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Body + BrainBody & Brain

Wave of the Future?

A powerful form of ultrasound could give doctors a new way to treat cancer.

ByKelsey Houston-EdwardsNOVA NextNOVA Next
Wave of the Future?

Two years ago, in a hospital in Paris, a 38-year-old man lay dying from a golf ball-sized brain tumor. Doctors pumped chemotherapy into his bloodstream through an IV.

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Under normal circumstances, it would have been a pointless treatment. The drugs never would have reached their target. Large-molecule drugs like chemotherapies are barred by the blood-brain barrier, a vascular sealant that isolates the brain from the blood vessels that wind through it. Its purpose is to keep dangerous substances—like chemotherapy, bacteria, and viruses—away from the delicate brain.

But this man’s blood-brain barrier had been pushed wide open.

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Inside his skull, researchers had implanted a button-sized device which emitted a pulsing beam of ultrasound focused on the tissue in and around his tumor. Next, they injected tons of tiny bubbles into his bloodstream that vibrate in the beam. The animated bubbles burrow through the blood-brain barrier, leaving a hole for the chemotherapy drugs to infiltrate.

Ultrasound waves vibrate bubbles injected into the bloodstream, prying open the blood-brain barrier so chemotherapy drugs can enter.

The 38-year-old patient was the first to be treated in a series of clinical trials led by Dr. Alexandre Carpentier, a neurosurgeon at the Pitié-Salpêtrière Hospital in Paris. He and his team began treating patients with low levels of ultrasound and slowly ramped up the power as they grew more confident in the procedure’s safety. “We found the optimal ultrasound intensity and sequence to repeatedly open the blood-brain barrier,” Dr. Carpentier said of the results, published recently in the journal

Science Translational Medicine .

For decades, doctors have been experimenting with therapeutic ultrasound, or the use of ultrasound to treat diseases and injuries as opposed to the more prosaic use for imaging babies and gallbladders. It’s not the first time that the technology has been heralded as a breakthrough. But the current applications might be the most promising.

Today, scientists are experimenting with using ultrasound to do everything from cure Alzheimer’s to treat fibroid pain. The recent experiments in France, says Dr. Neal Kassell, chairman of the Focused Ultrasound Foundation, are “just the tip of the iceberg.”

The Case of the Prostate

Thirteen years ago, Dr. George Suarez attended a meeting of the European Urological Association that transformed the way he treats prostate cancer. At the meeting, Dr. Suarez, a urologist based out of Miami, Florida, learned how doctors in Europe were using focused ultrasound to essentially cook tumors in their place. In ultrasound, he saw the future of medicine—an incarnation of Star Trek’s fantastical bloodless surgery.

But at the time, focused ultrasound had not been approved for use in the United States. So Dr. Suarez opened a clinic in the Dominican Republic. For the next eleven years, men with prostate cancer would fly to the Caribbean, perhaps spend a few days on the beach, and then receive this promising new treatment.

Had these men been treated in the United States instead, they likely would have had either radiation therapy or a prostatectomy, where the prostate is removed surgically. Both treatments are well-studied and highly effective at eliminating the cancer—most men never have a recurrence. However, erectile dysfunction and urinary incontinence are common side-effects, prevalent enough to discourage some men from getting treated and drive others to experiment with high-intensity focused ultrasound abroad. HIFU, as it’s known, uses the energy of ultrasound waves to heat tumors, destroying the cancerous cells.

Dr. Suarez is unabashed in his enthusiasm for the technology. He sees HIFU as a “total game changer in treating prostate cancer,” an effective treatment with far fewer side-effects than surgery or radiation, he says.

But not all urologists share in his excitement, and many express skepticism whether the benefits outweigh the risks. Dr. Peter Scardino, a urologist and chair of the Department of Surgery at Memorial Sloan Kettering Cancer Center, is one of them. “When I look at the results of HIFU for prostate cancer—which has been used in Europe for the last 15 years—what I see is cancer control rates that are no better than radiation therapy of the past, and that’s not very good. And complication rates that are comparable to surgery,” he says. “It seems to me that it’s the worst of both worlds.”

The FDA partially agrees with Dr. Scardino’s assessment. In October 2015, after a decade of clinical trials and investigations, it approved the use of HIFU as part of a treatment regimen for prostate cancer—with a major caveat. The FDA panel noted that there was insufficient evidence to suggest that HIFU could serve as a cancer treatment; instead, they said it was capable of safely destroying prostate tissue. It’s a subtle but significant distinction, one that suggested the FDA was not confident in answering whether HIFU can effectively treat cancer.

Even skeptics like Dr. Scardino think that ultrasound probably has some role in treating prostate cancer, but maybe only for men with a specific form of the cancer. Dr. Scardino is glad HIFU was approved by the FDA because now doctors have room to explore its use and find the best candidates for HIFU treatment. For example, men with medium-level cancer—those who are too advanced to simply monitor, but who might not require the full strength of surgical or radiological treatment—might stand to benefit from HIFU.

Still, many questions about focused ultrasound treatment remain unanswered. Currently, there’s not a lot of data on the long-term risk of recurrence after the treatment, and doctors don’t know what size and location of tumor is best treated by HIFU. But at least in some men with specific cases, it appears to be a promising, and arguably better, cancer treatment.

Tumors Elsewhere

At a technical level, high-intensity focused ultrasound is appealingly blunt. Faced with an offending lump of tissue, you blast it with a wall of ultrasound, melting it. Ablating prostate tissue is perhaps the most widely implemented use of focused ultrasound, but doctors are also testing it to treat liver, kidney, and pancreas cancers. Dr. Pejman Ghanouni, an assistant professor of radiology at Stanford University Medical Center, is currently using focused ultrasound to treat an array of ailments, from soft tissue tumors and bone metastasis to uterine fibroids.

Focused ultrasound can even be used to ablate tissue in the brain, though it’s not as straightforward as elsewhere in the body. “In the brain, the challenge is the skull. The bone is really highly absorbing of ultrasound, so it heats up very easily,” says Nathan McDannold, an associate professor of radiology at Brigham and Women’s Hospital. Because the brain is surrounded by thick skull bone, focused ultrasound can only be directed at tissue in the center of the brain, far from skull.

Early trials have used networks of ultrasound emitters to treat brain tumors.

The device that delivers focused ultrasound to the central brain resembles “those old-style hairdryers in a woman’s hair salon, the kind of hemispherical thing,” Dr. Ghanouni says. Instead of hot air, the nodes along the cap emit ultrasound beams, each pointing at the target in the center of the brain. The pressure from each individual beam is low enough to not damage the skull, but at their focused intersection, they heat and destroy tissue.

While researchers have refined the technique, directly ablating tumors in the brain remains  complicated, and clinical trials of the technique are still in their early phases. The consequences of one misstep are grave, and scientists are proceeding cautiously.

Powerful ultrasound beams tend to heat the skull rather than the targeted tumor, so doctors use a network of less powerful beams that converge on the tumor to ablate cancer cells.

Opening the Blood-Brain Barrier

Many drugs which might be useful in the treatment of brain diseases—from cancer to Parkinson’s—can’t get from the bloodstream into the brain. They are simply too large to squeeze through the blood-brain barrier.

The blood-brain barrier is a complex collection of cells that function as a sheath around the blood vessels that wind through the brain. “Just like a mainframe computer needs a very constant environment, the brain, which is an electric organ, needs a very constant environment,” says Dr. Edward Neuwelt, director of the Blood Brain Barrier Program at Oregon Health and Science University.

In the late 1800s, Nobel Prize winning scientist Paul Ehrlich first observed the effects of the blood-brain barrier. When Ehrlich injected dye into an animal’s bloodstream, it colored all of the organs except the brain. Shortly after, his student observed the opposite—dye injected into the brain doesn’t flow to the rest of the body. The mystery remained unsolved for another half century, when scientists could finally explain what Ehrlich observed, the blood-brain barrier.

Last year, a team of scientists at Sunnybrook Hospital in Toronto opened the blood-brain barrier with ultrasound for the first time. Where the French researchers implanted the ultrasound device inside the skull—allowing them easily and repeatedly open the blood-brain barrier in a fixed region around the implant—the Canadian researchers used external ultrasound beams, which are guided by magnetic resonance imaging and can be focused to a particular region of the brain. “They are very complementary techniques,” Carpentier says. External ultrasound works best when the tumor is located in the center of the brain, whereas ultrasound emitted from an internal implant works best for tumors located in the outer layers of the brain.

Doctors are experimenting with ultrasound to ablate tumors deep in the brain.

Both share some of the same risks, though. The blood-brain barrier is an key part of our body’s natural defense system, and it’s possible that microbes—harmlessly floating through the bloodstream—could leak through an open barrier and into the brain where they can wreak havoc.

But in these and other clinical trials, scientists have not observed any adverse effects from either the ultrasound or from repeatedly opening the blood-brain barrier. The opening created by the ultrasound closes within six hours, quickly enough that no one has observed any damage to the brain.

Future Potential

If focused ultrasound really does provide a temporary, non-invasive way to open the blood-brain barrier and allow any drug to enter the brain, its potential applications reach far beyond brain cancer. It could enable unprecedented access to the brain and inspire new lines of research and medication in the treatment of Alzheimer’s, Parkinson’s, and more.

Immune sensitization is another application of focused ultrasound that’s on the horizon. When cancer cells are cooled or heated, they release a protein which stimulates the body’s natural immune response, making it more sensitive to immunotherapy drugs. Earlier, scientists tried to elicit the response using cryotherapy, the freezing of tissue. Similar to HIFU, cryotherapy offered a way to destroy cancerous tissue while also prompting an immune response.

It was approved as a treatment for prostate cancer over thirty years ago. “There was a wave of enthusiasm for it, and then it cooled off when people really looked at the results and said, ‘You know, the chances of curing the cancer weren’t that great, and the side-effects were significant,’” Dr. Scardino says. “It just didn’t have a good risk-benefit ratio, and I think HIFU is going to be the same.”

For now, McDannold says, “I think the drug delivery has a lot more potential.”

Image credits: Sunnybrook/Doug Nicholson/Media Source, Alicia DeWitt

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