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Improving liver cancer radiotherapy using ultrasound-triggered microbubble destruction
Dissertation   Open access

Improving liver cancer radiotherapy using ultrasound-triggered microbubble destruction

Corinne E. Wessner
Doctor of Philosophy (Ph.D.), Drexel University
May 2026
DOI:
https://doi.org/10.17918/00011373
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Abstract

The two leading primary liver cancers are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, metastatic disease to the liver (MDL) is common given the liver's dual blood supply via main portal vein and main hepatic artery. A relatively common radiation-based locoregional therapy to treat these unresectable tumors is transarterial radioembolization (Y90-TARE). Unfortunately, Y90-TARE response rates vary greatly. Therefore, additional therapeutic regimens are needed to augment treatment. Several pre-clinical and more recent clinical trials show that incorporating therapeutic contrast-enhanced ultrasound (CEUS) (e.g., ultrasound-triggered microbubble destruction (UTMD)) using ultrasound contrast agents (UCAs) in combination with radiotherapy improves tumor radiosensitivity by inducing endothelial cell apoptosis via a ceramide-mediated pathway, which acts as a radiosensitizer. Consequently, incorporating UTMD in liver cancer patients that receive Y90-TARE is a potential way to improve the therapeutic response. In this thesis, participants with HCC, ICC and MDL were recruited to be part of two different institutional review board-approved clinical trials. The first aim of this thesis characterizes the ability of localized UTMD to improve HCC response to Y90-TARE in a randomized clinical trial in 98 participants. The treatment group received three UTMD sessions, while the control group received standard of care Y90-TARE. Safety analysis demonstrated no significant differences in vital signs and general lab values between groups (p>0.07). Importantly, the participants in the treatment group showed a statistically significant difference in favorable response distribution on long-term imaging compared to control group (p=0.01). Additionally, there was a statistically significant improvement in overall survival in the study group (p=0.03). The second aim of this thesis focused on translating microbubble-based radiosensitization into ICC and MDL participants that received 2D and 3D UTMD to evaluate feasibility, safety, and treatment response compared to historical controls. In this aim, there were no differences in general lab values between groups (p>0.15). In treatment participants, there were no differences in physiological monitoring between pre and post UTMD sessions (p>0.20). There was a trend toward an improved response distribution in the treatment group compared to the control group when evaluating long-term imaging, (p=0.06). When evaluating specifically ICC participants, there was a statistically significant difference in the distributions of response in the treatment group compared to control group (p = 0.02), however no differences in treatment response were seen in the MDL participants (p = 0.37). The last aim of this thesis was an analysis of quantitative CEUS to predict HCC response to Y90-TARE. CEUS could predict response in HCC as early as two weeks post Y90-TARE. Fractional tumor vascularity (FTV) showed a difference between nonviable and viable tumors at 2 weeks post-Y90-TARE (38% ± 24% vs 62% ± 28%, p = 0.008). In addition, there was a statistically significant difference in the change in fractional tumor vascularity from immediately post Y90-TARE to 2 weeks after treatment between participants with viable and nonviable disease (41% ± 31% vs 11% ± 26%, p = 0.006). These findings have the potential to change clinical management and allow participants to potentially get retreated earlier.

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