Microbubbles May Boost Response to Transarterial Radioembolization for the Most Common Form of Liver Cancer

By Thomas Crocker
Wednesday, May 26, 2021

In a first-of-its-kind clinical trial, researchers at Thomas Jefferson University demonstrated the safety of combining ultrasound-triggered microbubble destruction and transarterial radioembolization (TARE) to treat patients with hepatocellular carcinoma — and found that combining the therapies was nearly twice as effective as TARE alone.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, a disease that kills about 27,000 people in the U.S. annually, according to the CDC. Liver cancer’s toll has grown substantially in recent decades — the American Cancer Society reports that liver cancer death rates have more than doubled since 1980.

A common treatment for many individuals with advanced HCC is TARE, which involves injecting yttrium-90-infused beads into the hepatic artery. Once settled in the artery, the beads deliver radiation to the liver tumor.

“The optimal treatment for primary liver cancer depends on tumor stage, liver function, patient performance status and local interventional radiology expertise,” says Colette Shaw, MD, interventional radiologist and Associate Professor of Radiology at Thomas Jefferson University and lead clinical author of a recent pilot study examining the safety and efficacy of combining TARE and ultrasound-triggered destruction of microbubbles. “TARE is indicated as a palliative treatment in those with hepatocellular carcinoma confined to the liver who are not surgical resection candidates, as a bridge to transplant or to downstage patients whose tumor burden is beyond the accepted criteria for transplantation.”

TARE has limitations, including modest irradiation range and tumor penetration. Dr. Shaw, John Eisenbrey, PhD, Associate Professor of Radiology at Thomas Jefferson University and lead author of the TARE/microbubble pilot study, and fellow researchers at the university may have identified a way to enhance TARE — combining it with ultrasound-triggered destruction of gas-filled microbubbles.

Bursting Bubbles

As a radiation enhancer, microbubbles are made to be popped.

“Contrast-enhanced ultrasound uses intravenous injection of microbubbles to reflect the ultrasound wave and generate nonlinear signals, enabling improved visualization of the vasculature,” Eisenbrey says. “…At sufficient acoustic pressures, the microbubbles can either undergo stable oscillations in response to the ultrasound pressure wave, or be locally destroyed, a term called inertial cavitation.”

For nearly a decade, Eisenbrey and colleagues have used microbubbles to track how HCC responds to localized therapies. They have also explored microbubbles’ therapeutic potential. In a 2018 study, the team injected oxygen microbubbles into mice with human breast cancer tumors. When popped using ultrasound, the microbubbles increased the tumors’ oxygen levels better than injection of saline solution or intact microbubbles. Higher oxygen levels made the tumors nearly three times as sensitive to radiation therapy. That, in turn, led to better tumor control and improved survival.

After observing positive safety and efficacy results in a preclinical model, the researchers sought to translate the use of microbubbles to people with HCC receiving TARE. When combined with TARE, using ultrasound to burst microbubbles damages liver tumor blood vessels in a way that primes them to respond to radiation, according to Eisenbrey. In late 2020, he and his team published the initial results of their ongoing, NIH-funded, first-in-humans clinical trial in Radiology.

Efficacy Exceeds Expectations

For their pilot clinical trial, the researchers randomized 28 individuals to receive TARE or TARE combined with ultrasound-triggered destruction of microbubbles. Individuals in the latter group underwent microbubble infusion and popping 1–4 hours, one week and two weeks after TARE. Combining TARE with microbubble destruction proved safe, as the participants’ body temperature, heart rate and blood pressure remained essentially static before and after microbubble therapy. After one month, liver function between the TARE and combined therapy groups was similar.

The efficacy of TARE plus ultrasound-triggered microbubble destruction far outpaced that of TARE alone — 93% of the 15 tumors the researchers studied in the former cohort demonstrated partial or complete response to treatment, compared with 50% of the 10 tumors studied in the latter cohort.

“The most striking findings to date have been the improved tumoral response in patients receiving both TARE and microbubbles,” Eisenbrey says. “While these findings have mimicked our preclinical results, the overall effect in humans has exceeded our initial expectations.”

The study continues (see “Could Microbubbles Have Broader Radiotherapy Applications?”), but Eisenbrey and colleagues are pleased with the results thus far.

“TARE is an effective technique for the treatment of HCC, and our results suggest it may be further improved with the combination of ultrasound-triggered microbubble destruction,” Eisenbrey says. “From a clinical perspective, the study reinforces the safety and potential of contrast-enhanced ultrasound as a tool for monitoring locoregional treatments.”

Could Microbubbles Have Broader Applications for Radiotherapy?

An ongoing pilot study of transarterial radioembolization (TARE) combined with ultrasound-triggered destruction of microbubbles in patients with hepatocellular carcinoma seeks to enroll 104 patients in an effort to better define the efficacy of the treatment — compared with standalone TARE — demonstrated by initial results. The Thomas Jefferson University researchers behind the study think that popping microbubbles to increase tumors’ sensitivity to radiation could have wide-ranging applications.

“Results [of the pilot study] are based on a limited sample size at this point and are not conclusive enough to dictate clinical care,” says lead author John Eisenbrey, PhD, Associate Professor of Radiology at Thomas Jefferson University. “If results can be replicated in larger, multicenter trials, the data would justify adoption of TARE combined with microbubble-based therapy to improve patient outcomes. We believe the bioeffects associated with this study can be used to augment almost all forms of radiotherapy treatments of solid tumors, but … this must also be further studied.”