Development and Validation of a Spatial Dose Pattern Based Model Predicting Acute Pulmonary Toxicity in Patients Treated With Volumetric Arc-Therapy for Locally Advanced Lung Cancer.

PURPOSE/OBJECTIVE(S): (Chemo)-radiotherapy is the standard treatment for patients with locally advanced lung cancer (LALC) not accessible to surgery. Despite strict application of dose constraints, acute toxicities such as acute pulmonary toxicity (APT) remain frequent, and may impact treatment's compliance and patients' quality of life. Previously, on a population treated with intensity-modulated photon therapy or passive scattering proton therapy, spatial dose patterns associated with APT were identified in the lower lungs, especially in the lower right lung. In the present study, we aim to define these spatial dose patterns on a retrospective cohort treated by volumetric-arc therapy (VMAT) and to validate our findings prospectively. MATERIALS/METHODS For the training cohort, we retrospectively included all patients treated in our institution by VMAT for a LALC between 2015 and 2018. APT was scored according to the CTCAE v4.0 scale. All dose maps were registered to a thorax phantom using a segmentation-based elastic registration. Voxel-based analysis of local dose differences was performed with a non-parametric permutation test accounting for n = 10.000 permutations, producing a 3-dimensional significance maps on which clusters of voxels that exhibited significant dose differences (P < 0.05) between the two toxicity groups (APT ≥ grade 2 vs APT < grade 2) were identified. A dose cut-off was defined by maximizing the Youden-Index derived from the Receiver Operative Curve. For the validation cohort, we applied the predefined spatial dose pattern and the dose cut-off to an observational prospective cohort. The model was evaluated using the Area under the curve (AUC) and the balanced accuracy (Bacc: mean of the sensitivity and specificity). RESULTS 167 and 42 patients were included in the training and validation cohorts, with respective APT rates of 22.2% and 21.4%. In the training cohort, a cluster of voxels was identified in the lower right lung with a cut off of 30.3 Gy for the Dmean(mean-dose). This spatial-based model resulted in an AUC of 0.69 and a Bacc of 0.71. Using the same voxel cluster and the Dmeancut-off on the validation cohort, the model resulted in an AUC of 0.74 and a Bacc of 0.69. CONCLUSION Our model corroborates previous findings regarding the possible role of the lower right lung regarding the development of APT and successfully evaluates its robustness in a prospective cohort treated by VMAT. Regional radiosensitivity should be considered in usual lung dose constraints.