Abstract
Introduction
Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision.
Methods
A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology.
Results
Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood–brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood–brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood–brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound.
Conclusions
Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.
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Data availability
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
Ghanouni P et al (2015) Transcranial MR-guided focused ultrasound: a review of the technology and neuro applications. AJR Am J Roentgenol 205:150–159
Hughes A, Huang Y, Schwartz ML, Hynynen K (2018) The reduction in treatment efficiency at high acoustic powers during MR-guided transcranial focused ultrasound thalamotomy for essential tremor. Med Phys 45:2925–2936
McDannold N, Clement GT, Black P, Jolesz F, Hynynen K (2010) Transcranial magnetic resonance imaging–guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 66:323–332
Coluccia D et al (2014) First noninvasive thermal ablation of a brain tumor with MR-guided focused ultrasound. J Ther Ultrasound 2:17
Roberts WW (2014) Development and translation of histotripsy: current status and future directions. Curr Opin Urol 24:104–110
Bader KB, Vlaisavljevich E, Maxwell AD (2019) For whom the bubble grows: physical principles of bubble nucleation and dynamics in histotripsy ultrasound therapy. Ultrasound Med Biol 45:1056–1080
Sukovich JR et al (2018) In vivo histotripsy brain treatment. J Neurosurg 131:1331–1338
Lu N et al (2021) Transcranial MR-guided histotripsy system. IEEE Trans Ultrasonics Ferroelectr Freq Control. https://doi.org/10.1109/TUFFC.2021.3068113
Qu S, Worlikar T, Felsted AE, Ganguly A, Beems MV, Hubbard R, Pepple AL, Kevelin AA, Garavaglia H, Dib J, Toma M, Huang H, Tsung A, Xu Z, Cho CS (2020) Non-thermal histotripsy tumor ablation promotes abscopal immune responses that enhance cancer immunotherapy. J Immunother Cancer 8:e000200
Singh MP, Sethuraman SN, Miller C, Malayer J, Ranjan A (2021) Boiling histotripsy and in-situ CD40 stimulation improve the checkpoint blockade therapy of poorly immunogenic tumors. Theranostics 11:540–554
Ganguly A, Pepple A, McGinnis R et al (2020) 730 Histotripsy focused ultrasound ablation induces immunological cell death in treated and distant untreated tumors. J ImmunoTher Can. https://doi.org/10.1136/jitc-2020-SITC2020.0730
Schuster TG, Wei JT, Hendlin K, Jahnke R, Roberts WW (2018) Histotripsy treatment of benign prostatic enlargement using the Vortx Rx system: initial human safety and efficacy outcomes. Urology 114:184–187
Messas E et al (2021) Feasibility and performance of noninvasive ultrasound therapy in patients with severe symptomatic aortic valve stenosis. Circulation 143:968–970
Fotinos N, Campo MA, Popowycz F, Gurny R, Lange N (2006) 5-Aminolevulinic acid derivatives in photomedicine: characteristics, application and perspectives. Photochem Photobiol 82:994–1015
Wu S-K, Santos MA, Marcus SL, Hynynen K (2019) MR-guided focused ultrasound facilitates sonodynamic therapy with 5-aminolevulinic acid in a rat glioma model. Sci Rep 9:10465
Lyon PC et al (2018) Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial. Lancet Oncol 19:1027–1039
Fabiilli ML et al (2010) Delivery of chlorambucil using an acoustically-triggered perfluoropentane emulsion. Ultrasound Med Biol 36:1364–1375
Zardad A-Z et al (2016) A review of thermo- and ultrasound-responsive polymeric systems for delivery of chemotherapeutic agents. Polymers 8:359
Sarkaria JN et al (2018) Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data. Neuro Oncol 20:184–191
Leten C, Struys T, Dresselaers T, Himmelreich U (2014) In vivo and ex vivo assessment of the blood brain barrier integrity in different glioblastoma animal models. J Neurooncol 119:297–306
de Gooijer MC et al (2021) ATP-binding cassette transporters restrict drug delivery and efficacy against brain tumors even when blood-brain barrier integrity is lost. Cell Rep Med 2:100184
Meng Y et al (2019) Safety and efficacy of focused ultrasound induced blood-brain barrier opening, an integrative review of animal and human studies. J Control Release 309:25–36
Burgess A, Hynynen K (2014) Drug delivery across the blood–brain barrier using focused ultrasound. Expert Opin Drug Deliv 11:711–721
Cho H et al (2016) Localized down-regulation of P-glycoprotein by focused ultrasound and microbubbles induced blood-brain barrier disruption in rat brain. Sci Rep 6:31201
Marty B et al (2012) Dynamic study of blood-brain barrier closure after its disruption using ultrasound: a quantitative analysis. J Cereb Blood Flow Metab 32:1948–1958
Lipsman N et al (2018) Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 9:1–8
Treat LH et al (2007) Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound. Int J Cancer 121:901–907
McDannold N et al (2019) Acoustic feedback enables safe and reliable carboplatin delivery across the blood-brain barrier with a clinical focused ultrasound system and improves survival in a rat glioma model. Theranostics 9:6284–6299
Liu H-L et al (2014) Pharmacodynamic and therapeutic investigation of focused ultrasound-induced blood-brain barrier opening for enhanced temozolomide delivery in glioma treatment. PLoS ONE 9:e114311
Arvanitis CD et al (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci USA 115:E8717–E8726
Hooge MNL et al (2004) Preclinical characterisation of 111In-DTPA-trastuzumab. Br J Pharmacol 143:99–106
Tran VL et al (2020) Impact of blood-brain barrier permeabilization induced by ultrasound associated to microbubbles on the brain delivery and kinetics of cetuximab: an immunoPET study using 89Zr-cetuximab. J Control Release 328:304–312
Alkins R et al (2013) Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Cancer Res 73:1892–1899
DeCordova S et al (2020) Molecular heterogeneity and immunosuppressive microenvironment in glioblastoma. Front Immunol 11:1402
Aryal M, Vykhodtseva N, Zhang Y-Z, Park J, McDannold N (2013) Multiple treatments with liposomal doxorubicin and ultrasound-induced disruption of blood–tumor and blood–brain barriers improve outcomes in a rat glioma model. J Control Release 169:103–111
Mainprize T et al (2019) Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 9:321
Idbaih A et al (2019) Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res 25:3793–3801
Chen K-T et al (2021) Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. Sci Adv 7:eabd0772
Carpentier A et al (2016) Clinical trial of blood-brain barrier disruption by pulsed ultrasound. Sci Transl Med 8:343
Park SH et al (2020) One-year outcome of multiple blood-brain barrier disruptions with temozolomide for the treatment of glioblastoma. Front Oncol 10:1663
Park SH et al (2020) Safety and feasibility of multiple blood-brain barrier disruptions for the treatment of glioblastoma in patients undergoing standard adjuvant chemotherapy. J Neurosurg. https://doi.org/10.3171/2019.10.JNS192206
Lobbezoo DJA et al (2015) Prognosis of metastatic breast cancer: are there differences between patients with de novo and recurrent metastatic breast cancer? Br J Cancer 112:1445–1451
Witzel I, Oliveira-Ferrer L, Pantel K, Müller V, Wikman H (2016) Breast cancer brain metastases: biology and new clinical perspectives. Breast Cancer Res 18:8
Yonemori K et al (2010) Disruption of the blood brain barrier by brain metastases of triple-negative and basal-type breast cancer but not HER2/neu-positive breast cancer. Cancer 116:302–308
Terrell-Hall TB, Nounou MI, El-Amrawy F, Griffith JIG, Lockman PR (2017) Trastuzumab distribution in an in-vivo and in-vitro model of brain metastases of breast cancer. Oncotarget 8:83734–83744
Wu S-K et al (2014) Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer. Int J Nanomed 9:4485–4494
Park E-J, Zhang Y-Z, Vykhodtseva N, McDannold N (2012) Ultrasound-mediated blood-brain/blood-tumor barrier disruption improves outcomes with trastuzumab in a breast cancer brain metastasis model. J Control Release 163:277–284
Arvanitis CD et al (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption. PNAS 115:E8717–E8726
Alkins R, Burgess A, Kerbel R, Wels WS, Hynynen K (2016) Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival. Neuro Oncol 18:974–981
Vanan MI, Eisenstat DD (2015) DIPG in children—what can we learn from the past? Front Oncol 5:237
Hargrave D, Bartels U, Bouffet E (2006) Diffuse brainstem glioma in children: critical review of clinical trials. Lancet Oncol 7:241–248
Green AL, Kieran MW (2015) Pediatric brainstem gliomas: new understanding leads to potential new treatments for two very different tumors. Curr Oncol Rep 17:12
Schroeder KM, Hoeman CM, Becher OJ (2014) Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology. Pediatr Res 75:205–209
Himes BT, Zhang L, Daniels DJ (2019) Treatment strategies in diffuse midline gliomas with the H3K27M mutation: the role of convection-enhanced delivery in overcoming anatomic challenges. Front Oncol 9:1–10
Alli S et al (2018) Brainstem blood brain barrier disruption using focused ultrasound: a demonstration of feasibility and enhanced doxorubicin delivery. J Control Release 281:29–41
Englander ZK et al (2021) Focused ultrasound mediated blood–brain barrier opening is safe and feasible in a murine pontine glioma model. Sci Rep 11:1–10
Zhang X et al (2020) Magnetic resonance imaging-guided focused ultrasound-based delivery of radiolabeled copper nanoclusters to diffuse intrinsic pontine glioma. ACS Appl Nanomater 3:11129–11134
Ishida J et al (2021) MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma. J Control Release 330:1034–1045
Ye D et al (2018) Focused ultrasound-enabled delivery of radiolabeled nanoclusters to the pons. J Controlled Release 283:143–150
Van Vulpen M, Kal HB, Taphoorn MJB, El Sharouni SY (2002) Changes in blood-brain barrier permeability induced by radiotherapy: implications for timing of chemotherapy? (Review). Oncol Rep 9:683–688
Englander ZK et al (2020) Focused ultrasound-mediated blood brain barrier opening is safe and feasible in diffuse intrinsic pontine glioma after radiation treatment. Int J Radiat Oncol Biol Phys 108:e242
Zhu L et al (2019) Ultrasound hyperthermia technology for radiosensitization. Ultrasound Med Biol 45:1025–1043
Merchant TE, Conklin HM, Wu S, Lustig RH, Xiong X (2009) Late effects of conformal radiation therapy for pediatric patients with low-grade glioma: prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27:3691–3697
Sneed PK et al (1998) Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40:287–295
Schneider CS, Woodworth GF, Vujaskovic Z, Mishra MV (2020) Radiosensitization of high-grade gliomas through induced hyperthermia: review of clinical experience and the potential role of MR-guided focused ultrasound. Radiother Oncol 142:43–51
Guthkelch AN et al (1991) Treatment of malignant brain tumors with focused ultrasound hyperthermia and radiation: results of a phase I trial. J Neurooncol 10:271–284
Wang T-Y et al (2009) Quantitative ultrasound backscatter for pulsed cavitational ultrasound therapy-histotripsy. IEEE Trans Ultrason Ferroelectr Freq Control 56:995–1005
Wang T-Y, Hall TL, Xu Z, Fowlkes JB, Cain CA (2014) Imaging feedback for histotripsy by characterizing dynamics of acoustic radiation force impulse (ARFI)-induced shear waves excited in a treated volume. IEEE Trans Ultrason Ferroelectr Freq Control 61:1137–1151
Macoskey JJ et al (2018) Bubble-induced color doppler feedback correlates with histotripsy-induced destruction of structural components in liver tissue. Ultrasound Med Biol 44:602–612
O’Reilly MA, Hynynen K (2012) Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions–based controller. Radiology 263:96–106
Fontanilles M, Duran-Peña A, Idbaih A (2018) Liquid biopsy in primary brain tumors: looking for stardust! Curr Neurol Neurosci Rep 18:13
Miller AM et al (2019) Tracking tumour evolution in glioma through liquid biopsies of cerebrospinal fluid. Nature 565:654–658
Bettegowda C et al (2014) Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 6:224
Pacia CP et al (2020) Feasibility and safety of focused ultrasound-enabled liquid biopsy in the brain of a porcine model. Sci Rep 10:7449
Zhu L et al (2018) Focused ultrasound-enabled brain tumor liquid biopsy. Sci Rep 8:6553
Meng Y et al (2021) Focused ultrasound enabled liquid biopsy enriches the signal of circulating biomarkers in patients with brain tumors (in revision). Neuro-Oncology 23(10):1789–1797. https://doi.org/10.1093/neuonc/noab057
Cohen-Inbar O, Xu Z, Sheehan JP (2016) Focused ultrasound-aided immunomodulation in glioblastoma multiforme: a therapeutic concept. Journal of Therapeutic Ultrasound 4:2
Liu F et al (2010) Boosting high-intensity focused ultrasound-induced anti-tumor immunity using a sparse-scan strategy that can more effectively promote dendritic cell maturation. J Transl Med 8:7
Yuan J, Ye D, Chen S, Chen H (2021) Therapeutic ultrasound-enhanced immune checkpoint inhibitor therapy. Front Phys 9:102
Eranki A et al (2020) High-Intensity Focused Ultrasound (HIFU) triggers immune sensitization of refractory murine neuroblastoma to checkpoint inhibitor therapy. Clin Cancer Res 26:1152–1161
Kovacs ZI et al (2017) Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation. Proc Natl Acad Sci USA 114:E75–E84
McMahon D, Hynynen K (2017) Acute inflammatory response following increased blood-brain barrier permeability induced by focused ultrasound is dependent on microbubble dose. Theranostics 7:3989–4000
Chen P-Y et al (2015) Focused ultrasound-induced blood–brain barrier opening to enhance interleukin-12 delivery for brain tumor immunotherapy: a preclinical feasibility study. J Transl Med 13:1–12
Sabbagh A et al (2021) Opening of the blood-brain barrier using low-intensity pulsed ultrasound enhances responses to immunotherapy in preclinical glioma models. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-20-3760
Arlachov Y, Ganatra RH (2012) Sedation/anaesthesia in paediatric radiology. Br J Radiol 85:e1018–e1031
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YM, CP, and NL conceptualized the project. YM, CP, DB, DL, and SS contributed to literature review. YM and CP wrote the first draft. All authors critically revised the manuscript.
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NL has received honorarium for serving on an expert steering committee for the Focused Ultrasound Foundation. SS is an advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board). Other authors have nothing to disclose.
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Meng, Y., Pople, C.B., Budiansky, D. et al. Current state of therapeutic focused ultrasound applications in neuro-oncology. J Neurooncol 156, 49–59 (2022). https://doi.org/10.1007/s11060-021-03861-0
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DOI: https://doi.org/10.1007/s11060-021-03861-0