BackgroundAdult‐type diffuse gliomas are among the central nervous system's most aggressive malignant primary neoplasms. Despite advancements in systemic therapies and technological improvements in radiation oncology treatment delivery, the survival outcome for these patients remains poor. Fast and accurate assessment of tumor response to oncologic treatments is crucial, as it can enable the early detection of recurrent or refractory gliomas, thereby allowing timely intervention with life‐prolonging salvage therapies.PurposeRadiomics is a developing field with great potential to improve medical image interpretation. This study aims to apply a radiomics‐based predictive model for classifying response to radiotherapy within the first 3 months post‐treatment.MethodsNinety‐five patients were selected from the Burdenko Glioblastoma Progression Dataset. Tumor regions were delineated in the axial plane on contrast‐enhanced T1(CE T1W) and T2 fluid‐attenuated inversion recovery (T2_FLAIR) magnetic resonance imaging (MRI). Hand‐crafted radiomic (HCR) features, including first‐ and second‐order features, were extracted using PyRadiomics (3.7.6) in Python (3.10). Then, recursive feature elimination with a random forest (RF) classifier was applied for feature dimensionality reduction. RF and support vector machine (SVM) classifiers were built to predict treatment outcomes using the selected features. Leave‐one‐out cross‐validation was employed to tune hyperparameters and evaluate the models.ResultsFor each segmented target, 186 HCR features were extracted from the MRI sequence. Using the top‐ranked radiomic features from a combination of CE T1W and T2_FLAIR, an optimized classifier achieved the highest averaged area under the curve (AUC) of 0.829 ± 0.075 using the RF classifier. The HCR features of CE T1W produced the worst outcomes among all models (0.603 ± 0.024 and 0.615 ± 0.075 for RF and SVM classifiers, respectively).ConclusionsWe developed and evaluated a radiomics‐based predictive model for early tumor response to radiotherapy, demonstrating excellent performance supported by high AUC values. This model, harnessing radiomic features from multi‐modal MRI, showed superior predictive performance compared to single‐modal MRI approaches. These results underscore the potential of radiomics in clinical decision support for this disease process.