Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study

Abstract

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of "sonicated" and "unsonicated" tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15-50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

Trial registration: ClinicalTrials.gov NCT02343991.

Figure 1

Overview of study.

Figure 2

Axial T1-weighted post gadolinium MRI of patient one immediately after MRgFUS BBB disruption demonstrates contrast extravasation in the grid pattern (see enlargement) where sonication occurred. The contrast extravasation is discrete and precise. There is no evidence of edema secondary to the procedure.

Figure 3

Sample T1 weighted post-gadolinium MRI from patient five obtained 30 days prior to BBB opening procedure (left), immediately following BBB disruption (middle) and 20 hours post BBB disruption (right). Ill-defined contrast enhancement is seen in the peritumoral region on images acquired immediately after MRgFUS (white arrows). This contrast enhancement has resolved in the peritumor region on the day 1 follow-up image indicating closure of the BBB. T2* sequence acquired immediately following BBB disruption for this patient show no evidence of microhemorrhages.