Dosiomics and radiomics-based prediction of pneumonitis after radiotherapy and immune checkpoint inhibition: The relevance of fractionation

Objectives: Post-therapy pneumonitis (PTP) is a relevant side effect of thoracic radiotherapy and immunotherapy with checkpoint inhibitors (ICI). The influence of the combination of both, including dose fractionation schemes on PTP development is still unclear. This study aims to improve the PTP risk estimation after radio(chemo) therapy (R(C)T) for lung cancer with and without ICI by investigation of the impact of dose fractionation on machine learning (ML) -based prediction. Materials and Methods: Data from 100 patients who received fractionated R(C)T were collected. 39 patients received additional ICI therapy. Computed Tomography (CT), RT segmentation and dose data were extracted and physical doses were converted to 2-Gy equivalent doses (EQD2) to account for different fractionation schemes. Features were reduced using Pearson intercorrelation and the Boruta algorithm within 1000-fold bootstrapping. Six single (clinics, Dose Volume Histogram (DVH), ICI, chemotherapy, radiomics, dosiomics) and four combined models (radiomics + dosiomics, radiomics + DVH + Clinics, dosiomics + DVH + Clinics, radiomics + dosiomics + DVH + Clinics) were trained to predict PTP. Dose-based models were tested using physical dose and EQD2. Four ML-algorithms (random forest (rf), logistic elastic net regression, support vector machine, logitBoost) were trained and tested using 5-fold nested cross validation and Synthetic Minority Oversampling Technique (SMOTE) for resampling in R. Prediction was evaluated using the area under the receiver operating characteristic curve (AUC) on the test sets of the outer folds. Results: The combined model of all features using EQD2 surpassed all other models (AUC = 0.77, Confidence Interval CI 0.76-0.78). DVH, clinical data and ICI therapy had minor impact on PTP prediction with AUC values between 0.42 and 0.57. All EQD2-based models outperformed models based on physical dose. Conclusions: Radiomics + dosiomics based ML models combined with clinical and dosimetric models were found to be suited best for PTP prediction after R(C)T and could improve pre-treatment decision making. Different RT dose fractionation schemes should be considered for dose-based ML approaches.