Synergistic effects of microbubble-mediated focused ultrasound and radiotherapy in a F98 glioma model

Combined microbubble-mediated focused ultrasound (FUS) and radiation therapy (RT) has been shown to improve outcomes in tumors outside the brain. Here, we study the effects of FUS + RT in a F98 glioma model. Tumor cells were implanted into the brains of 45 Fischer rats (n = 4–8 per group): Controls, FUS, RT (4,8,15-Gy), and FUS + RT (4,8,15-Gy). 9 days after implantation, tumors were targeted using FUS (1–2 W, 220 kHz, 5 ms bursts, 1 Hz PRF, 180 s, 20 μL/kg Definity microbubbles), followed by RT. Tumor progression was monitored using MRI. At 4Gy, FUS + RT increased tumor doubling time by 11% compared to RT only and Controls (P < 0.01). At higher doses, where RT alone had a significant effect, there were no significant differences in doubling time compared to RT alone. Tumor volumes were reduced by 21–57% (4Gy) and 20–48% (15Gy) compared with RT alone (P < 0.05). No significant benefit was observed at 8Gy. A moderate, but not significant, increase in median survival was observed: 28 versus 27days (4Gy), 30 versus 29days (8Gy), and 35 vs. 33 days (15Gy). However, at 4Gy, FUS + RT significantly improved survival by 6% compared to the control group (median survival = 27days), while RT only offered no improvement. This study indicates that FUS + RT may improve therapeutic outcomes in glioblastoma, particularly at low RT doses, where RT alone has no therapeutic benefit.