Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide and the incidence is increasing. While surgical resection and transplantation offer the possibility of long-term cure, the majority of patients are not eligile for these treatments. Transarterial chemoembolization (TACE) is standard of care for patients with Barcelona Clinic Liver Cancer stage B disease but may also be used as bridging therapy in patients who are potential transplant candidates. Current guidelines recommend follow-up imaging 4-6 weeks after all tumor-bearing areas have been treated. Incomplete treatment is defined as persistence of enhancing areas inside the treated lesions seen at the first imaging study after loco-regional treatment and is observed in up to two-thirds of patients post TACE. Contrast-enhanced magnetic resonance imaging (CE-MRI) has been established as the clinical standard imaging modality for evaluating treatment response and contrast-enhanced computed tomography (CE-CT) is used when CE-MRI is contraindicated. However, there are multiple reasons patients may not undergo cross-sectional imaging follow-up - metallic implants, renal impairment, allergies to contrast medium, and anxieties related to confined space or radiation exposure. Additionally, the cost and availability of these techniques are disadvantageous compared to ultrasound imaging. Contrast-enhanced ultrasound (CEUS) is a well-established technique for enhancing echocardiograms in the United States and is approved for a wide range of vascular and oncologic applications worldwide. These contrast agents function as blood pooling agents and unlike the contrast agents used in MRI/CT, are not nephrotoxic and have no renal contraindications, making them an exceptionally safe imaging agent. Additionally, CEUS imaging is not influenced by residual ethiodol or post-surgical inflammation in the liver, potentially offering an earlier option for monitoring treatment response of TACE compared to the current clinical standard. In this study, we propose a multi-center clinical trial to determine the sensitivity and specificity of two and real time three-dimensional (2D and 4D, respectively) CEUS for evaluating TACE. In addition, quantitative biomarkers based on parametric imaging will be defined for identifying patients in need of retreatment. These techniques may provide a safer, more accurate imaging alternative for evaluating TACE effectiveness, as well as earlier identification of residual disease requiring retreatment. The multi-center nature of this proposed study allows sufficient sample sizes to define the sensitivity and specificity of CEUS within an adequate confidence interval, as well as investigate its operator and reader dependencies. Once properly validated, this technique is expected to improve patient outcomes by offering a viable imaging alternative in cases where CE-MRI/CT is contraindicated and enabling earlier identification of residual disease in need of retreatment.

Public Health Relevance

Contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) one month post transarterial chemoembolization of hepatocellular carcinoma is the current clinical standard in identifying patients in need of retreatment. However, contrast-enhanced MRI/CT is associated with significant costs, patient discomfort, and contraindications and this 1 month imaging follow-up also delays essential tumor retreatment. Based on our pilot studies, we propose a multi-center clinical trial to evaluate qualitative and quantitative two dimensional and real-time three dimensional (i.e. 4D) contrast-enhanced ultrasound as an earlier and alternative screening tool for identifying patients in need of retreatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Farahani, Keyvan
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Thomas Jefferson University
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United States
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Li, Jingzhi; Needleman, Laurence; Liu, Ji-Bin et al. (2018) Influence of Data Parsing on Contrast Enhanced Ultrasound Exams. Acad Radiol :
Gummadi, Sriharsha; Stanczak, Maria; Lyshchik, Andrej et al. (2018) Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization. Radiol Case Rep 13:713-718
Gummadi, Sriharsha; Eisenbrey, John R; Lyshchik, Andrej (2018) Contrast-enhanced ultrasonography in interventional oncology. Abdom Radiol (NY) 43:3166-3175
Gummadi, Sriharsha; Eisenbrey, John R; Lyshchik, Andrej (2018) A Narrative Review on Contrast-Enhanced Ultrasound in Aortic Endograft Endoleak Surveillance. Ultrasound Q 34:170-175
Nam, Kibo; Stanczak, Maria; Lyshchik, Andrej et al. (2018) Evaluation of Hepatocellular Carcinoma Transarterial Chemoembolization using Quantitative Analysis of 2D and 3D Real-time Contrast Enhanced Ultrasound. Biomed Phys Eng Express 4:035039