We are enthusiasts but are careful to use the word ‘potential.’ This technology is in an early stage.
—Neal F. Kassell, MD
I’m excited to see it work, to see patients [with bone metastases] with no other options [for managing their pain] to be able to pursue normal activities again.
—Pejman Ghanouni, MD, PhD
In the United States, it’s been a good 2 years for focused ultrasound. The technology, which uses multiple, intersecting ultrasound beams to treat cancer and other diseases, completed its first successful U.S. phase III oncology trial—to alleviate the pain of bone metastases—and received approval from the U.S. Food and Drug Administration (FDA) in 2012. Medicare began covering it in 2013, and in 2014, Health Care Service Corporation, a large Blue Cross/Blue Shield insurer, began providing coverage.
An FDA panel did not recommend approval of two other focused ultrasound devices for treating prostate cancer in 2014 but left the door open for future consideration.
Not surprisingly, next steps and future directions were a major theme at a recent meeting of the Focused Ultrasound Foundation in Washington, DC. Speakers described studies not only in pain palliation, but also for tumor ablation in several cancers. Recent successes with essential tremor and other neurologic diseases were also discussed.
Still, speakers were careful to point out that the field was young. “We are enthusiasts but are careful to use the word ‘potential,’ said Neal F. Kassell, MD, Professor of Neurosurgery at the University of Virginia, who chairs the Foundation. “This technology is in an early stage.”
Studies of focused ultrasound to treat cancer go back several decades. In the 1990s, INSERM, the French national research institute, and a commercial firm, EDAP-TMS, developed the Ablatherm® system, which uses ultrasound imaging to guide high-intensity beams. Ablatherm won approval in Europe 1999 as an alternative to radiation therapy in early prostate cancer.
In the meantime, the Israeli firm InSightec began studying magnetic resonance-guided focused ultrasound to treat painful bone metastases, the system that won FDA approval in the United States.
The focused ultrasound systems combine beams that heat and destroy targeted tissue with a real-time imaging component—either magnetic resonance or ultrasound—that enables precise targeting and potentially a lower risk of collateral damage. In the ExAblate trial, the magnetic resonance–guided beam was used to destroy pain-causing nerves in the outer membrane of the bone overlying a painful metastasis.
Focused ultrasound has the advantage of being noninvasive compared with other thermal treatments, such as cryotherapy, and can be performed on an outpatient basis. Its risks include damage to healthy tissue and skin burns, among others.
Painful Bone Metastases Clinical Trial
The trial that led to FDA approval enrolled 147 patients who still had pain after radiation therapy or other standard interventions for painful bone metastases or who were not eligible for or had refused radiation therapy. Participants were randomly assigned to receive either focused ultrasound or placebo treatment. Nearly two-thirds of those on the focused ultrasound arm had an improvement in self-reported pain score without an increase in pain medication, compared with about 20% on the placebo arm.
Pain scores improved by an average of 3.6 points on a 10-point scale (more than a 50% improvement in pain), indicating the treatment had a significant impact, said principal investigator Mark Hurwitz, MD, Director of Thermal Oncology at Jefferson University in Philadelphia. Patients on the focused ultrasound arm also reported less pain-related interference with functioning, often within a day of treatment. Adverse events included two pathologic fractures (one outside the treatment field), one skin burn, and one neuropathy. The study was published in the Journal of the National Cancer Institute in April 2014.1
New randomized trials of focused ultrasound for bone metastases are now on the horizon. In October 2013, the Focused Ultrasound Foundation convened a workshop in Rome, bringing together researchers and industry representatives to talk about future trials. Many believe that the ideal study would be a three-arm trial comparing radiation therapy alone, focused ultrasound alone, and the combination of radiation therapy and focused ultrasound, Dr. Hurwitz said. Another, possibly more feasible, option would compare radiation alone with radiation therapy plus focused ultrasound. A consensus statement with recommendations from the workshop is in press.
Another approach to painful bone metastases is to ablate the entire tumor as well as the nerve endings. This might lead to even better results, said Dr. Hurwitz, since some of the pain may be due to mechanical factors, such as the tumor pressing on expansion within bones.
In other cancers, tumor ablation is the goal. Localized prostate cancer remains a prime candidate for focused ultrasound treatment, with five actively recruiting phase I and II trials listed in ClinicalTrials.gov. Two companies have completed trials of ultrasound-guided focused ultrasound and submitted premarket approval applications to the FDA.
One of these trials, a phase II/III study looking at EDAP-TMS’s Ablatherm system in localized prostate cancer, was designed to determine its “substantial equivalence” to cryotherapy. An FDA advisory panel recommended against its approval in July 2014, indicating that benefits did not appear to outweigh risks, but kept open the possibility of future consideration. In a statement, EDAP-TMS said that the FDA recommended it provide more data on patients at higher risk, such as those with Gleason scores > 6.
Also this year, SonaCare Medical asked an FDA panel to approve its Sonablate system. The panel responded, as it did with Ablatherm, that it would be useful to have data in patients with Gleason scores > 6. According to a company statement by SonaCare Medical, “several panel members suggested that for this more specific indication for use, the efficacy, safety profile, and benefit-risk ratio for the device may provide the basis for a more favorable recommendation.”
Both firms said they were moving ahead on the recommendations.
Focused ultrasound is in early clinical studies in other cancers, including pancreatic and breast cancers, sarcoma, brain metastases, and glioblastomas, with 51 open trials listed in ClinicalTrials.gov. For example, a sarcoma study at Stanford University is evaluating safety in patients who receive focused ultrasound followed by surgery. It is also looking at efficacy, comparing the magnetic resonance imaging results with pathology findings. Pejman Ghanouni, MD, PhD, the principal investigator, along with Raffi Avedian, MD, said that results so far have been encouraging.
Researchers are also thinking in terms of applications beyond ablation, said Jessica Foley, PhD, the Focused Ultrasound Foundation’s Scientific Director. For instance, the concentrated ultrasound beams can loosen the network of endothelial cells joined by tight junctions within the blood-brain barrier, allowing drugs to get through.
Another potential use of this approach is for the localized delivery of chemotherapy, she said. A liposomal drug, for instance, could be injected in conjunction with focused ultrasound. The liposome would be activated or disrupted to release its contents at the precise focus of the ultrasound.
In addition, focused ultrasound might be used to “jump start” an antitumor immune response. Thermal therapies including focused ultrasound can stimulate anti-immune responses in part through heat shock protein–mediated pathways, said Dr. Hurwitz. “We are actively exploring how best to both stimulate and effectively target this response to the tumor,” he said.
For the present, focused ultrasound enthusiasts are glad to have another tool to manage metastatic bone pain. Radiation therapy does not work in everyone, and as Dr. Ghanouni pointed out, patients are now living longer with bone metastases. “I’m excited to see it work,” he said, “to see patients with no other options [for managing their pain] to be able to pursue normal activities again.” ■
Disclosure: Dr. Hurwitz has provided consulting services to Insightec. Dr. Ghanouni has participated in multicenter clinical trials that were funded by InSightec. Dr. Foley reported no potential conflicts of interest.
1. Hurwitz MD, Ghanouni P, Kanaev SV, et al: Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: Phase III trial results. J Natl Cancer Inst 106(5):dju082, 2014.