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Pericardial effusion (PCE) is one of the most common cardiac complication associated with thoracic radiation therapy (RT). Prior studies have identified a wide range of heart dosimetric parameters as predictors for cardiac toxicities; though producing conflicting results [Ning et al., IJROBP 2017; Xue et al., Radiother Oncol 2019]. Aim of our study is to investigate the thoracic dose patterns associated with PCE in patients enrolled in a randomized trial of Intensity Modulated RT (IMRT) versus Passive Scattering Proton Therapy (PSPT) for locally advanced Non-Small-Cell Lung Cancer (NSCLC).

A total of 177 patients treated with PSPT or IMRT for NSCLC in a prospective study were reviewed for this analysis. All patients were treated to a prescribed dose of 66 or 74 Gy in conventional daily fractionation with concurrent chemotherapy (CHT). Median patient age was 66 years (range: 33–85 years). Seventy-seven patients (43.5%) developed grade ≥2 (G2)-PCE diagnosed on radiographic criteria and graded according to CTCAE v. 4.0.
Each planning CT and dose map was spatially normalized to a common anatomical reference using a B-spline inter-patient registration algorithm after masking the gross tumor volume. The tumor-subtracted dose maps were converted into biologically effective dose maps (α/β=3 Gy). The Voxel-Based Analysis (VBA) of local dose differences between patients with and without G2-PCE was performed according to a non-parametric permutation test accounting for multiple comparisons [Palma et al., Phys Med Biol 2019]. The underlying general linear model (GLM) of PCE was designed to include dose maps and each non-dosimetric variables significantly correlated with G2-PCE. The clusters of voxels with dose differences significantly correlated with G2-PCE at a significance level of 0.05 (S_0.05) were generated. 

Age (p=0.004) and adjuvant CHT (p=0.001) were the independent clinical variables significantly correlated with G2-PCE and included within the GLM adjusted for covariates. Of note, the RT technique did not impact PCE incidence (p=0.34).
Patients with G2-PCE received significantly higher doses in two voxel clusters S_0.05 in the heart and in the lungs (Figure). Median doses delivered to voxel clusters located in heart and in the lungs are reported in the Table.

Younger age at irradiation and adjuvant CHT may both increase the risk of PCE. No significant differences in PCE incidence was found between PSPT and IMRT treatment modality. The VBA analysis highlighted dose patterns associated with cardiac toxicity in both the heart and the lungs, thus paving the way to further studies on spatial dose distributions to elucidate the multi-organ contribution to thoracic toxicities.