Thank you. I want to thank the ASLD, the organizers of this hepatology associate course and the chairpersons for inviting both myself and my colleague, Caitlin Musto, to present the management and outcomes of local regional therapy in hepatocellular cancer. We have no disclosures. So in terms of learning objectives, I want to emphasize the importance of approaching these patients with a multidisciplinary approach to the care and management of patients with hepatocellular cancer. Our focus will be in this talk on local regional therapies for hepatocellular cancer. We're going to be focusing on nonsurgical treatments in this circumstance, looking at local ablative therapies, and then also looking at transarterial therapies. So one of the things that's very important to remember about these patients with hepatocellular cancer is that it develops in the setting of liver disease, and in most circumstances it develops in the setting of cirrhosis. So when you're considering these patients for management, it becomes important to consider what is their etiology of liver disease, what is their hepatic, both in terms of their transaminases and in terms of this concept of function, which we've been talking about, looking again at their INR, their bilirubin, and their albumin, whether or not they have portal hypertension, whether or not it's localized disease or metastatic disease. These are things which will influence our treatment strategies for these patients. And so again, it really becomes important to establish this framework of a multidisciplinary care, but really at the center of the patient management strategy is the hepatology team. And often in many circumstances, it's really the advanced practice provider who has the most direct contact with that patient, helps that patient to sort of navigate through this system with interventional radiology, oncology, and others, helps with their follow-up, and then also helps with their strategies for surveillance moving forward. So even though nobody in this room may be an interventional radiologist or an oncologist, I think it's important in terms of counseling your patients, in terms of advising and who they are forwarded to in terms of additional consultations, because I think in many circumstances you will be the navigators of these patients' care. There are several different treatment options, sort of algorithms that can be used in terms of trying to establish the management of these patients. We'll be focusing on those who have very early stage and early stage disease, so those that are demonstrated here in blue. And this is a slide which we'll be using frequently as we move through the discussion about the recommendations for treatment. What we're looking here then is of patients who are sort of stage zero to AB, not those who have metastatic disease, and we're also looking at patients for whom their liver disease is stable enough that we can consider these local regional therapies. So I'll be deferring the rest of this discussion to my colleague, Caitlin Musto. Caitlin's a PA that's been working with us for eight years. Very early in her career, when she was first interested in hepatology, she had the Clinical Hepatology Fellowship Award that was through the ASLD, and she really focuses her practice on the management of these patients with hepatobiliary malignancy. Thank you, Dr. Harnoy. So now we'll discuss the role of local regional therapy in treatment of HCC. HCC presentation is not uniform, and treatment options depend on tumor size, number, and location. Patients have varying treatment goals. They can be curative or non-curative based on the patient's liver function, physical status, and cancer-related symptoms. More than 70% of all patients with HCC will see treatment by an interventional radiologist. First we'll discuss the role of local regional therapy for BCLC stage zero and A disease. These are patients with very early to early stage disease. They often have one small tumor or multiple tumors less than three centimeters in size, but no more than three. The concept to remember behind ablative therapy is that the destruction of tumor cells can be completed by the injection of chemical substances or modifying local tumor temperature. This can be completed percutaneously or during surgery. Radiofrequency ablation, or RFA, is a hyperthermic treatment. Electrical current agitates ions within the cells to result in a rise in cell temperature and death. Centrally located lesions are usually targeted measuring less than three centimeters in size. Location can be a limitation to this treatment, as there can be injury to adjacent structures. Heat sink is also something to consider. If lesions are located near large blood vessels, it can cause a cooling effect, making the treatment less effective. Ablative ablation, or MWA, is also a hyperthermic treatment, but in this case, electromagnetic waves are used to generate tumor heat and result in cell death. This can be used in tumors a little bit larger than what you would use for RFA. It can be used in tumors up to five centimeters. It's less sensitive to heat sink, and higher temperatures can be reached in a shorter amount of time. The treatment does vary between different devices, and there's no reliable endpoint for how much energy is deposited. Stereotactic radiation therapy, or SBRT, is another treatment that can be considered for small lesions, typically less than four centimeters in size. It is important to note, though, that when this treatment is recommended, it's typically in lesions that are not amenable to ablation or resection. This is a study that was published in Hepatology. It compares the outcomes of RFA versus SBRT. As you can see, they're very similar. However, again, you would typically not do SBRT if a lesion was amenable to RFA. Some key points about local ablation are that it is the standard of care for patients with BCLC stage A tumors not suitable for surgery. Adults with child's A cirrhosis should undergo resection if the lesion is amenable to it. The use of adjuvant therapy is not recommended for patients if they have undergone successful resection or ablation, and the use of ablation should be dependent on the local expertise. Next we'll talk about BCLC stage B disease. This is typically multinodular or bilobar disease. An important concept to remember when talking about transarterial therapies is that HCC is supplied by the hepatic arterial blood supply, while surrounding tissues can be supported by the portal venous system. TACE, or transarterial chemoembolization, is a macroembolic therapy where the blood supply to the tumor is cut off by blocking the arterial blood supply. This can be completed with bland particles, transarterial embolization, use with chemotherapeutic agents or TACE, or drug eluting beads known as Dub-TACE. This has been extensively studied in safety proven treatment and has shown improved survival over best supportive care in BCLC B and C disease. Some limitations with TACE are that it is contraindicated in the setting of portal vein thrombosis, and there is an elevated risk of acute liver failure if patients are not selected appropriately. Post-embolization syndrome is something that your patients may experience. It's self-limited, typically with a full recovery in one to two weeks. Your patients may complain of fever, pain, nausea. You may notice a transient elevation of bilirubin or their liver chemistries. More rarely, liver rupture, abscess, or biloma can occur. The benefits of TACE have been strongly demonstrated when patients are selected appropriately, and it is the standard of care for patients with BCLC stage B disease. Local regional therapy is recommended over no treatment for patients with this stage of disease. The use of drug eluting beads has shown similar outcomes to the use of conventional TACE and either can be utilized. TACE should not be used in patients with decompensation from their liver disease, vascular invasion, or if metastases are present. This is a study that was published in the Journal of Clinical Oncology. This is comparing TACE versus ablation versus RFA alone. As you can see in the charts, the overall survival for patients treated with combination as well as the recurrence-free survival is much improved with a combination of TACE and ablation. Next, we'll talk about BCLC stage C disease. This typically involves vascular invasion and may involve metastatic disease as well. Transarterial radioembolization, CARE, selective internal radiotherapy, SIRT, or Y90 can be utilized for this stage of disease. This can be completed with glass spheres, also known as therasphere. This is FDA approved for patients with unresectable HCC, or resin spheres. This is SIRT spheres, and this is FDA approved for patients with unresectable metastatic liver tumors. A TARE or Y90 is a two-part procedure that needs to be completed to prevent extrahepatic microsphere administration. A planning angiogram is completed to map the hepatic anatomy, and any branches supplying extrahepatic structures are included. A technetium-99 scan is then completed. This confirms the perfusion is limited to the liver and also measures the lung shunt fraction. This is very important as this determines the amount of radiation a patient will get. Once the planning procedure has been completed, the Y90-coated microspheres are delivered via a catheter to the tumor arterial blood supply. This is different from TACE in that it's a microembolic therapy, so the hepatic artery remains patent. TARE can be indicated in BCLC stage A, B, and C disease. Unlike TACE, portal vein thrombosis is not a contraindication. There has been studies that showed prolonged time to progression with use of TARE versus TACE, and there is a lower incidence in tumor progression and favorable toxicity when compared to systemic therapy in BCLC A and B patients. Some of the limitations with TARE is that there can be a longer time to initial treatment versus TACE due to the planning stage, and tumors with a high hepato-pulmonary shunting cannot be treated. TARE has been looked at in BCLC stage A disease for bridging to transplantation, stage B disease in comparison with TACE, and stage C disease in comparison with seraphinib. All of the data has shown a good safety profile with good local tumor control. It has failed to show an overall survival benefit when compared to seraphinib in patients with BCLC stage B and C disease. Patients who are ineligible or progress after TARE or TACE should be considered for systemic therapy, and systemic therapy is the standard of care for patients with advanced HCC that have vascular invasion, metastasis, and has shown improved overall survival when compared to best supportive care. This is a study that was published in Gastroenterology. It's comparing TARE versus TACE. As you can see, the patients treated with Y90 do have a prolonged time to progression. However, the overall survival in these patients is very similar. This is a study that shows, or sorry, a slide that shows some different applications for the use of TARE. As we said, it can be used in stage A, B, and C disease. Some circumstances where you may consider using it in early stage disease rather than ablation would be if there's unfavorable anatomy or a tumor's in a location where it wouldn't be amendable to ablation. It may be considered if you are considering resection for your patient, if there's an inadequate future liver remnant. It may also be considered as a way to downstage your patients to transplant or to treat while they're waiting for transplant because there is a prolonged time to tumor progression. A phase three study that has been done, there's actually two, the SARA study and the CERVINEM study. This is comparing TARE and CERT versus SARAPINIB in patients with BCLC stage B and C disease. Both were negative trials. They did not show that there was superiority of TARE or CERT over SARAPINIB. However, the Y90 group did have fewer treatment adverse events and Y90 should not be recommended if a patient can be given systemic therapy. Another phase three trial is the CERAMIC study. This was a study that was completed to show the combination of Y90 and SARAPINIB versus SARAPINIB alone in patients with BCLC. This study also did not show any improvement in the patients given combination therapy versus SARAPINIB alone. Different methods should be used to determine the response assessment for different treatments. Assessment for the response of HCC treated by local regional therapy should be based on MRESIST, which is the Modified Response Evaluation Criteria in Solid Tumors. It's also recommended that CT or MRI be used for assessment of response after resection, local regional therapy, or systemic therapies. Dr. Harnoy will now come back to review the case that Amanda presented for us earlier. Thank you. So, in the case that was presented, we had a 59-year-old African American male. He had had, as was pointed out earlier, evidence of decompensated liver disease with portal hypertension, complications with ascites, some encephalopathy. Initial studies showed a roughly two-centimeter lesion confirmed on MRI to be 2.5 centimeters with the typical patterning that we would see, as was discussed in the postgraduate course yesterday, for patients who have hepatocellular cancer. So in this circumstance with this patient, we would recommend that this patient be referred to a transplant center, as was done in this circumstance. And if the patient is a transplant candidate, we'll need something to be able to bridge this patient to transplant. And if they're not a candidate for transplant, we still need to be looking at the application of these local regional therapies. Now, to some extent, a decision about which therapy is best applied for an individual patient has to do with some of the findings that you see on imaging studies, which was already reviewed, in terms of if they're close to vascular structures. Some of it can depend on the expertise of the group overall. And then, of course, this issue that we were mentioning about the presence or absence of portal vein thrombus. So really, any of the therapies, whether it's going to be a local ablative therapy or a transarterial therapy, may be appropriate in this circumstance. I will say that within our own center, we've been moving increasingly towards radioembolization for many of the treatments that we've done, because I think we're seeing a greater durability with radioembolization than we were, really, with the TACE procedures. Some key takeaway points, then, is that local ablative therapy involves tumor destruction. So this is by either chemicals, such as ethanol injection, or modifying local tumor temperatures, such as radiofrequency ablation and microwave ablation. This is, according to guidelines, the recommendation for those with BCLC stage A disease, particularly if they're not surgical candidates. Transarterial therapies, then, can be divided into two groups, those that are macroembolic and those that are microembolic. The transarterial macroembolic therapies, bland embolization, chemoembolization, or drug-eluting beads, are recommended for patients with BCLC stage B disease. And tear, radioembolization, isn't really fit yet into the guidelines, in terms of from the ASLD. It is not contraindicated in portal vein thrombosis. That's important to remember. And it can be an indication across many of the stages of disease. I think, as was the theme this morning in the discussions, a multidisciplinary care and approach to these patients is critical. Very much at the center of their management is the hepatology team. And we see from studies that demonstrate that in patients who come into these systems with this multidisciplinary approach, we see improved survival in these patients. Thank you for your attention and the opportunity.

hepatocellular cancer

local regional therapy

multidisciplinary approach

local ablative therapies

transarterial therapies