Microbubbles Create Greater Radiation Sensitivity in Liver Tumors

Bursting gas bubbles next to liver tumors with ultrasound waves can improve the effect of radiation therapy, potentially leading to better overall survival.

In a first-in-human clinical trial, published Dec. 15 in Radiology, a team of investigators from Thomas Jefferson University showed that adding gas-filled, lipid-shell micro-bubbles to transarterial embolization (TARE) – and popping them in close proximity to tumors – can make these masses more susceptible to treatment.

Liver cancer is notoriously difficult to treat, and its impact has been growing for the past 40 years. According to the American Cancer Society, deaths from the disease have double since 1980, claiming approximately 750,000 lives worldwide annually. The results of this study show that previous micro-bubble successes achieved in animal studies can translate to the clinic.

“This approach has shown to be effective in preclinical studies using animal models of other solid tumors like bladder, prostate, and breast cancer,” said lead study author John Eisenbrey, Ph.D., associate professor of radiology. “This is the first work to demonstrate this approach is safe and shows promise in humans with liver cancer, which is very exciting.”

TARE, a therapy that injects radioactive glass beads into blood vessels in the liver, is recommended for roughly 15 percent to 25 percent of patients who have advanced liver cancer. It works by emitting a therapeutic radiation dose near the tumor to destroy it, but its efficacy can be hit-or-miss depending upon how far the beads are from the tumor itself.

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But, adding micro-bubbles to TARE offers two benefits, he said. Not only does the combination increase treatment effectiveness, but it also does so with less dose to the patient. The procedure to access the tumors via the blood vessels is the same, and these micro-bubbles can be targeted directly to where the radiation beads are to maximize their impact. Hitting the micro-bubbles with ultrasound waves causes them to vibrate and burst, and the resulting physical and chemical damage makes the tumors more susceptible to the radiation.

Example contrast-enhanced US series show the sequence of US-triggered microbubble (MB) destruction in an 80-year-old male participant 2 hours after radioembolization. Imaging was performed in dual mode with the nonlinear contrast mode (left side of A–D) images showing MB signal and B mode (right side of A–D) used for anatomic guidance. A, Marked MB enhancement within the tumor (arrows) was observed 2 hours after radioembolization. B, At the initiation of the destructive pulse, a higher mechanical index pulse was generated, causing US-triggered MB destruction. Immediately following the 4-second destructive pulse, US-triggered MB destruction was confirmed by, C, an absence of contrast signal in the tumor and surrounding liver followed by, D, gradual MB reperfusion (required for repeat US-triggered MB destruction) back into the tumor. Courtesy: RSNA

So far, the team noted, this micro-bubble technique has been shown to be highly effective with prostate cancer, demonstrating a nearly 10-fold improvement in radiosensitivity of tumors. To see if similar results were possible with liver cancer, the team enrolled 28 patients between July 2017 and February 2020 and randomly assigned them to two arms of the study. One group received TARE alone, and the other underwent TARE plus ultrasound-triggered destruction of micro-bubbles.

Example series of from a 54-year-old male participant undergoing hepatocellular carcinoma radioembolization with US-triggered microbubble (MB) destruction. The series shows baseline contrast-enhanced MRI scans in, A, transverse plane, B, technetium 99m macroaggregated albumin SPECT-CT in the transverse plane during treatment planning, C, angiography during yttrium 90, D, B-mode US immediately after radioembolization, and peak contrast-enhanced US enhancement during US-triggered MB destruction, E, 2 hours, F, 1 week, and, G, 2 weeks after radioembolization. Courtesy: RSNA

The team gathered data on temperature, heart rate, and blood pressure on all patients both before and after the ultrasound-triggered treatment, and their analysis showed no change. Their evaluation also showed no compromise in liver function – both groups experienced similar changes in albumin, alanine aminotransferase, aspartate transaminase, bilirubin, hemoglobin, and white blood cell count. Additionally, patients saw no side effects.

In addition, SPECT imaging of the abdomen revealed no radiopharmaceutical activity outside the liver was detected. And, all CT, chest X-ray, MRI scans, and clinical records showed no evidence of adverse effects, such as pulmonary fibrosis, radiation pneumonitis, and gastroduodenal injury.

Overall, Eisenbrey said, patients who received the combined therapy saw much better results. Based on an assessment of 10 tumors in the TARE group and 15 in the combination group, 93 percent of tumors in the combination group showed partial-to-complete response to the therapy while only 50 percent of the tumors in the TARE group alone saw a response.

Using micro-bubbles also made a difference in who was deemed eligible for a liver transplant, the team said.

“Consensus interpretation by a hepatologist and transplant surgeon of transplant eligibility aside from tumor burden deemed four participants from the TARE-alone group and 10 participants in the TARE with [ultrasound]-triggered [micro-bubble] destruction group eligible for orthotopic liver transplant,” they wrote.

Of the eligible patients, 50 percent of the TARE group and 70 percent of the combination group were listed to actually undergo transplant.

The team’s evaluation also revealed that combination patients needed fewer re-treatments than TARE alone. While only 35 percent of combination patients needed another treatment, 55 percent of TARE only patients had to pursue the subsequent therapy.

While these findings are early and with a small patient population, said lead clinical study author Colette Shaw, M.D., associate professor and interventional radiologist, they reveal that the combined therapy can significantly improve tumor outcomes. The next step, she said, it to bring more patients into clinical trial to demonstrate key benchmarks.

Eisenbrey agreed.

“Our findings are really setting the stage for a whole range of studies to be done in humans,” he said. “This approach could be effective in treating metastatic liver tumors, but also other types of primary cancer. The bubbles themselves can also be engineered to deliver chemotherapy or oxygen as they burst. This is really the tip of the iceberg.”

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