Role of Perfluorobutane in Lesion Detection, Targeting and Response Assessment for Ablation of HCC

International status:

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with increasing incidence due to hepatitis B and C viruses . Ultrasound (USG) with, or without alpha feto-protein levels is a standard tool for surveillance of HCC. However, it leads to suboptimal detection rate and false referrals in the US . Use of an ultrasound contrast agent can be helpful in surveillance and diagnosis of focal liver lesions . Second generation ultrasound contrast agents like sulfur hexafluoride (SonoVue), perflutren lipid (Definity) and perfluorobutane (Sonazoid) are microbubbles composed of a phospholipid shell encompassing a low-solubility gas . The characteristic property of Sonazoid is its ability to accumulate in the reticuloendothelial system (such as the Kupffer cells in the liver) for a sustained period of time (up to 60 mins), which is not seen with other second generation contrast agents . Malignant liver lesions do not contain Kupffer cells so these lesions appear hypoechoic in the Kupffer phase (10-60 minutes) .

CEUS has been previously used for targeting of lesions for radiofrequency ablation, however the contrast agent used in the study was Definity . CEUS with Sonazoid has been frequently used in Japan, South Korea and Norway for diagnosis and surveillance. Diagnosis with Sonazoid involves the vascular phase (10 sec to 5 minutes) and the Kupffer phase (10-60 minutes). The vascular phase shows the tumor vascularity and the Kupffer phase shows the absence of reticuloendothelial cells in the lesion (2-4). In case of a new lesion detected in the Kupffer phase or a doubt regarding a previously detected lesion, defect reperfusion imaging can be done for confirmation and diagnosis . In a comparison between SonoVue and Sonazoid in diagnosis of liver lesions, Sonazoid was not inferior to SonoVue in diagnosis and significantly better in detecting lesions during whole liver scanning .

A study was done using Sonazoid enhanced ultrasound for targeting lesions not detected by conventional USG for ablation therapy, and it was found that CEUS detected 97% of the viable tumours compared to 83% by conventional USG. Furthermore, 93% of the lesions which were not detected on conventional USG were treated successfully using late phase of the contrast agent as a guiding tool . However, CEUS using Sonazoid was not used to assess treatment response in this study. A meta-analysis assessing the treatment response after radiofrequency ablation of HCC using CEUS concluded that technical success was higher with Sonazoid compared to other agents .

National status: A study evaluated the role of CEUS in guiding RFA of HCC, however the contrast used was SonoVue and no comparison was made of the post op CEUS with routine 1 month imaging .

The purpose of this study is to evaluate role of perfluorobutane in guiding ablation (RFA/MWA) of HCC and to compare treatment response two hours post procedure using the same ultrasound contrast agent with routine follow up CT/MRI at 1 month post procedure.

• Why this study- Sonazoid is available in only limited countries as of now (Japan, South Korea, Norway)
• So only limited efficacy studies have been done and none in India.
• Also, no study as yet has simultaneously evaluated role of Sonazoid in both lesion targeting as well as response assessment.
• Hypothesis- Immediate post-procedure CEUS with Sonazoid is not inferior to routine contrast CT/MRI at 1 month follow-up for response assessment.

Inclusion criteria

• Adult s (18 80 years) with HCC and who refused surgical resection
• Tumour number not more than five and the largest tumour size not larger than 5.0 cm;
• Ill defined lesions which are not easily detected on grey scale USG for lesion targeting.
• Liver function status at Child Pugh class A or B;
• East Coast Oncology Group (ECOG) performance status value 0 or 1;
• No severe coagulopathy (e.g. platelets ≥50,000/ prothrombin time ratio ≥ 50%).
• Available medical records and/or imaging studies.

Exclusion criteria

• Presence of vascular invasion and extrahepatic metastases at pre procedure imaging study;
• Ongoing anticoagulant treatment that cannot be stopped;
• Combined TACE and ablation for a larger lesion