Search

Purpose:The blood–brain barrier (BBB) limits the efficacy of drug therapies for glioblastoma (GBM). Preclinical data indicate that low-intensity pulsed ultrasound (LIPU) can transiently disrupt the BBB and increase intracerebral drug concentrations.Patients and Methods:A first-in-man, single-arm, single-center trial (NCT02253212) was initiated to investigate the transient disruption of the BBB in patients with recurrent GBM. Patients were implanted with a 1-MHz, 11.5-mm diameter cranial ultrasound device (SonoCloud-1, 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 SonoCloud-1; 19 patients received at least one sonication. In 65 ultrasound sessions, BBB disruption was visible on T1w MRI for 52 sonications. Treatment-related adverse events observed were transient and manageable: a transient edema at H1 and at D15. No carboplatin-related neurotoxicity was observed. Patients with no or poor BBB disruption (n = 8) visible on MRI had a median progression-free 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:SonoCloud-1 treatments were well tolerated and may increase the effectiveness of systemic drug therapies, such as carboplatin, in the brain without inducing neurotoxicity.See related commentary by Sonabend and Stupp, p. 3750

Supplementary Table 1. The acoustic pressure levels are determined by a calibration of the implants in water prior to implantation in patients. The 95% confidence interval given in the table denotes the measurement uncertainty inherent to this process. Acoustic pressure levels reported previously (19) were re-evaluated using enhanced acoustic calibration methods with reduced uncertainty. The former values are given in the pold column to ease comparison with our previous publication. Supplementary Table 2. BBB disruption grade and acoustic pressure. Data are n (%). Supplementary Table 3. The secondary outcomes of the trial were calculated based on the grading assigned to post-contrast MR images evaluating the level of BBB disruption. Greater amounts of post-sonication BBB disruption resulted in a trend towards longer PFS and OS.