Intrahepatic cholangiocarcinoma (ICC) is an aggressive epithelial tumor with poor prognosis and high
morbidity arising from the lining of the biliary tract. Management options for ICC are limited and the disease
generally carries a poor prognosis. Treatment options for patients not eligible for resection are currently not
standardized and include systemic therapies and loco-regional therapies such as ablation, transarterial
chemoembolization (TACE), and transarterial radioembolization (TARE). Using TARE, radioactive microspheres
are delivered via a catheter placed in the hepatic artery branch supplying the tumor, thereby providing a localized
and sustained release of radiation. However, response rates on modified response evaluation criteria in solid
tumors (mRECIST) range from 25-60% and median survival remains at approximately 13-15.5 months.
Contrast-enhanced ultrasound (CEUS) utilizes the intravenous injection of gas microbubbles. Our group
has demonstrated the ability of 2D and 3D dynamic CEUS to predict hepatocellular carcinoma (HCC) response
to TACE a priori and also monitor response. We have also shown the ability to use the subharmonic frequency
components from these agents to non-invasively measure tumor interstitial fluid pressures (IFP) over the course
of chemotherapy. Additionally, a unique property of these ultrasound contrast agents is their ability to generate
stable or inertial cavitation using higher intensity ultrasound pulses. Importantly, microbubble cavitation has been
shown to sensitize angiogenic vessels to radiotherapy by inducing vascular endothelial-cell apoptosis.
The aims of this project are 1) to determine the ability of quantitative volumetric CEUS to predict ICC
response to TARE prior to therapy, 2) to characterize the safety and preliminary efficacy of using localized UCA
inertial cavitation to improve ICC response to radioembolization, and 3) to determine if CEUS estimated tumor
perfusion, IFP, and residual vascularity can predict ICC response to radioembolization 7-14 days post treatment.
As part of this clinical trial, patients will undergo 4 volumetric CEUS exams combined with their standard
of care radioembolization. Quantitative data from the first exam will be obtained prior to TARE and used to
determine if CEUS can predict the likelihood of treatment response (aim 1). CEUS exams 2-4 will be obtained 2
hours to 2 weeks post TARE and will include flash-replenishment sequences to induce inertial microbubble
cavitation. Safety and tumor response will then be compared to historical controls to determine the effect of
microbubble cavitation on therapy (aim 2). Finally, tumor perfusion and vascularity data obtained during CEUS
exams 2-4 will be quantified to determine if these parameters can be used to predict longer term treatment
response (aim 3). If successful, the techniques validated in this proposal are expected to improve ICC
management by identifying which patients would benefit most from TARE, improving tumoral response to TARE,
identifying non-responding disease early and thereby reducing the time to retreatment with alternative therapies.