Safety and feasibility of multiple blood-brain barrier disruptions for the treatment of glioblastoma in patients undergoing standard adjuvant chemotherapy

Restricted access

OBJECTIVE

Glioblastoma (GBM) remains fatal due to the blood-brain barrier (BBB), which interferes with the delivery of chemotherapeutic agents. The purpose of this study was to evaluate the safety and feasibility of repeated disruption of the BBB (BBBD) with MR-guided focused ultrasound (MRgFUS) in patients with GBM during standard adjuvant temozolomide (TMZ) chemotherapy.

METHODS

This study was a prospective, single-center, single-arm study. BBBD with MRgFUS was performed adjacent to the tumor resection margin on the 1st or 2nd day of the adjuvant TMZ chemotherapy at the same targets for 6 cycles. T2*-weighted/gradient echo (GRE) MRI was performed immediately after every sonication trial, and comprehensive MRI was performed at the completion of all sonication sessions. Radiological, laboratory, and clinical evaluations were performed 2 days before each planned BBBD.

RESULTS

From September 2018, 6 patients underwent 145 BBBD trials at various locations in the brain. The authors observed gadolinium-enhancing spots at the site of BBBD on T1-weighted MRI in 131 trials (90.3%) and 93 trials (64.1%) showed similar spots on T2*-weighted/GRE MRI. When the 2 sequences were combined, BBBD was observed in 134 targets (92.4%). The spots disappeared on follow-up MRI. There were no imaging changes related to BBBD and no clinical adverse effects during the 6 cycles.

CONCLUSIONS

This study is the first in which repetitive MRgFUS was performed at the same targets with a standard chemotherapy protocol for malignant brain tumor. BBBD with MRgFUS was performed accurately, repeatedly, and safely. Although a longer follow-up period is needed, this study allows for the possibility of other therapeutic agents that previously could not be used due to the BBB.

Clinical trial registration no.: NCT03712293 (clinicaltrials.gov)

ABBREVIATIONS AU = arbitrary unit; BBB = blood-brain barrier; BBBD = disruption of the BBB; GBM = glioblastoma; GRE = gradient echo; MB = microbubble; MRgFUS = MR-guided focused ultrasound; P-gp = P-glycoprotein 1; TMZ = temozolomide.
Article Information

Contributor Notes

Correspondence Jin Woo Chang: Yonsei University College of Medicine, Seoul, Republic of Korea. jchang@yuhs.ac.INCLUDE WHEN CITING Published online January 3, 2020; DOI: 10.3171/2019.10.JNS192206.Disclosures Dr. J. W. Chang received funding from InSightec for this clinical trial. Mr. Rachmilevitch and Dr. Zadicario are employees of InSightec.
Headings
References
  • 1

    Adkins CEMittapalli RKManda VKNounou MIMohammad ASTerrell TB: P-glycoprotein mediated efflux limits substrate and drug uptake in a preclinical brain metastases of breast cancer model. Front Pharmacol 4:1362013

    • Search Google Scholar
    • Export Citation
  • 2

    Ayaz MBoikov ASHaacke EMKido DKKirsch WM: Imaging cerebral microbleeds using susceptibility weighted imaging: one step toward detecting vascular dementia. J Magn Reson Imaging 31:1421482010

    • Search Google Scholar
    • Export Citation
  • 3

    Chang WSJung HHZadicario ERachmilevitch ITlusty TVitek S: Factors associated with successful magnetic resonance-guided focused ultrasound treatment: efficiency of acoustic energy delivery through the skull. J Neurosurg 124:4114162016

    • Search Google Scholar
    • Export Citation
  • 4

    Deng JHuang QWang FLiu YWang ZWang Z: The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles. J Mol Neurosci 46:6776872012

    • Search Google Scholar
    • Export Citation
  • 5

    Fan CHTing CYChang YCWei KCLiu HLYeh CK: Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood-brain barrier opening and brain-tumor drug delivery. Acta Biomater 15:891012015

    • Search Google Scholar
    • Export Citation
  • 6

    Hochberg FHPruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30:9079111980

  • 7

    Hynynen KJolesz FA: Demonstration of potential noninvasive ultrasound brain therapy through an intact skull. Ultrasound Med Biol 24:2752831998

    • Search Google Scholar
    • Export Citation
  • 8

    Hynynen KMcDannold NVykhodtseva NJolesz FA: Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology 220:6406462001

    • Search Google Scholar
    • Export Citation
  • 9

    Idbaih ACanney MBelin LDesseaux CVignot ABouchoux G: Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. Clin Cancer Res 25:379338012019

    • Search Google Scholar
    • Export Citation
  • 10

    Kinoshita MMcDannold NJolesz FAHynynen K: Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Proc Natl Acad Sci U S A 103:11719117232006

    • Search Google Scholar
    • Export Citation
  • 11

    Lipsman NMeng YBethune AJHuang YLam BMasellis M: Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun 9:23362018

    • Search Google Scholar
    • Export Citation
  • 12

    Mainprize TLipsman NHuang YMeng YBethune AIronside S: Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 9:3212019

    • Search Google Scholar
    • Export Citation
  • 13

    O’Reilly MAHough OHynynen K: Blood-brain barrier closure time after controlled ultrasound-induced opening is independent of opening volume. J Ultrasound Med 36:4754832017

    • Search Google Scholar
    • Export Citation
  • 14

    O’Reilly MAHynynen K: Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller. Radiology 263:961062012

    • Search Google Scholar
    • Export Citation
  • 15

    Ostrom QTGittleman HFulop JLiu MBlanda RKromer C: CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro Oncol 17 (Suppl 4):iv1iv622015

    • Search Google Scholar
    • Export Citation
  • 16

    Pandey PKSharma AKGupta U: Blood brain barrier: an overview on strategies in drug delivery, realistic in vitro modeling and in vivo live tracking. Tissue Barriers 4:e11294762015

    • Search Google Scholar
    • Export Citation
  • 17

    Patrick JTNolting MNGoss SADines KAClendenon JLRea MA: Ultrasound and the blood-brain barrier. Adv Exp Med Biol 267:3693811990

    • Search Google Scholar
    • Export Citation
  • 18

    Sheikov NMcDannold NSharma SHynynen K: Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium. Ultrasound Med Biol 34:109311042008

    • Search Google Scholar
    • Export Citation
  • 19

    Song KHHarvey BKBorden MA: State-of-the-art of microbubble-assisted blood-brain barrier disruption. Theranostics 8:439344082018

    • Search Google Scholar
    • Export Citation
  • 20

    Stepanenko AAChekhonin VP: Recent advances in oncolytic virotherapy and immunotherapy for glioblastoma: a glimmer of hope in the search for an effective therapy? Cancers (Basel) 10:102018

    • Search Google Scholar
    • Export Citation
  • 21

    Stupp RHegi MEMason WPvan den Bent MJTaphoorn MJJanzer RC: Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:4594662009

    • Search Google Scholar
    • Export Citation
  • 22

    Stupp RMason WPvan den Bent MJWeller MFisher BTaphoorn MJ: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:9879962005

    • Search Google Scholar
    • Export Citation
  • 23

    Yang FYFu WMChen WSYeh WLLin WL: Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood-brain-barrier disruption. Ultrason Sonochem 15:6366432008

    • Search Google Scholar
    • Export Citation
TrendMD
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 350 350 350
Full Text Views 120 120 120
PDF Downloads 78 78 78
EPUB Downloads 0 0 0
PubMed
Google Scholar