Introduction
Methodology
Results
Study and therapy characteristics
Authors | Stage | Country | Disease | Sample size (n) | Sample type | Therapy | F/U |
---|---|---|---|---|---|---|---|
Mehier-Humbert et al. (2005)[29] | 0 | Switzerland | Mammary carcinoma | NR | Rat MAT B III cells (in vitro) | Device: Sonoporation via 1.15 MHz air backed transducer and a 2.25 MHz FUS transducer combined with US contrast agent (UCA) | None |
Kinoshita et al (2006)[17] | 0 | USA | NR | NR | Mouse brain (in & ex vivo) | Drug: Herceptin Device: 0.69-MHz FUS transducer and the injection of 50 μl of Optison (GE Healthcare) + MRI | None |
McDannold et al (2006)[25] | 0 | USA | NR | 9 | Rabbit brain (in & ex vivo) | Device: FUS exposures in conjunction with an US contrast agent (Optison) + passive cavitation detector | None |
Treat et al. (2007)[40] | 0 | USA | NR | 2 | Rat brain (in & ex vivo) | Drug: Doxorubicin Device: FUS exposure in conjunction with an US contrast agent (Optison) | None |
Mei et al. (2009)[30] | 0 | China | NR | 20 | Rabbit brain (in & ex vivo) | Drug: Methotrexate (MTX) Device: FUS using in-house–manufactured single-element focused transducer with contrast agent (SonoVue; Bracco Imaging, Geneva, Switzerland) + 1.5-T MRI (Magnetom Symphony; Siemens AG) | None |
Liu et al. (2010)[20] | 0 | USA | NR | NR | Porcine brain and rat brain + human tumor (in vitro), cynomol- gus monkey brain (in & ex vivo) | Device: 3 custom-built, non-focused, piezoelectric transducers (CytoDome Inc., Atlanta, Georgia, USA) with operating frequencies of 85 kHz, 174 kHz, and 1 MHz | None |
Liu et al. (2010)[21] | 0 | Taiwan | NR | NR | Rat brain (in & ex vivo) + Rat glioma C6 cells (in vitro) | Device: MR compatible spherical US transducer (diameter, 60 mm; radius of curvature, 80 mm; frequency, 400 kHz, electric-to-acoustic efficiency, 70%; Imasonics) | None |
McDannold et al. (2012)[27] | 0 | USA | NR | 7 | Rhesus macaques brain (in & ex vivo) | Device: ExAblate 4000 low-frequency TcMRgFUS system (InSightec; 30-cm-diameter hemispherical 1,024-element phased array transducer operating at 220 kHz coupled with a 1,024-channel driving system, a treatment planning workstation, and a water cooling/circulation/ degassing system) | None |
Ziadloo et al. (2013)[43] | 0 | USA | NR | NR | Murine SCC (SCCVII) cell line implanted onto female mice (in & ex vivo) | Drug: naked TNF-alpha plasmid Device: custom built, image guided, FUS system, modified from a SonoblateVR 500 (Focus Surgery, Indianapolis, IN; 1 MHz, at a spatial average, temporal peak intensity of 2660W cm–2, using 50 ms pulses, given at a pulse repetition frequency of 1 Hz) | None |
Hsu et al. (2013)[12] | 0 | Taiwan | NR | 74 | Mouse brain (in & ex vivo) | Drug: Recombinant adeno-associated viral (rAAV) vectors Device: 0.3 mL/kg microbubbles bolus injection (SonoVueH SF6-coated ultrasound microbubbles, mean diameter 2–5 mm, 2.5 mg/kg, Bracco Diagnostics Inc., Milan, Italy; 0.03 mL/kg for clinical diagnostic application); ultrasonic energy was delivered to the brain transcranially using a spherically focused transducer (Imasonics, Besancon, France; diameter = 60 mm, radius of curvature = 80 mm, frequency = 1.5 MHz) | 1–6 weeks |
Wei et al. (2013)[42] | 0 | Taiwan | GBM | 85 | 9L rat glioma cell implanted onto mouse brain (in & ex vivo) | Drug: Temozolomide (TMZ) Device: FUS transducer (Imasonics, Besancon, France; diameter = 60 mm, radius of curvature = 80 mm, frequency = 500 kHz) was used to generate concentrated ultrasound energy"—"arbitraryfunction generator (33120A, Agilent, Palo Alto, CA; and DS345, Stanford Research Systems, Sunnyvale, CA) was used to produce the driving signal, which was fed to a radio frequency power amplifier (150A100B, Amplifier Research, Souderton, PA) operating in burst mode" | 7–40 days |
Alonso et al. (2013)[1] | 0 | Germany | NR | 14 | Rat brain (in & ex vivo) | Drug: Chimeric adeno-associated virus 2/1 (AAV2/1) Device: 500 kHz transducer (H-104MR) driven by a function generator (Agilent 33,120 A Function/Arbitrary Waveform Generator; Agilent Technologies, Santa Clara, CA) and amplifier (model 40AD1; AR Amplifier Research, Souderton, PA) | None |
Fan et al. (2015)[7] | 0 | Taiwan | Glioma | NR | Rat brain (in & ex vivo) | Drug: 1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU Device: The first FUS transducer operated at 1 MHz (diameter = 25.4 mm focus length = 52.7 mm; V302, Panametrics, MA, USA) and the second at 10 MHz (diameter = 23.0 mm, focus length = 31.0 mm; SU-110, Sonic Concepts Inc., WA, USA). A function generator (WW2571, Tabor Electronics, Haifa, Israel) created sonication pulses which were amplified with a radio frequency (RF) power amplifier (150A100B, AR, PA, USA) to drive the transducer | 6–35 days |
Chen et al. (2015)[4] | 0 | Taiwan | Glioma | 50 | Healthy and tumor-bearing rats (in & ex vivo) | Drug: Interleukin-12 Device: Focused US transducer (Sonic Concepts, Seattle, WA, USA) + MRI + microbubbles | 27–45 days |
McDannold et al. (2019)[28] | 0 | USA | Glioma | 23 | Healthy and tumor-bearing rats (in & ex vivo) | Drug: Carboplatin Device: ExAblate Neuro low-frequency TcMRgFUS system (InSightec) + MRI + microbubbles | 23–53 days |
Carpentier A et al. (2016)[3] | 1/2a | France | Recurrent GBM | 15 | Humans | Drug: Carboplatin Device: 11.5-mm SonoCloud (CarThera) US device + MRI | 2–6 months |
Mainprize, T et al. (2019)[23] | 1 | Canada | Glioma | 5 | Humans | Drug: n = 1 liposomal doxorubicin, n = 4 temozolomide Device: ExAblate Neuro (InSightec Tirat Carmel, Israel) system MRgFUS (MRI) | 3 months |
Idbaih A et al. (2019)[14] | 1 | France | GBM | 19 | Humans | Drug: Carboplan Device: 1-MHz, 11.5-mm diameter cranial US device (SonoCloud-1, CarThera) + MRI | 12 months |
Park SH et al. (2020)[34] | 1/2a | South Korea | GBM | 6 | Humans | Drug: TMZ Device: ExAblate low-frequency MRgFUS system (ExAblate Neuro Model 4000 Type 2.0 220 kHz system, InSightec, Haifa, Israel) + MRI + IV microbubble | 15.17 ± 1.72 months |
NCT | Year | Status | Stage | Disease | Therapy | Primary outcome measure | Sample size (n) | Age limit |
---|---|---|---|---|---|---|---|---|
NCT04804709 | 2021 | Active, not recruiting | 1 | Diffuse Intrinsic Pontine Glioma Diffuse Pontine and Thalamic Gliomas Diffuse Midline Glioma, H3 K27M-Mutant | Drug: Panobinostat Device: Focused Ultrasound with neuro-navigator-controlled sonication | AE | 3 | 4—21 |
NCT03744026 | 2018 | Active, not recruiting | 1/2a | Recurrent glioblastoma | Drug: Carboplatin (AUC 4–6) Device: SonoCloud-9 | 1) Dose limiting toxicity (DLT) of number of activated ultrasound beams 2) BBB opening will be evaluated by contrast-enhanced T1w magnetic resonance imaging (MR | 33 | ≥ 18 |
NCT04614493 | 2020 | Active, recruiting | 2 | Newly diagnosed glioblastoma | Drug: Temozolomide Device: SonoCloud-9 (SC9) device | PFS | 66 | ≥ 18 |
NCT04528680 | 2020 | Active, recruiting | 1/2a | Recurrent glioblastoma | Drug: Albumin-bound paclitaxel (stage 1 and 2), Carboplatin (stage 2) Device: Sonication for opening of blood–brain barrier | Dose limiting toxicity (Phase1) 1-year survival rate (Stage 2) | 39 | ≥ 18 |
NCT04021420 | 2019 | Active, recruiting | 1/2a | Metastatic melanoma | Drug: Nivolumab Device: SONOCLOUD | MSD | 21 | > 18 |
NCT03551249 | 2019 | Active, not recruiting | 1 | Glioblastoma | Device: FUS ExAblate, Type 2 | AE | 20 | 18—80 |
NCT03616860 | 2018 | Active, not recruiting | 1 | Glioblastoma | Device: FUS BBB Disruption Exablate Neuro | AE | 20 | 18—80 |
NCT03714243 | 2019 | Active, recruiting | 1 | Breast cancer metastases | Device: ExAblate Model 4000 Type-2 | AE | 10 | 18—80 |
NCT03712293 | 2018 | Unknown | 1 | Glioblastoma | Drug: Temozolomide Device: ExAblate Type 2.0 BBBD | AE | 10 | 19—80 |
NCT04440358 | 2020 | Active, recruiting | 1/2a | Recurrent glioblastoma | Drug: Carboplatin Device: ExAblate Type 2.0 BBBD | AE | 50 | 18 -80 |
NCT04417088 | 2020 | Active, recruiting | 1/2a | Recurrent glioblastoma | Drug: Carboplatin Device:ExAblate Type 2.0 BBBD | AE | 30 | 18—80 |
NCT04446416 | 2020 | Active, recruiting | 1/2a | Recurrent glioblastoma | Drug: Bevacizumab Device: NaviFUS System | AE & PFS at 6 months | 10 | 18—80 |
Outcomes and complications
Authors | Primary & secondary outcomes | Main findings | Complications and SE |
---|---|---|---|
Mehier-Humbert et al. (2005)[29] | 1) Size of the pores; 2) Duration of pore opening | 1) Internalization of molecules with diameters up to 37 nm using sonification was efficient and occurred with little complications, but 75 nm particles entered only a few cells | NR |
Kinoshita et al (2006)[17] | 1) Leakage through the BBB; 2) Herceptin delivered through the BBB; 3) Histological damage | 1) Herceptin can be delivered into the mouse CNS through the BBB employing an MRI-guided FUS; 2) Amount of Herceptin delivered correlated with extent of barrier opening; 3) Few adverse histological changes | 1) None |
McDannold et al (2006)[25] | 1) Association of cavitation activity with the induction of blood–brain barrier disruption (BBBD) | 1) BBBD resulting from focused ultrasound pulses in the presence of Optison occur without indicators for inertial cavitation in vivo, wideband emission and extravasation | NR |
Treat et al. (2007)[40] | 1) Successful BBB disruption; 2) Fluorometric measurements of DOX; 3) Histological damage; 4) Correlation of MRI signal and DOX delivery | 1) Targeted delivery by focused ultrasound may make DOX chemotherapy a viable treatment option against CNS tumors; 2) MRI signal enhancement in the sonicated region correlated strongly with tissue DOX concentration | 1) Severe macroscopic tissue damage in rats administered 0.5 mL/kg Optison |
Mei et al. (2009)[30] | 1) Optimal exposure time for reversible BBB disruption; 2) Comparison to cohort with internal carotid artery (ICA) injections of MTX | 1) MTX concentration in the sonicated group notably higher than that in the IV control group and ICA group (p < 0.01) | 1) Degree of vascular effects and tissue necrosis correlated with increased exposure |
Liu et al. (2010)[20] | 1) Successful transport of large molecules across brain tissue in vitro; 2) Validation by examining the effect of US in monkey brain in vivo | 1) Exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritiumlabeled molecules with molecular weight up to 70 kDa across porcine brain tissue | NR |
Liu et al. (2010)[21] | 1) Successful delivery of macromolecular therapeutic agents to the CNS; 2) Ideal use of technology | 1) FUS can temporarily disrupt the BBB, increasing local EPR in the CNS; 2) This technology is ideally suited for transcranial delivery of drugs with molecular weights greater than 400 Da | 1) Penetration is hampered at molecular weights of 2,000 kDa |
McDannold et al. (2012)[27] | 1) Identification of a safety window for BBB disruption without evident tissue damage | 1) Study shows feasibility of reliably and repeatedly inducing focal BBB disruption without significant vascular or brain tissue damage in a clinically-relevant animal model using a TcMRgFUS system designed for human use | NR |
Ziadloo et al. (2013)[43] | 1) Effect of exposure on tumor growth | 1) Exposures alone had no effect on tumor growth; 2) Significant growth inhibition was observed with injection of TNF-a plasmid, tumor growth was inhibited with pFUS | NR |
Hsu et al. (2013)[12] | 1) Successful delivery of AAV2 vector and GFP expression | 1) IV-administered AAV2-GFP (green fluorescence protein) with a low viral vector titer (16109 vg/g) can successfully penetrate the BBB-opened brain regions to express GFP | NR |
Wei et al. (2013)[42] | 1) Effects of treatment on tumor progression, animal survival, and brain tissue histology | 1) Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days | NR |
Alonso et al. (2013)[1] | 1) Successful opening of the BBB, gene transfer, and expression rate in transduced cells | 1) Chimeric adeno-associated virus 2/1 (AAV2/1) particles containing the coding region for the LacZ gene were efficiently delivered into the rat brain upon IV administration after BBB FUS opening with vascular acoustic resonators | NR |
Fan et al. (2015)[7] | 1) Successful FUS-induced drug release by acoustic emission; 2) In vivo BBB opening by FUS exposure with BCNU bubbles | 1) Excitation of BCNU bubbles by FUS resulted in stable cavitation, significantly reduced the occurrence of hazards of exposure; 2) BCNU bubbles with FUS showed control of tumor progression, improved survival from 26 to 35 days | NR |
Chen et al. (2015)[4] | 1) Efficacy in inducing BBB opening; 2) Effect on tumor progression; 3) Effect of the immune response | 1) BBB opening had no effect on T lymphocytes; 2) IL-12 administration triggered increase in all TIL populations; 3) Combined FUS-BBB opening with IL-12 administration produced most significant IL-12 increase | NR |
McDannold et al. (2019)[28] | 1) Safety; 2) Efficiency of opening BBB; 3) Survival | 1) Tumor volume doubling time FUS and carboplatin in rats increased by 96% and 126% compared to rats that received carboplatin alone and non-sonicated controls; 2) Increases in median survival were 48% and 66% | 1) None |
Carpentier A et al. (2016)[3] | 1) Feasibility of repeated transient opening of the BBB by pulsed US; 2) Safety of procedure with recurrent GBM before receiving chemotherapy | 1) Contrast-enhanced MRI indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic or clinical examination | 1) None |
Mainprize, T et al. (2019)[23] | 1) Safety and feasibility of opening the BBB in brain tumor patients using MRgFUS; 2) Feasibility of chemotherapy delivery | 1) The BBB within the target volume showed radiographic evidence of opening with an immediate 15–50% increased contrast enhancement; 2) Biochemical analysis suggest chemotherapy delivery is safe and feasible | 1) None |
Idbaih A et al. (2019)[14] | 1) Safety and tolerance to sonication with the SonoCloud-1 device; 2) Disruption of the BBB using the SonoCloud-1 system; 3) PFS and the OS of the patients treated with SonoCloud-1 device; 4) Biocompatibility of the device; 5) Practical feasibility for future trials | 1) Patients with no or poor BBB disruption visible on MRI had a median progression-free survival (PFS) of 2.73 months, and a median overall survival (OS) of 8.64 months; 2) Patients with clear BBB disruption had a median PFS of 4.11 months, and a median OS of 12.94 months | NR |
Park SH et al. (2020)[34] | 1) Survival; 2) Recurrence; 3) MRgFUS related complications | 1) Survival rate up to 1 year was 100% | 1) No short- or long-term complications from BBBD; 2) Two patients (of six) had GBM recurrence |