PurposeThe purpose of this study was to investigate the dosiomics features of the interplay between CT density and dose distribution in lung SBRT plans, and to develop a model to predict treatment failure following lung SBRT treatment.MethodsA retrospective study was conducted involving 179 lung cancer patients treated with SBRT at the University of Nebraska Medical Center (UNMC) between October 2007 and June 2022. Features from the CT image, Biological Effective Dose (BED) and five interaction matrices between CT and BED were extracted using radiomics mathematics. Our in-house feature selection pipeline was utilized to evaluate and rank features based on their importance and redundancy, with only the selected non-redundant features being used for predictive modeling. We randomly selected 151 cases and 28 cases as training and test datasets. Four different models were trained utilizing the Balanced Random Forest framework on the same training dataset to differentiate between failure and non-failure cases. These four models utilized the same number of selected features extracted from CT-only, BED-only, a combination of CT and BED, and a composite of CT and BED including their interaction matrices, respectively.ResultsThe cohort included 125 non-failure cases and 54 failure cases, with a median follow-up time of 34.4 months. We selected the top 17 important and non-redundant features (with the Pearsons’s coefficient < 0.5) in each model. When evaluated on the same independent test set, the four models—CT features-only, BED features-only, a combination of CT and BED features, and a composite model including features from CT and BED that includes their interaction matrices—achieved AUC values of 0.56, 0.75, 0.73, and 0.82, respectively, with corresponding accuracies of 0.61, 0.79, 0.71, and 0.79. The composite model demonstrated the highest AUC and accuracy, indicating that incorporating interactions between CT and BED reveals more predictive capabilities in distinguishing between failure and non-failure cases.ConclusionThe dosiomics model integrating the interaction between CT and Dose can effectively predict treatment failure following lung SBRT treatment and may serve as a useful tool to proactively evaluate and select lung SBRT treatment plans to reduce treatment failure in the future.