Microbubble-based Radiosensitization for Hepatocellular Carcinoma: Evaluation of Safety and Efficacy in a Phase II Randomized Trial
Microbubble-based Radiosensitization of Hepatocellular Carcinoma: Evaluation of Safety and Efficacy in a Phase II Randomized Trial
Microbubble-based Radiosensitization of Hepatocellular Carcinoma: Evaluation of Safety and Efficacy in a Phase II Randomized TrialRadiology
Abstract
Background
Contrast-enhanced ultrasound agents are gas-filled microbubbles that can be destroyed locally by methods such as ultrasound-triggered microbubble destruction (UTMD). UTMD may induce biological effects that sensitize tumors to radiation. However, the efficacy and safety of combining UTMD with radiotherapy in patients with hepatocellular carcinoma (HCC) remain unclear.
Purpose
To evaluate the therapeutic efficacy and safety of UTMD in patients with HCC undergoing 90Y (yttrium-90) transarterial radioembolization (TARE).
Materials and Methods
This prospective phase II clinical trial was conducted from July 2017 to February 2024. Patients with HCC scheduled for 90Y-TARE were randomly assigned to either 90Y-TARE combined with three sessions of UTMD (treatment group) or 90Y-TARE alone (control group). The primary endpoint was therapeutic efficacy assessed by modified RECIST using MRI or CT. Secondary endpoints included safety, overall survival, time to next treatment, liver transplantation rate, and pathological therapeutic efficacy at the time of transplantation. Changes in general laboratory values and vital signs were compared using paired and unpaired t-tests, survival and time to next treatment were compared between groups using the log-rank test, and the distribution of therapeutic efficacy was compared using the Mann-Whitney U test.
Results
The study subjects were 98 patients (mean age 69 ± 8.4 years, 71 males). In the safety analysis, no significant differences were observed in vital signs before and after the initial UTMD in the treatment group (all P ≥ .07). Furthermore, no significant differences were observed in changes in general laboratory values before and after treatment between the treatment and control groups (all P ≥ .08).
Regarding therapeutic efficacy, the control group showed stable disease (SD) in 34% (17/50), partial response (PR) in 22% (11/50), and complete response (CR) in 44% (22/50). In contrast, the treatment group showed SD in 4% (2/48), PR in 35% (17/48), and CR in 60% (29/48). In other words, the combination of UTMD increased the rate of CR+PR by 30 percentage points (treatment group 96% [46/48] vs control group 66% [33/50]; P = .01).
Overall survival was better in the treatment group than in the control group, with a hazard ratio for death of 0.51 (95% CI: 0.28–0.95, P = .03).
Conclusion
Compared with 90Y-TARE alone, microbubble radiosensitization therapy combined with UTMD provided equivalent safety, improved therapeutic efficacy, and prolonged survival.
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This is a multicenter phase II trial from Thomas Jefferson University, published in the September 2025 issue of Radiology. I have not read the full text. In the West, a technique called radioembolization, in which yttrium-90 is impregnated into embolic materials, has been performed for over a decade, as it is considered to outperform transarterial chemoembolization. I have heard of basic experiments involving the introduction of anticancer drugs into cancer cells through cavitation of microbubbles via ultrasound irradiation, but I was not familiar with the radiosensitizing effect.
Although the treatment results are very good, one point of concern is that it took seven years to enroll 98 patients for a phase II trial. Because radioactive materials are used, shielding equipment is required throughout the catheterization room, making it a large-scale operation, which means the number of facilities where it can be introduced is quite limited. This is likely a major reason why radioembolization has not been widely accepted in Japan.
The figure shows images of ultrasound irradiation, but the brightness of the overall image is not that high, so I imagine the sound pressure is not very high. I felt that treatments using ultrasound irradiation, such as HIFU and histotripsy, are gradually expanding.