Optical Coherence Tomography Angiography (OCTA) Captures Early Micro-Vascular Remodeling in Non-Melanoma Skin Cancer During Superficial Radiotherapy: A Proof-of-Concept Study

<b>Background/Objectives</b>: This proof-of-concept study evaluated whether optical coherence tomography angiography (OCTA) can non-invasively capture micro-vascular alterations in non-melanoma skin cancer (NMSC) lesions during and after superficial orthovoltage radiotherapy (RT) using radiomics and vascular features analysis. <b>Methods</b>: Eight patients (13 NMSC lesions) received 36-50 Gy in 6-20 fractions. High-resolution swept-source OCTA volumes (1.1 × 10 × 10 mm³) were acquired from each lesion at three time points: pre-RT, immediately post-RT, and three months post-RT. Additionally, healthy skin baseline was scanned. After artifact suppression and region-of-interest cropping, (i) first-order and texture radiomics and (ii) skeleton-based vascular features were extracted. Selected features after LASSO (least absolute shrinkage and selection operator) were explored with principal-component analysis. An XGBoost model was trained to classify time points with 100 bootstrap out-of-bag validations. Kruskal-Wallis tests with Benjamini-Hochberg correction assessed longitudinal changes in the 20 most influential features. <b>Results</b>: Sixty-one OCTA volumes were analyzable. LASSO retained 47 of 103 features. The first two principal components explained 63% of the variance, revealing a visible drift of lesions from pre- to three-month post-RT clusters. XGBoost achieved a macro-averaged AUC of 0.68 ± 0.07. Six features (3 texture, 2 first order, 1 vascular) changed significantly across time points (adjusted <i>p</i> < 0.05), indicating dose-dependent reductions in signal heterogeneity and micro-vascular complexity as early as treatment completion, which deepened by three months. <b>Conclusions</b>: OCTA-derived radiomic and vascular signatures tracked RT-induced micro-vascular remodeling in NMSC. The approach is entirely non-invasive, label-free, and feasible at the point of care. As an exploratory proof-of-concept, this study helps to refine scanning and analysis protocols and generates knowledge to support future integration of OCTA into adaptive skin-cancer radiotherapy workflows.