Dose to Highly Functional Ventilation Zones Improves Prediction of Radiation Pneumonitis for Proton and Photon Lung Cancer Radiotherapy

Abstract Purpose We hypothesize that the radiation dose in high-ventilation portions of the lung better predicts radiation pneumonitis (RP) outcome for patients treated with proton (PR) and photon (PH) radiotherapy. Methods and Materials 74 patients (38 protons, 36 photons) with locally advanced non-small cell lung (NSCLC) cancer treated with concurrent chemoradiation (CRT) were identified, of whom 24 exhibited RP (graded using CTCAE v4.0) after proton or photon radiotherapy, and 50 were negative controls. The inhale and exhale simulation CT scans were deformed using Advanced Normalization Tools (ANTs). The 3D lung ventilation maps were derived from the deformation matrix and partitioned into low- and high-ventilation zones for dosimetric analysis. Receiver operating curve analysis was employed to study the power of relationship between RP and ventilation zones to determine an optimal ventilation cutoff. Univariate logistic regression was used to correlate dose in high/low ventilation zones with risk of RP. A non-parametric random forest process was employed for multivariate importance assessment. Results The optimal high-ventilation zone definition was determined to be the higher 45-60% of the ventilation values. The parameter vV20Gy_high (high ventilation volume receiving ≥ 20Gy) was found to be a significant indicator for RP (PH: p=0.002, PR: p=0.035) with improved AUCs compared with the traditional V20Gy for both photon and proton cohorts. The relationship of RP with dose to the low-ventilation zone of the lung was insignificant (PH:p=0.123, PR:p=0.661). Similar trends were observed for ventilation mean lung dose and ventilation V5Gy. Multivariate importance assessment determined vV20Gy_high, vV5_high and MLD were the most significant parameters for the proton cohort with a combined AUC=0.78. Conclusion Dose to the high-ventilated regions of the lung can improve predictions of RP for both photon and proton radiotherapy.