BIOMED PhD Thesis Defense
Title:
Improving Liver Cancer Radiotherapy using Ultrasound-triggered Microbubble Destruction
Speaker:
Corinne Wessner, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
91ÖÆƬ³§
Advisors:
Margaret Wheatley, PhD
John M. Reid Professor
School of Biomedical Engineering, Science and Health Systems
91ÖÆƬ³§
John Eisenbrey, PhD
Professor of Radiology
Sidney Kimmel Medical College
Thomas Jefferson University
Details:
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) account for roughly 70% and 15% of all primary liver cancers, respectively. Additionally, metastatic disease to the liver (MDL) is cancer originating elsewhere in the body and traveling to the liver. The preferred curative treatment for these tumors is surgical resection or liver transplantation. Unfortunately, most patients are not eligible for these treatment options due to tumor burden, extrahepatic disease, or poor medical conditions. Locoregional therapies such as transarterial radioembolization (TARE) are essential in managing disease in patients with liver tumors. TARE is comprised of small glass beads encapsulating the radioisotope yttrium-90 (Y90). These glass beads are delivered to the liver tumor. Although Y90-TARE has been proven effective for downstaging disease, the treatment response after Y90-TARE is between 30-70% using standard criteria, highlighting the need for improvements in treatment response.
Traditionally, treatment efficacy for Y90-TARE is determined by a CT or MRI scan 2-6 months post-treatment. Patients often have to wait 4-6 months to conclusively determine if the treatment is effective. An imaging technique that could be performed earlier than a CT or MRI is contrast-enhanced ultrasound (CEUS). CEUS uses small gas filled ultrasound contrast agents (UCA) (1-10 µm in diameter) that enhance ultrasound signals in the vascular system and has the capability to image in real time without ionizing radiation.
A unique characteristic of a UCA is its ability to generate nonlinear responses at sufficient pressures. UCAs undergo oscillations, and at higher pressures produce bioeffects via inertial or stable cavitation. Cavitation-related bioeffects have been shown to produce endothelial cell apoptosis via a ceramide-mediated pathway. Endothelial cells are susceptible to stress, and when activated by inertial cavitation (i.e., ultrasound-triggered microbubble destructions (UTMD)), this destruction can mechanically perturb cell membranes of the tumor endothelial cells. This stress within the tumor vasculature leads to the upregulation of ceramide, leading to endothelial cell apoptosis. Consequently, one way to improve the therapeutic response in patients that receive Y90-TARE is to perform UTMD to increase the ceramide-induced endothelial cell apoptosis.
The first aim of this thesis characterizes the safety and treatment response of localized UTMD to improve HCC response to Y90-TARE in a randomized clinical trial in 98 participants. The second aspect of this thesis focuses 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 thesis, I found that UTMD is feasible and safe. Additionally, the patients that received Y90-TARE with UTMD had improved response rates compared to the patients who received Y90-TARE alone. Additionally, in the HCC cohort, the patients that received Y90-TARE with UTMD had prolonged survival compared to Y90-TARE alone patients. 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. These findings have the potential to change clinical management and allow participants to potentially get retreated earlier.