Pulsed low-dose irradiation of orthotopic glioblastoma multiforme (GBM) in a pre-clinical model: Effects on vascularization and tumor control

Background and purpose: To compare dose-escalated pulsed low-dose radiation therapy (PLRT) and standard radiation therapy (SRT). Methods and materials: Intracranial U87MG GBM tumors were established in nude mice. Animals received whole brain irradiation with daily 2-Gy fractions given continuously (SRT) or in ten 0.2-Gy pulses separated by 3-min intervals (PLRT). Tumor response was evaluated using weekly CT and [18F]-FDG-PET scans. Brain tissue was subjected to immunohistochemistry and cytokine bead array to assess tumor and normal tissue effects. Results: Median survival for untreated animals was 18 (SE ± 0.5) days. A significant difference in median survival was seen between SRT (29 ± 1.8 days) and PLRT (34.2 ± 1.9 days). Compared to SRT, PLRT resulted in a 31% (p < 0.01), 38% (p < 0.01), and 53% (p = 0.01) reduction in normalized tumor volume and a 48% (p < 0.01), 51% (p < 0.01), and 70% (p < 0.01) reduction in tumor growth rate following the administration of 10 Gy, 20 Gy, and 30 Gy, respectively. Compared to untreated tumors, PLRT resulted in similar tumor vascular density, while SRT produced a 40% reduction in tumor vascular density (p = 0.05). Compared to SRT, PLRT was associated with a 28% reduction in degenerating neurons in the surrounding brain parenchyma (p = 0.05). Conclusions: Compared to SRT, PLRT resulted in greater inhibition of tumor growth and improved survival, which may be attributable to preservation of vascular density