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Background Although the classic radiobiologic principles of radiotherapy are well understood, the unique effects of the large fractional does that characterize stereotactic radiotherapy (SRT), specifically in terms of antitumor immune cellular processes, vascular damage, tumor necrosis, and apoptosis on brain metastasis have yet to be adequately demonstrated. The objective of this study is to provide the first in-human evaluation of the biological effects of SRT in resected brain metastasis. Methods All paired primary tumors and metastases for patients who underwent dose-escalated preoperative SRT followed by resection were evaluated for tumor necrosis using hematoxylin-eosin staining. T cells (CD3+, CD4+, CD8+), natural killer cells (CD56+), vessel density (CD31+), and apoptotic factors (caspase-3) were determined by immunohistochemical analysis. Results Fifteen patients with brain metastases from solid tumors received a median preoperative SRT dose of 18 Gy (range: 15–18 Gy) in 1 fraction, with 2 patients receiving 27–30 Gy in 3–5 fractions, followed by resection within a median interval of 90 hours (Range: 17.1–260 hours). The rate of necrosis was found to be significantly higher in irradiated brain metastases than in non-irradiated primary tumor samples (mean paired difference: 30.47, SD: 29.28, p=0.001). A decrease in all immunomodulatory cell populations was found in irradiated metastasis: CD3 (mean paired difference -19.4, SD: 31.7, p=0.03), CD4 (-10.0, SD: 20, p=0.01), and CD8 (-17.4, SD: 22.1, p=0.008). While irradiated samples had numerically lower CD 31+, CD 56+, and caspase-3 scores, the difference was not statistically significant. Time interval from SRT to surgery had no effect on these parameters. Conclusions There is complex interplay between tumor-associated cells and the unique radiobiological effects of SRT on tumor tissue. Although time interval from SRT to surgery was associated with increased tumor necrosis, differences in immunomodulatory factors may be multifactorial, including concurrent corticosteroids or the immunosuppressive effect of SRT.

RADI-11. Evaluating the Tissue Effects of Dose-escalated Pre-operative Stereotactic Radiotherapy for Resectable Brain Metastasis