Spatial signature of dose patterns associated with acute radiation-induced lung damage in lung cancer patients treated with stereotactic body radiation therapy

Thoracic radiation therapy (RT) is often associated with lung side effects, whose etiology is still controversial. Our aim was to explore correlations between local dose in the thoracic anatomy and the radiation-induced lung damage (RILD). To this end, we designed a robust scheme for voxel-based analysis (VBA) to explore dose patterns associated with RILD in non-small-cell lung cancer (NSCLC) patients receiving stereotactic body RT (SBRT). We analyzed 106 NSCLC SBRT patients (median prescription dose: 50 Gy; range: [40-54] Gy) in 4 fractions (range: [3-5]) with clinical and dosimetric records suitable for the analysis. The incidence of acute G1 RILD (RTOG grade 1) was 68%. 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 (?/? = 3 Gy). VBA was performed according to a non-parametric permutation test accounting for multiple comparison, based on a cluster analysis method. The underlying general linear model of RILD was designed to include dose maps and each non-dosimetric variable significantly correlated with RILD. The clusters of voxels with dose differences significantly correlated with RILD at a given p-level (S ) were generated. The only non-dosimetric variable significantly correlated with RILD was the chronic obstructive pulmonary disease (p = 0.034). Patients with G1 RILD received significantly (p 0.05) higher doses in two voxel clusters S in the lower-left lung (14 cm) and in an area (64 cm) largely included within the ventricles. The applied VBA represents a powerful tool to probe the dose susceptibility of inhomogeneous organs in clinical radiobiology studies. The identified subregions with dose differences associated with G1 RILD in both the heart and lower lungs endorse a trend of previously reported hypotheses on lung toxicity radiobiology.