A noninvasive, nonthermal targeted ultrasound technique called “histotripsy” has the potential to improve and expand cancer treatment administered by interventional radiologists.
Histotripsy could replace minimally invasive ablation therapies, if current clinical trials show the same promising results as animal models and early clinical data, according to Fred T. Lee Jr., MD, chief of abdominal intervention and the Robert Turrell Professor of Imaging Science at the University of Wisconsin School of Medicine and Public Health.
Histotripsy was invented by biomedical engineers at the University of Michigan led by the late Charles Cain, PhD. Dr. Lee’s team at the University of Wisconsin became involved when the technique was ready to translate from the lab to treatment of abdominal tumors.
About 20 years ago, a pediatric cardiologist told the Michigan biomedical engineers he would love to have a noninvasive way to create a delicate hole in the upper two heart chambers of his pediatric patients to allow for appropriate oxygen transfer before birth. “That was the motivation, so we started trying to find different methods,” says Zhen Xu, PhD, biomedical engineering professor at the University of Michigan, who was a graduate student working with Dr. Cain.
One day in the lab in 2002, Dr. Xu was working with various ultrasound parameters in an attempt to damage excised tissue in a water tank. According to Dr. Xu, she was becoming frustrated when her lab mate complained that the parameters she was trying were making a lot of noise. Dr. Xu had been using a pulse repletion frequency within the hearing range, a typical therapeutic ultrasound parameter set.
Unlike diagnostic ultrasound, which is noiseless, the pauses between sound waves created audible noise. Dr. Xu then thought about trying to use microsecond ultrasound pulses and a relatively high pulse repetition frequency to reduce the noise and generate cavitation. Cavitation creates “gas bubbles” in the microseconds between sound waves. The mechanical force generated by the expansion and collapse of these microbubbles can damage things such as kidney stones and metals.
“Cavitation was a physical phenomenon that was known for decades, but everyone’s consensus at the time was that it cannot be controlled enough for soft tissue damage, so people were trying to avoid it in ultrasound imaging or therapy,” said Dr. Xu.
But Dr. Xu decided to turn up the ultrasound pressure as high as it would go—she worried she might even break the device—and intentionally shortened the ultrasound pulses to microsecond-length. According to Dr. Xu, the area of cardiac tissue where she focused the ultrasound point was almost beginning to smoke as tiny tissue debris was destroyed by the focused ultrasound.
“That was the first time we observed that ultrasound can be used to literally break tissue into submicron debris and can be used to mechanically remove tissue that way,” she said.
More research showed that cavitation—once considered harmful, uncontrollable and unpredictable—could be controlled and harnessed to destroy tissue. The Michigan team named the technique histotripsy, which means “crushing of tissue.”
“What happens is that these pulses of ultrasound are exquisitely timed, so they arrive at the tissue in such a way that they pull the tissue apart,” Dr. Lee said. “It’s a little bit like pulling taffy apart. When you pull the tissue, you create a very high negative pressure inside of the tissue when you stretch it. The dissolved gas inside the tissues then gets pulled out and forms into gas bubbles.”
The pulling apart of the tissue happens rapidly, with the bubbles quickly expanding and collapsing. “It’s that mechanical stress and strain on the tissue by the rapid creation and destruction of these gas bubbles that tears tissue apart at the microscopic level,” Dr. Lee says.
Histotripsy inspires med student to consider IR
Biomedical engineer Emily Knott has been involved in histotripsy research since 2017 as an undergraduate student of Fred T. Lee Jr., MD, at the University of Wisconsin. The potential of ultrasound to destroy tumors noninvasively has so fascinated Knott that she is considering becoming an interventional radiologist. She is now a first-year medical student at the Cleveland Clinic Lerner College of Medicine.
Then-biomedical engineering undergraduate Emily Knott talks with Tim Ziemlewicz, MD, associate professor of radiology in the section of abdominal imaging and intervention at the University of Wisconsin and principal investigator of the #HOPE4LIVER trial.
“I’ve been really excited about this project since I started,” Ms. Knott says. “As a sophomore in biomedical engineering, when I first got brought down to the lab, I didn’t know much about medical devices or anything.”
She was tasked with assisting a researcher on an early histotripsy liver study in a swine model. Later, she was able to visit one of the first trial sites in Spain. “I was amazed by the technology, and it has been incredible to see the progress.”
Ms. Knott is particularly enthusiastic about histotripsy’s potential for renal therapy. “The current clinical trial is for the liver, but I did a project with the kidney and we saw some cool findings that are challenges with thermal ablation right now, such as ablation in the central kidney where thermal ablation is limited. We saw [where the] cells around the collecting system were completely destroyed in this pig model and the collecting system itself was spared.”
Although she had already planned to go to medical school, Ms. Knott didn’t know anything about interventional radiology, ultrasound or ablation until she joined Dr. Lee’s lab. Now, she’s seriously considering specializing in IR.
“The combination of using things less invasively and using image guidance has been fascinating to me,” she says. “I’m kind of a nerd for medical devices and imaging. That’s leading me toward IR.”
Potential for IR
Histotripsy has the most promise in organs that have good ultrasound windows, such as the liver, kidney, pancreas and thyroid, Dr. Lee says. The technique would allow IRs to bypass some of the barriers they face when considering ablation techniques for a patient.
Only a small percentage of patients with liver tumors are considered good candidates for surgery. While minimal ablation therapies can remove tumors in some patients, the therapy also has its limitations. Ablation might not be possible or be considered too risky because of tumor size, location or patient condition. However, histotripsy is very precise and avoids damage to surrounding structures.
“At the doses we’re using to break up tumors, structures such as bile ducts, ureters, bowel wall and the liver capsule tend to be resistant to damage by histotripsy,” Dr. Lee says.
The inventors of histotripsy formed a University of Michigan spin-off company called HistoSonics, which is conducting clinical trials with its investigational HistoSonics system. It plans to commercialize the histotripsy technology and its automated delivery platform, called Edison™. The system looks like an ultrasound machine with a robotic arm and a shoebox-sized transducer.
The primary role for an IR using histotripsy would be to locate tumors for destruction and set appropriate target parameters. The IR would use test pulses to calculate and personalize the amount of energy required to destroy each tumor. The machine would then take over, using a robot arm to move the transducer over the target at an established speed and time. The procedure time would vary depending on the size and number of tumors to be treated but would be in line with similar therapies.
Liver cancer clinical trials
HistoSonics is focusing on liver tumors initially. Liver cancer incidence rates have more than tripled in the U.S. since 1980 and death rates have more than doubled, according to the American Cancer Society (ACS). In 2021, ACS estimated that about 42,230 new cases (29,890 in men and 12,340 in women) will be diagnosed and about 30,230 people will die. The 5-year relative survival rate for liver cancer in 2011–2017 was 20.3%, according to the National Cancer Institute.
Results from HistoSonics’ THERESA Study, a phase 1 liver cancer trial in 2018–2019 in Spain, showed technical success of the system. Physicians in Spain performed histotripsy ablations on 11 liver lesions in eight patients ages 46–87. The trial showed that the technique was able to successfully target the tumors and led to no serious adverse effects.
The company is now conducting the #HOPE4LIVER studies, one in the United States and one in Europe. They are multicenter, open-label, single-arm trials with eight sites in the United States and six in Europe. The principal investigators in the two trials plan to enroll up to 45 patients each. Dr. Lee expects the data to be submitted to the U.S. Food and Drug Administration within the next year.
In the initial study in Spain, two of the eight patients experienced off-target immune response after histotripsy. Although the treatment targeted a liver tumor, at 8 weeks, imaging showed that nontarget tumors were stable or had decreased.
“If we can eliminate some of the barriers to local regional therapy, some of those stumbling blocks that exist right now, it would expand the reach of interventional radiology,” Dr. Lee says. “I see that in my own mind as the floor for histotripsy, and then the ceiling would be if we’re able to prove out some of the immune effects that we’re seeing in animal models right now. Then the ceiling becomes very high, and we’re going to be very busy.”
Dr. Lee sees an opportunity for IRs to be an even more integral part of a patient’s oncology team, combining histotripsy with immunotherapies, radiation therapy or conventional ablation therapy.
Another benefit for IRs is that, because histotripsy is noninvasive, it doesn’t have to be done in a particular surgical suite. Patients currently undergo general anesthesia, but conscious sedation could potentially be used, Dr. Lee says. The technology hasn’t been used on conscious patients with liver or kidney tumors, but in early studies on prostate cancer some patients were awake and reported only a mild tingling feeling.
Researchers are also considering histotripsy’s potential in treating oligometastatic sites of disease. Physicians have traditionally considered it futile to treat patients with a small number of metastatic tumors, such as pancreatic tumors, lung cancers and melanomas. But combining histotripsy with other therapies could allow physicians to treat tumors in difficult locations, such as in the bowel, retroperitoneum or next to the ureter, Dr. Lee says.
“My personal belief is that histotripsy is best delivered by people who have a very deep knowledge about the imaging of various anatomical parts,” Dr. Lee says. “To me, that’s radiologists. I think it’s going to be really important that IRs understand this technology and get involved early.”
To learn more about histotripsy, read “Breaking down histotripsy” by the technique’s creators or listen to the article via IRQ audio.
