Brain cancer patients are left with few options when tumor cells spread, as most potent chemotherapies are unable to cross the blood-brain barrier. But a study published last week in the Lancet offers some hope: an ultrasound device implanted in 17 patients’ skulls successfully increased the concentration of drugs in their brains.
It’s the first, in-human trial of the novel device, which is manufactured by French device maker Carthera. The study, led by Northwestern University researchers, also reported no treatment-related deaths or worsening of neurological symptoms. Drug levels increased almost sixfold in the part of the brain activated by the device.
While promising, the study results are not definitive. Carthera will need to prove that its device helps people live longer before it’s available to the masses. And it will need to work with other cancer researchers to decide which drugs work best for brain cancer patients. Many of these more powerful chemotherapies have never made it into the brain before, so it’s unclear how severely they’ll damage healthy brain tissue.
“We’re trying to see what is the best drug to use, where do we see the most efficacy, and also the safety profile,” said Michael Canney, head of research and development at Carthera.
The study focused on patients with glioblastoma, a deadly form of cancer that infiltrates brain tissue nearby the original tumor site. Adam Sonabend, a neurosurgeon and lead researcher on the study, said doctors typically don’t have many treatment tools after they have surgically removed the original tumor. Radiation is an option, but doesn’t always work. The next step would be chemotherapy, but drugmakers haven’t made much progress in developing therapies that are able to cross the blood-brain barrier, a structure that protects the brain from unsavory particles floating around the bloodstream. There are some drugs that do cross the barrier, but they’re often ineffective.
“The drugs that we are left with that do cross the blood-brain barrier are not necessarily sufficient or the most powerful,” Sonabend said. “This is part of the reason why these tumors always come back.”
The next best solution, then, is to build a device that would open the barrier and allow drugs to pass through. First, you inject microscopic bubbles into the bloodstream that make their way to blood vessels in the brain. Then, the ultrasound device agitates the bubbles with sound waves, creating gaps in the blood-brain barrier.
One approach is to deliver the sound waves across the skull, as Israeli company Insightec does with an MRI-guided ultrasound. But high-energy ultrasound, applied during a lengthy procedure, is required to traverse the thick human skull. Carthera’s idea was to cut out a bone flap and replace it with the device, so the ultrasound could send the sound waves directly to the patient’s brain with lower energy.
In this trial, Sonabend and his colleagues implanted Carthera’s device after removing the patients’ tumors. Two weeks later, the patients came back so Sonabend could activate the device and deliver the chemotherapy via infusion. Patients received treatment every three weeks for up to a year. The device isn’t big enough to break the barrier around the entirety of the brain, so Sonabend was able to compare the drug levels between the guarded and unguarded areas.
“At least for a beginning first step, this study is extremely elegant, and it’s very exciting,” said Cheng-Chia Wu, a radiation oncologist who works on focused ultrasound at Columbia and was not involved in the study.
Carthera earned breakthrough device designation from the Food and Drug Administration last June. Canney said the company is in close communication with the FDA, particularly as it works to launch a Phase 3 trial that will measure survival rates.
“The bar for efficacy for this disease is pretty clear,” Canney said. “Showing an increase in overall survival in patients, against patients that are on a control arm. That’s what we’re pursuing now.”
Brian Carro, a middle school math teacher in Palatine, Ill., suddenly started losing speech and vision on Christmas Eve in 2019. He and his wife rushed to the hospital, where doctors pinpointed the source of his brain bleed: a glioblastoma tumor. Surgeons removed the tumor. In the following weeks, some of his vision and speech returned, though both continue to be challenging.
“That’s probably one of the hardest things,” Carro said. “You know what you want to say, and the more frustrated you get, the longer it’s going to take.”
After surgery, Carro went through radiation therapy to try and kill the rest of the cancer. But it stopped working. He then learned about the ultrasound trial at Northwestern and promptly volunteered in August 2021. He felt that “if there’s something new that we could try, I’m willing to be that guy.”
The surgery was painful, as he had to stay awake throughout. His doctors have put him through several different chemotherapy treatments in the past couple of years. It’s been a process of trial and error, with early treatments flat-out not working or even causing seizures. But later treatments enabled him to go back to work teaching eighth graders. This past July, he went on a trip with family and friends to Peru, visiting Machu Picchu.
“A year ago, telling me we’re going to cut a piece of your head out and we’re going to put this device in, it sounds insane,” Carro said. “But there are people that are doing things that are really different and I hope that people are willing to try something new and positive.”