PURPOSE: Recent papers suggested a correlation between the risk of distant metastasis (DM) and dose outside the PTV, though conclusions in different publications conflicted. This study resolves these conflicts and provides a compelling explanation of prognostic factors. MATERIALS AND METHODS: A dataset of 478 NSCLC patients treated with SBRT (IMRT or VMAT) was analyzed. We developed a deep learning model for DM prediction and explainable AI was used to identify the most significant prognostic factors. Subsequently, the prognostic power of the extracted features and clinical details were analyzed using conventional statistical methods. RESULTS: Treatment technique, tumor features, and dosiomic features in a 3 cm wide ring around the PTV (PTV3cm) were identified as the strongest predictors of DM. The Hazard Ratio (HR) for Dmean,PTV3cm was significantly above 1 (p < 0.001). There was no significance of the PTV3cm dose after treatment technique stratification. However, the dose in PTV3cm was found to be a highly significant DM predictor (HR > 1, p = 0.004) when analyzing only VMAT patients with small and spherical tumors (i.e., sphericity > 0.5). CONCLUSIONS: The main reason for conflicting conclusions in previous papers was inconsistent datasets and insufficient consideration of confounding variables. No causal correlation between the risk of DM and dose outside the PTV was found. However, the mean dose to PTV3cm can be a significant predictor of DM in small spherical targets treated with VMAT, which might clinically imply considering larger PTV margins for smaller, more spherical tumors (e.g., if IGTV > 2 cm, then margin ≤ 7 mm, else margin > 7 mm).

Department of Machine Learning H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Radiation Oncology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Faculty of Nuclear Sciences and Physical Engineering Czech Technical University Prague Prague Czechia

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