Do a search on focused
ultrasound (FUS), and you'll quickly discover that it's a kind of fairy-tale
cure, helpful in the treatment of almost everything: Parkinson's disease,
uterine fibroids, atrial fibrillation, congestive heart failure, Alzheimer's
disease, depression, diabetes, obesity, cancers of the prostate, kidneys,
pancreas, bladder, breast, and dozens more.
FUS also has its own
website, run by the Focused Ultrasound Foundation, a manufacturer-supported
organization dedicated to "accelerating the development and adoption of
focused ultrasound." Neal Kassell, MD, the founder and chairman of the
foundation and a professor emeritus of neurosurgery at the University of
Virginia School of Medicine, said in a 2015 TEDx talk that
FUS "could improve the health and happiness of millions of people around
the world."
The technology has
not, however, been greeted with universal acclaim. It has proven controversial
enough in the treatment of essential tremor -- for which it has FDA approval --
that the American Academy of Neurology's 2017 meeting this week featured it in
a plenary-session "controversies in neurology" debate.
At that session, Paul
Fishman, a neurologist at the University of Maryland, took the "pro"
side, arguing that serious adverse event rates with FUS are dramatically lower
than with a more established alternative -- deep brain stimulation (DBS).
Fishman also said that DBS has a significant incidence of hardware failure
requiring additional surgery.
Michael S. Okun, MD,
the chairman of neurology at the University of Florida -- who argued the
"con" side -- did not dispute those points, but noted that the
opportunity for later surgery was an advantage, because mistakes and
complications can often be corrected. That's not possible with FUS, which burns
away tissue. "You can't troubleshoot a focused ultrasound problem," he
said.
Okun also noted that
the target for FUS in Parkinson's disease is very small -- "the size of a
squashed pea" -- and can't be visualized well in MRI scans. That, along
with difficulties focusing the beam because of interference from the skull, means
off-target ablation is likely to occur periodically. And FUS can be used on
only one side of the brain, because thalamic ablation on both sides has
consistently been shown to have unacceptable adverse effects. DBS, in contrast,
can be safely used on both sides to achieve more complete symptom control.
Okun did acknowledge
that FUS holds a great deal of promise for other neurological applications,
calling the potential of using it to open the blood-brain barrier to allow
larger molecules into the brain, "brilliant."
In an interview the
day before the debate, Okun said that using FUS to treat essential tremor
"is like trying to make an omelet without opening the egg ... You're
shooting from outside the brain." And the targets are not only small but
also "somatotropically organized." Particular regions of the brain
are mapped to specific parts of the body, and a misplaced lesion can have
harmful side effects. A wrongly mapped attempt to ease a tremor in an arm, for
example, could weaken a leg, leaving a patient unable to walk, Okun said.
Further, he said,
neurologists already have a powerful means of treating essential tremor.
"The gold standard of making lesions in the brain is radiofrequency
[ablation]. Once you've mapped a brain out and you know where the structures
are, you can insert a probe and burn it."
Fishman said before
the debate that the use of FUS for Parkinson's disease could be a cheaper
alternative to deep-brain stimulation. And he said he is eager to see it
approved by the FDA, because until then it isn't covered by insurance. "We
have a waiting list of over 200 patients," he said, but he can do the
procedure only on those who can pay $25,000-$35,000 out of pocket. Asked if he
was excited about FUS, he said, "It's a gas!"
At the conclusion of
the AAN debate, audience members were asked whether they sided with Okun or
Fishman. Okun's arguments "con" won with 90% of those voting, but
most audience members didn't raise their hands for either one, suggesting that
they found both sides persuasive.
Kassell acknowledged
the criticism, but it doesn't dampen his enthusiasm. He was able to persuade a
Charlottesville, Va., neighbor, John Grisham, the best-selling author of legal
thrillers, to write a short book
called The Tumor, which shows how FUS could one day be
used to treat glioblastoma. "This is not fiction," Grisham said.
"This is the future, and it is rapidly approaching."
FUS operates by a
variety of mechanisms, including ablating tissue, delivering drugs in high
concentrations to a particular point in the body, and enhancing the
effectiveness of cancer immunotherapy drugs -- 18 different mechanisms in all.
Kassell said there are
several areas in which the technology is nearest to routine use. One is to
deliver drugs to a precise target. The drugs can be tucked inside hollow lipid
spheres which are injected into the bloodstream. "You can inject millions
of these into the bloodstream, and they are everywhere blood goes. But the drug
is inactive except where the ultrasound is focused. At that point the
microbubble bursts and delivers its pharmacological payload," Kassell
said.
A second is to ablate
tissue, and a third is to modulate the immune system, meaning ultrasound might
have a role to play in enhancing the effectiveness of cancer chemotherapy or
other drugs.
Kassell said FUS has
been approved by the FDA for three things in addition to essential tremor:
uterine fibroids; pain from bone metastases; and the ablation of prostate
tissue to treat prostate cancer or BPH. But more are coming.
"As of today,
there are almost 80 clinical indications in various stages of research and
development," Kassell said. He notes that FUS can potentially be much
cheaper than alternative treatments. Deep-brain stimulation for Parkinson's
disease costs some $60,000 to $100,000, he said, but ultrasound can do the job
for one-third of that. (Okun said in the interview that data does not yet exist
to show that FUS is cheaper.)
Kassell said that the
foundation works with three dozen companies that make ultrasound equipment, but
that the foundation is not intended to promote commercial interests -- only to
spread interest in what he sees as an extremely valuable new technology.
"What we're doing here at the foundation is to be engaged in a variety of
activities which can move quickly to save people and save lives," he said.
Prostate cancer is one
of the applications for which ultrasound looks most promising. Last year, at
the annual meeting of the American Urological Association, researchers
reported that almost 90% of patients with early prostate cancer
remained free of radical intervention two years after treatment of a single
lobe with high-intensity FUS. The report generated "cautious
optimism" that the technology could play a role in the treatment of early
prostate cancer.
Another application is
for use with Alzheimer's disease. FUS's ability to gently open the blood-brain
barrier can allow amyloid-scavenging drugs to reach and potentially destroy
plaques characteristic of Alzheimer's disease.
The first human trials
for Alzheimer's disease were launched in March by a neurosurgeon, Nir Lipsman,
MD, PhD, at Sunnybrook Health Sciences Center in Toronto. Two of a total of six
patients were treated to assess the safety of the technique before it's used
more widely.
Other Alzheimer's
specialists were divided over whether or not human trials are premature, but
because ultrasound has been used in the brains of Parkinson's patients, some
felt that it was likely to be safe for use in Alzheimer's disease. The study is
also predicated on the fact that the plaques are a cause of the illness; not
everyone agrees that that's the case.
Now we come to the
question: Is FUS a wise buy?
"I would say
definitely yes," said Fishman. "There is a product out there already,
which is deep brain stimulation. For a certain fraction of those patients, they
would likely opt for FUS, which is a cheaper technology, and less
onerous." Asked if neurologists are excited by FUS, Fishman said,
"The field is still very unaware of this technology. There may be a
thousand articles in the medical literature on DBS and maybe 50 on this."
He also offered "a little disclaimer ... I have the passion of a recent
convert."
Asked the same
question, Kassell said, "The answer is ... it depends." The economics
will be hard to sort out until insurance companies begin to cover it, he said.
"Some sites can fight with the insurance companies, but there is not a lot
of reimbursement. People are paying cash."
At the same time, he's
frustrated and unhappy at the pace of research. Asked if he was enjoying this
work during what could be a relaxing retirement, he said no. Too often, he
said, he sees people who could be helped, and he knows that the data is not yet
there to offer them the treatment.
Kassell's vigorous
promotion of FUS could backfire -- it invites skepticism. Far too many
treatments that work like magic in mice or a handful of patients fail in proper
clinical trials.
It's too soon to know
whether FUS is one of them. It's not yet a wise buy. But when the evidence
comes in, it might be. It's simply too early to dismiss it or embrace it.
Wise Buy, a MedPage Today series,
assesses therapies -- new and old -- to determine if the treatment is not only
a wise choice, but also a wise buy.
https://www.medpagetoday.com/radiology/therapeuticradiology/64885
