Brain Cancer

Background

Clinical Trials SquareThere are many types of cancers in the brain, with glioblastoma IV as the most aggressive type of malignant brain tumor. Overall, there are approximately 140,000 people in the US with brain cancer. This section is limited to malignant tumors, for benign tumors, please see Brain Tumors, Benign. 

Common symptoms include headache; balance or coordination issues; trouble with vision, hearing or mental status symptoms; and/or seizures or numbness of the extremities. Most malignant tumors are metastatic, having spread from cancers primarily located in other organs. Malignant brain tumors are inherently serious and life-threatening — they are invasive and destroy brain tissue, as well as create pressure on brain because of the limited space within the skull.

Not all brain tumors cause symptoms. The most common symptoms that occur could be the result of increased intracranial pressure or damage to/irritation of nerve. Diagnosis is based on clinical evaluation and imaging.

Current Treatment

Treatment options for brain tumors include surgical removal or destruction of the tumor using heat, radiotherapy, and chemotherapy, or a combination of two or more of these modalities:

  • Surgery: complete or partial resection of the tumor to remove as much as possible. This has all the risks of open surgery, including bleeding, sensory and motor weakness, and neurologic injury. For malignant tumors, the challenge of tumor recurrence is a major concern.
  • Radiofrequency ablation: the most commonly used nonsurgical treatment for brain tumors. This stereotactic approach typically uses small lesions, which can limit the accuracy of energy delivery and the effectiveness in larger lesions. It also contains all the risks of invasive procedures.
  • Gamma Knife treatment: the use of Gamma Knife’s non-invasive approach to the patient is very attractive, but the drawbacks are significant. Using ionizing radiation is problematic, especially in pediatric patients. There is also a delayed response to treatment, risks to long term cognitive abilities, and oncologic risks.
  • Laser thermal therapy: is an invasive approach where the cranium is opened for placement of the probe via stereotactic techniques. The probe is then heated and ablates the tissue. While this is less invasive than open techniques, it still carries the risks of open interventions.
  • Chemotherapy: seldom used to treat brain tumors, as the blood-brain barrier prevents the drugs from reaching the cancerous cells.

Focused Ultrasound Treatment

Focused ultrasound has tremendous potential to improve the treatment of certain brain cancers. As this modality is non-invasive and accurate, it may be able to ablate only targeted tissue while sparing healthy adjacent tissue. This is especially critical in the brain where any damage to healthy tissue can result in significant loss of function. In addition, focused ultrasound has the potential to reduce the risk for infection and bleeding, lower procedural morbidity by not opening the skull, and avoid the toxicity of radiation.

Currently, focused ultrasound can effectively target tumors located in the center of the brain, in areas near the thalamus. The Foundation is collaborating with academia and industry on technical research to expand the area of the brain that can be reached by focused ultrasound.

While research continues for direct treatment of brain tumors with thermal heating of the tumor, additional work has expanded to other treatment options. One is to use focused ultrasound’s ability to temporarily disrupt the blood- brain barrier (BBB), which can allow therapeutic agents (genes, antibiotics, or chemotherapy) that cannot normally enter the brain to gain access via the temporary disruption. Another area is to incorporate the therapeutic agents into microbubbles, which will only release their payload when sonicated. This allows the treatment material to only impact the needed region, as opposed to the entire body.

Preclinical Research

Researchers at the University of Virginia - in collaboration with the Foundation and Insightec - are conducting a pre-clinical study to evaluate the safety and efficacy of using focused ultrasound’s different frequencies and impacts to expand the treatment envelope for clinical use.

Another area of research is to use focused ultrasound to temporarily disrupt the BBB, as mentioned above, to understand how this occurs and investigate inflammation that may occur. There is also a multi-site effort to determine the proper pathway, timing and other important factors for this technique.

Another approach that is being investigated is using focused ultrasound to enable the targeted delivery and/or activation of drugs. The goal is to deliver drugs into the brain tumor in high concentrations while minimizing systemic side-effects. One mechanism to accomplish this is embedding the agents in microbubbles, and releasing the agents via sonification.

Also, non-thermal destruction of tissue with focused ultrasound is being evaluated by several sites. In this method the acoustic energy is used to create non-thermal mechanical effects at the focal point which can damage and destroy tissue.

Clinical Trials

The main clinical research is on thermal ablation, implanted device ablation, and disrupting of the BBB to allow therapeutic agent entry. These are still early clinical trials, as optimal timing and methods are still being evaluated.

For a full list of known brain tumor clinical trials, please see here.

The following ongoing studies are recruiting patients with brain tumors for focused ultrasound treatment:

MRI-Guided Focused Ultrasound Feasibility Study for Brain Tumors
Purpose: Investigating the treatment of recurrent metastatic brain tumors using focused ultrasound

  • Swedish Medical Center - Seattle, Washington
    Contact: Colleen Ottinger at 206.320.2804


ExAblate (Magnetic Resonance-guided Focused Ultrasound Surgery) Treatment of Brain Tumors 
Purpose: Investigating a first-line treatment using focused ultrasound for patients with metastatic brain tumors

  • Sunnybrook Health Sciences Centre - Toronto, Canada
  • Contact: Nir Lipsman via email: 


Blood-Brain Barrier Disruption Using Transcranial MRI-Guided Focused Ultrasound 
Purpose: Evaluate the safety of BBB disruption using transcranial MRI-guided focused ultrasound in conjunction with a contrast agent to increase doxorubicin in brain tumours

  • Sunnybrook Health Sciences Centre - Toronto, Canada
  • Contacts: Allison Bethune at

Regulatory Approval and Reimbursement

Focused ultrasound is not approved by any regulatory bodies worldwide as a treatment for brain tumors, nor is it reimbursed by medical insurance providers for such.

More Information

There are many government bodies and patient groups dedicated to brain tumors, including the following:

Notable Papers

FUS for Glioblastoma Workshop PDF - November 9-10, 2015

O'Reilly MA, Hough O, Hynynen K. Blood-Brain Barrier Closure Time After Controlled Ultrasound-Induced Opening Is Independent of Opening Volume. J Ultrasound Med. 2017 Jan 21. doi: 10.7863/ultra.16.02005.

Hersh DS, Kim AJ, Winkles JA, Eisenberg HM, Woodworth GF, Frenkel V. Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation. Neurosurgery. 2016 Nov;79(5):643-654.

Park J, Aryal M, Vykhodtseva N, Zhang YZ, McDannold N. Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption. J Control Release. 2016 Oct 11. pii: S0168-3659(16)30955-5. doi: 10.1016/j.jconrel.2016.10.011.

Ter Haar G. HIFU Tissue Ablation: Concept and Devices. Adv Exp Med Biol. 2016;880:3-20. doi: 10.1007/978-3-319-22536-4_1.

Alkins R, Burgess A, Kerbel R, Wels WS, Hynynen K. Early treatment of HER2-amplified brain tumors with targeted NK-92 cells and focused ultrasound improves survival.
Neuro Oncol. 2016 Jan 26. pii: nov318.

Mead BP, Mastorakos P, Suk JS, Klibanov AL, Hanes J, Price RJ. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J Control Release. 2016 Feb 10;223:109-17. doi: 10.1016/j.jconrel.2015.12.034. Epub 2015 Dec 28.

Timbie KF, Mead BP, Price RJ. Drug and gene delivery across the blood-brain barrier with focused ultrasound. J Control Release. 2015 Dec 10;219:61-75. doi: 10.1016/j.jconrel.2015.08.059. Epub 2015 Sep 8.

Werner B, Martin E. Transcranial focused ultrasound: Neurological applications of magnetic resonance-guided high-intensity focused ultrasound. Radiologe. 2015 Nov;55(11):976-80, 982-3. doi: 10.1007/s00117-015-0026-1. German. 

Endo S, Kudo N, Yamaguchi S, Sumiyoshi K, Motegi H, Kobayashi H, Terasaka S, Houkin K. Porphyrin derivatives-mediated sonodynamic therapy for malignant gliomas in vitro. Ultrasound Med Biol. 2015 Sep;41(9):2458-65. doi: 10.1016/j.ultrasmedbio.2015.05.007. Epub 2015 Jun 10.

Ghanouni P, Pauly KB, Elias WJ, Henderson J, Sheehan J, Monteith S, Wintermark M. Transcranial MRI-Guided Focused Ultrasound: A Review of the Technologic and Neurologic Applications. AJR Am J Roentgenol. 2015 Jul;205(1):150-9. doi: 10.2214/AJR.14.13632.

Kovacs Z, Werner B, Rassi A, Sass JO, Martin-Fiori E, Bernasconi M. Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. J Control Release. 2014 May 27. pii: S0168-3659(14)00336-8. doi: 10.1016/j.jconrel.2014.05.033.

Monteith S, Sheehan J, Medel R, Wintermark M, Eames M, Snell J, Kassell NF, Elias WJ. Potential intracranial applications of magnetic resonance-guided focused ultrasound surgery. J Neurosurg. 2013 Feb;118(2):215-21. doi: 10.3171/2012.10.JNS12449. Epub 2012 Nov 23

Park J, Zhang Y, Vykhodtseva N, Akula JD, McDannold NJ. Targeted and reversible blood-retinal barrier disruption via focused ultrasound and microbubbles. PLoS One. 2012 Aug 13;7(8):e42754 Epub

McDannold N, Arvanitis CD, Vykhodtseva N, Livingstone MS. Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques. Cancer Res. 2012 Jul 15;72(14):3652-63

McDannold N, Clement GT, Black P, Jolesz F, Hynynen K. Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery 66:323-332; discussion 332, 2010

Click here for additional references from PubMed.


Video courtesy of InSightec

     

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