Focused ultrasound-mediated enhancement of blood-brain barrier permeability for brain tumor treatment: a systematic review of clinical trials.

Authors: Zhu H, Allwin C, Bassous MG, Pouliopoulos AN

Brain tumors, particularly glioblastoma multiforme (GBM), present significant prognostic challenges despite multimodal therapies, including surgical resection, chemotherapy, and radiotherapy. One major obstacle is the limited drug delivery across the blood-brain barrier (BBB). Focused ultrasound (FUS) combined with systemically administered microbubbles has emerged as a non-invasive, targeted, and reversible approach to transiently open the BBB, thus enhancing drug delivery. This review examines clinical trials employing BBB opening techniques to optimise pharmacotherapy for brain tumors, evaluates current challenges, and proposes directions for further research. A systematic literature search was conducted in PubMed and ClinicalTrials.gov up to November 2023, searching for "ultrasound" AND "brain tumor". The search yielded 1446 results. After screening by title and abstract, followed by full-text screening (n = 48), 35 studies were included in the analysis. Our analysis includes data from 11 published studies and 24 ongoing trials. The predominant focus of these studies is on glioma, including GMB and astrocytoma. One paper investigated brain metastasis from breast cancer. Evidence indicates that FUS facilitates BBB opening and enhances drug uptake following sonication. Exploration of FUS in the pediatric population is limited, with no published studies and only three ongoing trials dedicated to this demographic. FUS is a promising strategy to safely disrupt the BBB, enabling precise and non-invasive lesion targeting, and enhance drug delivery. However, pharmacokinetic studies are required to quantitatively assess improvements in drug uptake. Most studies are phase I clinical trials, and long-term follow-up investigating patient outcomes is essential to evaluate the clinical benefit of this treatment approach. Further studies involving diverse populations and pathologies will be beneficial.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To review clinical trials using focused ultrasound-mediated blood–brain barrier opening to enhance drug delivery for brain tumors, assess current challenges, and propose directions for future research.

Animal model / Human subject Homo sapiens (human); strain: N/A; age: patients with brain tumors (primarily adults; limited/ongoing pediatric trials); sex: not specified (presumably both sexes)

Disease model glioma (including glioblastoma multiforme and astrocytoma) / brain tumors

Outcomes and Safety

Summary of Outcomes Focused ultrasound (FUS) transiently and reversibly opened the blood–brain barrier and increased intraparenchymal drug uptake (reported increases e.g., paclitaxel ~3.7×, carboplatin ~5.9×, TMZ up to ~7.7×) with successful parameter regimes including low-frequency sonication (≈220–500 kHz) delivered by MRgFUS (ExAblate), neuronavigation systems (NaviFUS/UltraNav) or implanted SonoCloud, acoustic pressures in the ~0.78–1.03 MPa range (corresponding to MIs ~0.66–1.03) or powers ~3–24 W (reported up to 47 W), short duty cycles (~0.74–2.4%), and sonication durations of order ~50–270 s (SonoCloud showing BBBO resolving within ~1 h).

Duration of biological effect 24 h

Safety-related matter FUS-mediated BBB opening was generally reported as feasible and safe in early-phase trials, but adverse events included transient headaches, neurological deficits (weakness, dysarthria, dysphasia), seizures, and imaging abnormalities (brain edema, microhemorrhage); systemic toxicities related to concomitant chemotherapy (neutropenia, leukopenia, hypertension) were common and one trial reported dose-limiting encephalopathy at the highest paclitaxel dose that resolved after dose reduction. MRI changes and most neurologic effects were typically transient or steroid-responsive, and investigators note the need for careful ultrasound parameter control (e.g., MI <0.8) to minimise risks.

Brain Region

Visualization unavailable

Ultrasound Parameters

FUS Mode pulsed

Focal Characteristics Focal depth: None; Focal length: None; Aperture size: None

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