Good Vibrations
By Beth W. Orenstein
Radiology Today
Vol. 22 No. 2 P. 10

Microbubbles burst onto the scene to augment radiation therapy.

Microbubbles could hold the key to delivering some of the most effective cancer treatments ever, says Steven Feinstein, MD, a professor of cardiology at Rush University Medical Center in Chicago and copresident of the International Contrast Ultrasound Society. That’s why he’s excited about research at Thomas Jefferson University in Philadelphia, where they are conducting the first-ever human trial of microbubbles to improve the effectiveness of radiation therapy in patients with liver cancer.

Feinstein’s enthusiasm for this research is quite strong. This path of research is “phenomenal,” he says, and could lead to cures for numerous types of cancer that were never thought possible.

Primary liver cancer is on the rise around the world, thanks mostly to an increase in hepatitis C infections and chronic liver disease. More than 800,000 people are diagnosed with liver cancer each year worldwide, according to the American Cancer Society (ACS). Rates are more than twice as high in men compared with women. Because it is difficult to treat, liver cancer is deadly. It kills 750,000 people—again, more men than women—a year around the globe, the ACS says; furthermore, five-year survival rates are generally less than 20%.

About 15% to 25% of patients with advanced liver cancer are treated with transarterial radioembolization (TARE). During TARE, radioactive glass beads are inserted into blood vessels in the liver. The radiation emitted provides a therapeutic dose to the tumor, destroying it. However, the amount of radiation that can penetrate liver tissue is limited, and the tumor response is highly dependent on the tumor’s distance from the radioactive beads. By combining microbubbles with TARE, researchers believe it can reduce the dose of radiation needed to kill blood vessels in the tumors and increase the effectiveness of treatment, says John Eisenbrey, PhD, an associate professor of radiology at Thomas Jefferson University and lead author of a pilot study recently published in Radiology. Early results are extremely encouraging, Eisenbrey says.

The pilot study enrolled 28 patients. Enrollment took place between July 2017 and February 2020. The researchers eventually hope to enroll a total of 104 patients, Eisenbrey says.

Patients were randomly assigned to two treatment groups. One group received TARE alone and one group received TARE with ultrasound-triggered destruction of microbubbles (UTMD). The researchers found that the microbubbles were safe. They observed no changes in vital signs, such as body temperature, blood pressure, and heart rate, in patients who received UTMD. Most importantly, Eisenbrey says, UTMD did not compromise liver function, and those who were treated with the combined approach showed no additional side effects.

Treatment Cohorts
The researchers studied 10 tumors in the TARE-only group and 15 tumors in the group given TARE and UTMD. They found that 50% of the tumors in the TARE-only group responded to treatment, while 93% of tumors in the TARE and UTMD group showed partial to complete response to treatment.

The microbubbles were popped at three different time points, Eisenbrey says. The first was immediately after TARE in the IR suite where the TARE was performed. The second was one week later, and the third was two weeks post treatment. Each microbubble infusion session took about 10 minutes, he adds. Afterward, patients are monitored for 30 minutes. “When they come to see us, they’re out the door in about an hour,” he says.

To evaluate the efficacy of the two treatments, the researchers used modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images. They also evaluated the time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher’s exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a logrank Mantel-Cox test.

Ultimately, Eisenbrey says, “you want patients to be able to undergo a liver transplant because a transplant offers the best chance for long-term survival for patients with cirrhosis and liver cancer.” The researchers found that patients who received the combined therapy were more likely to receive a liver transplant.

Eisenbrey says the results of the first group of patients were not at all surprising and very encouraging. “What we saw was what we expected to see, and it was good to see,” he says. “It’s also nice to see that we got roughly twice the rate of tumor response to radiation when we combined radiation with the microbubbles.”

Dancing Bubbles
The microbubbles that were used are those that are found in commercially available ultrasound contrast agents, and the techniques used to get the microbubbles into the tumor involve similar techniques used to access blood vessels, says Colette Shaw, MD, an associate professor and interventional radiologist at Thomas Jefferson University and the lead clinical author of the study.

Eisenbrey explains how the microbubble treatment works: When an ultrasound wave hits them, they vibrate. If the wave is strong enough, they burst. These tiny explosions cause both physical and chemical damage to the blood vessels of the tumors, which makes them more sensitive to radiation. The key, Eisenbrey says, is to target the ultrasound waves exactly where the tumors are. That way, “You can burst or destroy the bubbles right where the radiation beads are and achieve highly localized sensitization.”

The study was conducted with an ultrasound scanner provided by Siemens Healthineers for research purposes. “The frequency of the ultrasound transducers happens to make these [bubbles] dance,” Feinstein says. “[The bubbles] resonate at low energies. If you turn up the acoustic energy a little more, they disrupt the cell and release the gas.” The process is called inertial cavitation (IC). IC occurs when the bubble diameter grows to at least twice its original diameter, generally during a single cycle of acoustic pressure. Driven by the inertia of the fluid, the bubble then collapses violently, potentially fragmenting into many smaller bubbles, Eisenbrey says.

Feinstein says it’s a promising treatment for such cancers because cancer grows fast and needs new blood vessels to support its rapid growth. “It has to have more and more blood supply. The blood vessels can’t keep up with the vigorous growth of the tumor,” he says. “What John [Eisenbrey] and his team are doing is disrupting the microcirculation, which accelerates the destruction of the cancer. It’s just lovely.”

In January 2018, Eisenbrey and colleagues published a study they performed in animal models that showed popping microbubbles with ultrasound immediately before radiation for breast cancer could triple sensitivity to the treatment. The study was published in the International Journal of Radiation Oncology Biology Physics. The researchers found that the microbubbles improved tumor control for 30 days and provided statistically significant improvements in tumor growth and animal survival.

Notable Contrast
To form images, ultrasound relies on the reception and interpretation of acoustic reflections scattered by blood and tissue. Because the scattering components associated with blood are weak, it is challenging to image blood flow in tissues and small vessels. The first use of contrast ultrasound was reported in the late 1960s by Raymond Gramiak, MD, and Pravin M. Shah, MD, who described their use of bubbles produced by rapid intracardiac saline injections to enhance delineation of aortic blood flow. The study was published in Investigative Radiology in 1968.

However, microbubbles did not become commercially available for use as an ultrasound contrast agent for two decades. Albunex was the first stable, commercially available, and FDA-approved ultrasound contrast agent. It was first described as “a safe and effective commercially produced agent for myocardial contrast echocardiography” in a Journal of American Society of Echocardiography study published in 1989. The FDA has since approved the use of ultrasound contrast microbubbles “for looking at things in the body, specifically liver lesions and the heart,” Eisenbrey says. “When injected intravenously into the blood supply, which circulates throughout the body, the microbubbles reflect ultrasound and enable us to see blood flow much better than normal doppler ultrasound.”

Jefferson has been involved with microbubbles for more than 25 years, Eisenbrey says. As a postdoctoral fellow in radiology at Thomas Jefferson University, Eisenbrey spent a great deal of time trying to put specific drugs inside the bubbles. “What’s unique about these bubbles, as compared to a CT or MRI contrast agent,” he says, “is that you can make them vibrate and pop. For a long time, people have been using that popping mechanism to, hopefully, create these ultrasound-sensitive drug carriers.”

Liver cancer is one of Jefferson’s specialty areas. “We do a lot of treatment for hepatocellular carcinoma and are a pretty big transplant center, as well,” Eisenbrey says. When the Jefferson team saw the work researchers at the University of Toronto were doing using microbubbles to enhance liver cancer treatment in small animals, they decided to pursue it. “A few years ago,” Eisenbrey says, “we replicated in an animal model of metastatic liver carcinoma and were able to show that using microbubbles to sensitize the tumor to radiation was safe. It sensitizes the tumor to radiation but doesn’t necessarily hurt the rest of the liver.”

Promising Future
Recently, the team sought approvals from Jefferson’s Cancer Center and the hospital’s ethics board so that it could take the next step and test the microbubbles in humans. They also secured a research grant from the National Institutes of Health. “After patients provide a signed, informed consent, they get randomized to receive either the standard of care, TARE, or TARE with UTMD,” Eisenbrey says.

As of the end of last year, the team had enrolled a little fewer than one-half of the patients it hopes to, Eisenbrey says. “We expect to go another two and a half years continuing to randomize patients.” No changes are planned to the trial. However, he says, “We are discussing ways to potentially expand this way of delivering radiation to other solid tumors.” Eisenbrey says he sees potential for this methodology to enhance treatments of not only other cancers that have liver metastases but also to cholangiocarcinoma—bile duct cancer. 

“The one caveat is that the organ has to be accessible to ultrasound,” Eisenbrey says. “For example, we are not able to visualize solid tumors in bone, so they would not be good for this. However, tumors like prostate, bladder, or breast cancer or a large percentage of pancreatic cancers and brain cancers could be. There are different applications out there for this. This is really the tip of the iceberg.”

Feinstein says he’s thrilled to see this “hitting the clinic and with good results.” He has spent a lifetime “doing this,” Feinstein says, “and I’m so happy to see it’s going to allow us to noninvasively change the way we treat cancer. It’s just beautiful.”

Beth W. Orenstein of Northampton, Pennsylvania, a freelance medical writer, is a regular contributor to Radiology Today.