Safety and Feasibility of Repeated and Transient Blood-Brain Barrier Disruption by Pulsed Ultrasound in Patients with Recurrent Glioblastoma

Purpose: The bloodbrain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that lowintensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations. Patients and Methods: A firstinman, singlearm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1MHz, 11.5mm diameter cranial ultrasound device (SonoCloud1, CarThera). The device was activated monthly to transiently disrupt the BBB before intravenous carboplatin chemotherapy. Results: Between 2014 and 2016, 21 patients were registered for the study and implanted with the SonoCloud1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatmentrelated adverse events observed were transient and manageable: a transient edema atH1and at D15. No carboplatinrelated neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progressionfree survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months. Patients with clear BBB disruption (n = 11) had a median PFS of 4.11 months, and a median OS of 12.94 months. Conclusions: SonoCloud1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.