Contrast-Enhanced Ultrasound for Diagnosis and Therapy of Cholangiocarcinoma

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Project Summary: 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.