Mri Evaluation Of The Effect Of Whole Brain Radiotherapy On Brain Metastasis

Abstract Poor prognosis of breast cancer brain metastasis partially results from the inability of therapeutics to penetrate the Blood-Brain-Barrier (BBB). Whole Brain Radiotherapy (WBRT) is standard-of-care for brain metastasis, however the early effects of fractionated WBRT on brain metastases have not been evaluated. Here, we applied longitudinal MRI to study WBRT’s effect on tumor volume, BBB permeability, and tumor-cell killing using anatomic, Dynamic Contrast Enhanced (DCE), and Diffusion-weighted (DW) MRI, evaluating tumor volume, permeability, and cytotoxic effect, respectively. The BCBM mouse model was established with left ventricle MDA-MB231-Br cell injection. MRI occurred before and 24h after 3 daily fractionated 4Gy WBRT (2.4Gy/min) or sham irradiation. In addition to anatomic MRI, DW MRI measured tissue ADC to study cytotoxic effect, and DCE MRI measured BBB permeability, quantified as the permeability variable Ktrans. Before treatment, T2-weighted images revealed hyperintense multifocal lesions in brains, and many had intact BBB indicated by no T1-w contrast-enhancement. WBRT tumors were smaller than sham irradiated tumors after 3 days (p< 0.05), while no difference in the number of new lesions was observed. DW MRI demonstrated increased ADC in WBRT tumors (p< 0.05), correlating well with elevated Caspase-3 staining of apoptotic cells. T1-w contrast enhanced images of tumors after treatment revealed no differences in the population of contrast-enhanced tumors between the WBRT and sham radiation groups. However, quantitative DCE MRI showed higher Ktrans in WBRT treated tumors relative to sham treated lesions, and an increase in Ktrans of WBRT tumors (p< 0.05), despite high permeability heterogeneity both inter- and intra-tumorally, indicating remaining impermeable BBB. In addition to monitoring tumor volume, longitudinal MRI provided non-invasive assessments of temporal and spatial changes in cellularity and vascular permeability of brain metastasis in response to WBRT, which may prove to be useful for defining an ideal treatment window for potential combination BCBM treatments.