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Focusing Ultrasound on Brain Tumors — Investigating MRI-Guided Noninvasive Therapy Without Ionizing Radiation

Posted on: 09/14/2006

September 19, 2005

Focusing Ultrasound on Brain Tumors — Investigating MRI-Guided Noninvasive Therapy Without Ionizing Radiation
By Beth W. Orenstein
Radiology Today

Vol. 6 No. 19 P. 14

Physicians, physicists, and engineers at Boston’s Brigham and Women’s Hospital (BWH), a Harvard Medical School affiliate, are working to prove it is possible to treat brain tumors noninvasively with highly focused ultrasonic waves.

The concept of using ultrasound, traditionally a diagnostic modality, as a treatment is not new. In 1949 when Lars Leksell, the famous Swedish physician and professor of neurosurgery, was looking for a way of treating deep-seated brain tumors without opening the skull, he experimented in animals using focused ultrasound.

Leksell found that the therapy was uncontrollable in the skull. “Sometimes he would get great results; sometimes he would get terrible results,” says Rob Newman, MS, RAC, vice president of InSightec-North America, which has developed a large array of ultrasound transducers that the BWH researchers are using.

Because Leksell’s results were so erratic, he abandoned the idea of focused ultrasound surgery (FUS) for the brain and went on to develop the Gamma Knife, which uses multiple beams of externally applied ionizing irradiation to treat deep-seated tumors. “Radiation was much more predictable in how it interacted with the skull,” Newman explains. The first Gamma Knife was developed in 1967 at the Karolinska Institute in Sweden. It pioneered technology and techniques widely used today in radiotherapy and radiosurgery.

Seeing the Target
Early researchers could not use ultrasound to treat brain tumors because they could neither see the target nor sharply focus waves onto the desired part of the brain, says Ferenc Jolesz, MD, vice-chairman of research and director of the division of MRI at BWH, who is in charge of the project.

More than 13 years ago, Jolesz, working with others, had the idea of using MRI to monitor and control the focused ultrasound procedure in real time. “MRI is the best technique to define tumor margins today,” he says. Additionally, because it is a temperature-sensitive imaging technique, MRI could be used to monitor the delivery of the concentrated ultrasound waves, he says.

Since then, colleagues Kullervo Hynynen, PhD, and Greg Clement, PhD, FInstP, of Harvard Medical School’s Focused Ultrasound Laboratory, found a way of getting focused sound waves through the intact bony skull. The uneven thickness and density of the skull bones scatters and weakens sound waves passing through the skull.

Hynynen, Clement, and the InSightec researchers realized the key was to predict how the waves would move through the skull. “If we know how they are going to be distorted, we can adjust the beams we deliver,” Clement says. The solution was to map the physical characteristics of the skull using CT. Then they developed an algorithm based on the thickness, density, and orientation of the skull that they could use to control the delivery of ultrasound using a hemispherical array of transmitters.

InSightec designed a helmetlike device that contains a 500-element transducer that distributes the ultrasound over the entire upper surface of the skull. “The device itself looks like an old-fashioned hairdryer. It’s about that size,” Clement says. It operates at a frequency near 0.8 megahertz. Taking the patient’s details from the CT and feeding them into the algorithm, they could then calculate the phase of the wave each ultrasound element must emit to produce a single focus at the desired location.

The researchers tested the helmet on 10 skulls that had been donated for medical research and found they came within 1/2 millimeter of the target.

Mapping the Skull
The focusing method they devised met their goal of being both accurate and practical. “We combined CT images with theoretical models that allow very rapid calculation and correction of the ultrasound beam,” Clement says. It is the nature of the models that makes the process fast enough to be used in the clinical setting, he notes.

Having devised the method in theory, the BWH researchers worked with InSightec to develop an integrated focused ultrasound-magnetic resonance imaging (MRgFUS) system with closed loop control of energy delivery and online tumor treatment control.

First, researchers were able to use the system to demonstrate the success of MRgFUS in benign breast tumors and later in uterine fibroids. In October 2004, following a study for the treatment of uterine fibroids at seven centers in the United States, Europe, and Israel, the FDA approved the use of focused ultrasound for the treatment of uterine fibroids. To date, more than 1,200 fibroid patients have been treated at more than 20 sites worldwide.

“Nevertheless, our goal all along has been to develop the technique for brain tumor treatment,” Jolesz says.

Recently, InSightec received FDA approval for a phase 1 clinical trial in collaboration with Jolesz and Brigham’s Chief of Neurosurgery Peter Black, MD, PhD, who is well known for his research and clinical work on brain tumors. The trial is approved for 10 patients. To date, three patients have been treated. The results have been promising.

“So far, the technique was safe with no complications or adverse effects,” Jolesz says. The data from the three patients have been sent to the FDA for analysis. “We will continue the trial after they let us do it,” Jolesz says. “This is the usual process.”

Because the phase 1 trial examines the method’s safety and not its treatment effectiveness, patients who were selected have inoperable brain tumors. “If it turned out that the tested method is not safe, we cannot hurt patients who cannot be saved with traditional techniques,” Jolesz says. “This is the usual way to test every new technique.”

In the future, Jolesz says, the MRgFUS method could be used in place of surgery for treatable tumors—mostly benign and operable malignant tumors. The method may also be used for tumors deemed inoperable because the surgeon cannot go through the surrounding crucial functioning brain such as the brainstem.

Tumor Margins
However, he says, FUS may not be so successful if used for cancerous tumors such as inoperable malignant gliomas—primary brain tumors—that are infiltrating and have no clear margins. “Such tumors do not have a well-defined target and may involve functioning brain tissue that cannot be removed or destroyed even with this noninvasive method,” Jolesz says.

The research at BWH, the only clinical site testing the InSightec system for brain tumors, is supported by InSightec and multiple grants from the National Institutes of Health.
FUS with MRI guidance is similar to the stereotactic radiosurgery in that it is a way of treating tumors without opening the skull. However, there are several advantageous differences.

The major difference, Jolesz says, is that “we see what we are doing. We see the target in real time. The MRI can show the tumor margins and by imaging the temperature changes in every part of the tumor, we can make sure that the treatment is involving the entire tumor.”

With radiosurgery, Newman says, “the person delivering the energy can’t see the energy hitting the target. So you’re assuming you did all your calculations correctly, but you don’t know for sure the energy is going where you want it to go.”

Another difference is that MRgFUS therapy is thermal ablation and the results are immediate. “With radiosurgery, you don’t know whether you have achieved your clinical end point,” Newman says.

“To deliver radiation, you have a dose-planning manual that tells you that if you want to ablate a lesion of this size, you should deliver this much energy over this volume of tissue over such a period of time,” he says, “but you don’t have any feedback to tell you that you have actually achieved that end point. The only thing you can do is to bring the patient back in three or six weeks and perform a CT or MR to see how much of the tumor has been affected.”

Rapid Feedback
With MRgFUS, Newman says, “you can measure the thermal effect on the MR image in real time, so you can see exactly where the energy is going on a second-by-second basis. You can tell when the temperature has gotten high enough that you are ablating the tissue. You can do an MR exam with contrast immediately post treatment and see the effects, which are immediate.” Once the tissue is heated above 57º centigrade, it is destroyed, whereas radiation takes several days to weeks for the full effect to occur, Newman notes.

Functional MRI can also show the activity of the brain surrounding the tumor in real time so radiologists know whether they are nearing sensitive areas. The MRgFUS procedure is done while the patient is awake. “Therefore, we can follow their brain activity during the treatment session,” Jolesz says.

Perhaps the most important potential advantage of MRgFUS is that ultrasound does not deliver ionizing radiation, so there is no maximum or cumulative dose. The procedure can be repeated safely numerous times. “With radiation, you can get to the point where you have received all the radiation you can have in a life time, and you can’t be treated again,” Newman says.

It’s not unusual for cancer patients to develop metastatic brain tumors. “They get one now and another one a month from now and another one a month after that,” Newman says. “They become inoperable because they keep popping up. Surgery is too invasive to keep going in and removing them with a scalpel.”

Repeat Treatment
Radiation may not be an option for repeated lesions because there’s a maximum dose the brain can receive without getting a general necrosis of the whole brain, Newman says. However, thermal ablation from ultrasound has no cumulative effect. “If you had to treat a patient today and again a year from now because the patient developed another metastatic lesion, you could,” he says.

Another promising area the investigators are researching is using MRgFUS to deliver chemotherapy to targeted areas in the brain, Clement says. The brain is very selective about what molecules it allows to pass through, he says. “It’s not totally understood why the blood-brain barrier allows certain molecules to pass through and not others.” The blood-brain barrier has been a hindrance to the use of targeted drug therapies.

Focused ultrasound may someday be used to open the blood-brain barrier in targeted areas and allow physicians to deliver cancer drugs or other chemicals that affect the brain directly to the lesions, Clement says.

The researchers caution that there is still some way to go before MRgFUS can be used to treat patients with brain lesions, but they are cautiously optimistic.

“Our focusing technique is the first clinically feasible method to produce a sharp controlled focus through the skull completely noninvasively,” Clement says, “and the first that shows a repeatable ability to focus through the skull.”

Black adds, “Focused ultrasound will require refinement before it will be routinely useful for brain tumors, but it has the promise of making a real difference in the way we treat some tumors, especially those that are presently inoperable. It is like the Gamma Knife without radiation and has potential applications for both malignant and benign tumors. We are very excited to be developing this technology here at the BWH.”

— Beth W. Orenstein of Northampton, Pa., is a freelance health writer and regular contributor to Radiology Today.


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