Radiation-Induced Esophagitis in Non-Small-Cell Lung Cancer Patients: Voxel-Based Analysis and NTCP Modeling

SIMPLE SUMMARY: Radiation-induced esophagitis (RE) is a common dose-limiting complication associated with concurrent chemoradiation therapy for Non-Small-Cell Lung Cancer (NSCLC), and a wide range of esophageal dosimetric parameters have been described as predictive of RE. In this study, we characterize the risk of RE for NSCLC patients enrolled in a prospective trial comparing intensity-modulated RT versus passive scattering proton therapy for locally advanced NSCLC. Dose patterns associated with RE were analyzed by applying voxel-based analysis approaches, and predictive models for RE were finally investigated. Two predictive models for acute RE with good cross-validated predictive performances and discrimination capability were developed (thoracic esophageal model: ROC-AUC = 0.73; whole esophagus model: ROC-AUC = 0.70). ABSTRACT: The aim of our study is to characterize the risk of radiation-induced esophagitis (RE) in a cohort of Non-Small-Cell Lung Cancer (NSCLC) patients treated with concurrent chemotherapy and photon/proton therapy. For each patient, the RE was graded according to the CTCAE v.3. The esophageal dose-volume histograms (DVHs) were extracted. Voxel-based analyses (VBAs) were performed to assess the spatial patterns of the dose differences between patients with and without RE of grade ≥ 2. Two hierarchical NTCP models were developed by multivariable stepwise logistic regression based on non-dosimetric factors and on the DVH metrics for the whole esophagus and its anatomical subsites identified by the VBA. In the 173 analyzed patients, 76 (44%) developed RE of grade ≥ 2 at a median follow-up time of 31 days. The VBA identified regions of significant association between dose and RE in a region encompassing the thoracic esophagus. We developed two NTCP models, including the RT modality and a dosimetric factor: V(55Gy) for the model related to the whole esophagus, and the mean dose for the model designed on the thoracic esophagus. The cross-validated performance showed good predictions for both models (ROC-AUC of 0.70 and 0.73, respectively). The only slight improvement provided by the analysis of the thoracic esophageal subsites might be due to the relevant sparing of cervical and lower thoracic esophagus in the analyzed cohort. Further studies on larger cohorts and a more heterogeneous set of dose distributions are needed to validate these preliminary findings and shed further light on the spatial patterns of RE development.