculated for all patients. A large Δr means that the manual delineation use for planning is relatively large in the direction. Cox-regression was performed for each set of angles using Δr, r2 and its interaction using overall survival as endpoint. Permutation testing is used to avoid multiple testing issues. The aim is to locate a region of the heart where bigger delineations lead to better sparing and hence better survival. On average the heart base in our manual contours extends 34 mm more superior than automatic contours, because our protocol stipulates the inclusion of the full pericardial sac. Δr was not correlated with any clinical variables and is therefore a good candidate as instrumental variable in causal inference. Univariable Cox regression of Δr showed a uniform worsening of survival with larger manual delineations, likely due to reduced overall sparing given the use of volumetric dose constraints. After including the interaction with r2, no significant heart regions were found. However, analysis using the overall volume of the manual and auto-delineated heart did show a small but significant interaction effect where larger manual delineations improved outcome for smaller hearts. Our interpretation is that delineation variability relative to autocontouring (e.g., 1.9 mm SD at right atrium, up to 15 mm SD at apex) is not big enough to impact significantly on the heart dose and therewith survival because volumetric costs functions are used. In the future we will extend this analysis to include planned dose. Variability in contouring in our cohort is not large enough to be used as a natural experiment to test the impact of selective heart sparing. However, larger volume delineations of small hearts are associated with reduced mortality, suggesting the importance of sparing the base of the heart where most contouring variability occurs.