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

Purpose: We hypothesized that the radiation dose in high-ventilation portions of the lung better predicts radiation pneumonitis (RP) outcome for patients treated with proton radiation therapy (PR) and photon radiation therapy (PH). Methods and Materials: Seventy-four patients (38 protons, 36 photons) with locally advanced non-small cell lung cancer treated with concurrent chemoradiation therapy were identified, of whom 24 exhibited RP (graded using Common Terminology Criteria for Adverse Events v4.0) after PR or PH, and 50 were negative controls. The inhale and exhale simulation computed tomography scans were deformed using Advanced Normalization Tools. The 3-dimensional 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 used 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- and low-ventilation zones with risk of RP. A nonparametric random forest process was used for multivariate importance assessment. Results: The optimal high-ventilation zone definition was determined to be the higher 45% to 60% of the ventilation values. The parameter vV20Gy_high (high ventilation volume receiving ≥20 Gy) was found to be a significant indicator for RP (PH: P = .002, PR: P = .035) with improved areas under the curve 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 = .123, PR: P = .661). Similar trends were observed for ventilation mean lung dose and ventilation V5Gy. Multivariate importance assessment determined that vV20Gy_high, vV5_high, and mean lung dose were the most significant parameters for the proton cohort with a combined area under the curve of 0.78. Conclusion: Dose to the high-ventilated regions of the lung can improve predictions of RP for both PH and PR.