Efficacy and safety of low- and high-intensity focused ultrasound in glioblastoma: a systematic review of preclinical and clinical studies

BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumour with a poor prognosis despite existing multimodal treatments, limited by the blood-brain barrier (BBB) and high recurrence rates. Focused ultrasound (FUS), encompassing low-intensity (LIFU) and high-intensity (HIFU) modalities, offers non-invasive approaches to enhance drug delivery and ablate tumour tissue, respectively. To systematically evaluate the efficacy and safety of LIFU-mediated BBB opening and HIFU-induced thermal ablation in GBM treatment, comparing preclinical and clinical outcomes. METHODS: This review searched PubMed, Scopus, and Web of Science (August 2024) for studies on FUS in GBM. Preclinical and clinical studies reporting efficacy (tumour response, survival) and safety outcomes were included. Data were extracted using a standardised form, with quality assessed via SYRCLE (preclinical) and ROBINS-I (clinical) tools. Narrative synthesis was performed due to study heterogeneity. RESULTS: From 1817 records, 40 studies (26 preclinical, 14 clinical with 139 patients) were included. LIFU enhanced delivery of chemotherapies, immunotherapies, and nanoparticles, reducing tumour growth and extending survival in preclinical models (e.g., 26-81.2 days vs. 18-30.4 days), with clinical trials showing progression-free survival of 2.5-4.11 months, overall survival of 10-14 months, and 100% one-year survival with temozolomide in a small cohort (n = 6). HIFU achieved ~70% tumour growth inhibition preclinically but only ~10% ablation clinically. Both modalities were safe, with no severe adverse events, only mild, transient effects like petechiae (LIFU) and warmth (HIFU). CONCLUSIONS: LIFU and HIFU are promising, complementary GBM treatments, with LIFU excelling in drug delivery and HIFU in ablation. Large-scale, multicentre randomised controlled trials with standardised parameters are needed to validate their efficacy and safety and optimise their integration into clinical practice. PROSPERO REGISTRATION: CRD42024627213.