Good afternoon. My name is Tiffany Kaiser, and I'd like to welcome you to the liver meeting and to the Hepatology Associate SIG program, Advances in Management of Liver Masses. The objectives of the session will be achieved through a series of four 20-minute presentations followed by a panel discussion. The first talk will review the evaluation and diagnosis of liver lesions. The second will provide an overview of management options including surgical resection, ablative techniques, and liver transplantation, followed by a review of recent advances in local regional therapies, and concluding with an overview of systemic treatment options. On behalf of myself, my program co-chair, Don Dresick, and the program faculty, we'd like to welcome you to this exciting virtual session and hope you'll join us afterwards for the panel discussion. Thank you. Hello, my name is Caitlin Mosco, and I'm a Physician Assistant at Mayo Clinic in Jacksonville, Florida. Today we'll be talking about evaluation of liver lesions. I have nothing to disclose. The learning objectives for this talk are to review the diagnostic approach to common liver lesions, characteristic and imaging findings of common benign and malignant liver lesions, and identify potential pitfalls in the evaluation of liver lesions. Liver lesions can present in many different ways. They are often clinically silent and an incidental finding on imaging. They are foreign to the normal anatomy of the liver and can be solid or liquid containing. They can also have different clinical courses being benign and indolent to malignant and aggressive. Accurate and reliable evaluation of liver lesions is necessary. For the benign lesion, it can offer those patients reassurance and avoid an unnecessary workup. And for those that have malignant lesions, it can avoid a misdiagnosis and delayed treatment. The differential diagnosis for liver lesions is expansive as you can see here. And for this reason, an extensive clinical and diagnostic imaging workup is necessary. Clinical evaluation should include a thorough patient history, including how was the lesion discovered, exploring systemic symptoms such as abdominal pain, weight loss, or fever. Features of liver disease on physical exam should be rolled out, as well as potential risk factors identified. As you can see in the table here, these are some risk factors associated with development of a liver lesion. They can include obesity with metabolic syndrome, cirrhosis, or other underlying liver disease, a history of an extrahepatic malignancy, foreign travel, family history, or medication exposure. Laboratory testing should also be completed when working up a liver lesion. This can include CBC and liver chemistries, as well as hepatitis testing and tumor markers. The diagram here does show some tumor markers that are associated with different lesions. Diagnostic imaging is also very important in evaluating liver lesions. Ultrasound is often the initial testing and can be sufficient for simple system screening. However, solid lesions require cross-sectional imaging with dynamic contrast for a multiphasic examination. This can be completed with CT or MRI, and arterial and venous phases are required for optimum imaging. It's important to remember not to rely on incomplete imaging for diagnosis of a solid lesion, and often non-liver dedicated imaging studies only include a venous phase image. Decision for whether or not to complete a CT or MRI will depend on availability, local expertise, and clinical suspicion. Another question that may come up is when to consider biopsy of a liver lesion. This can be considered in a benign lesion with atypical imaging features when there is an indeterminate lesion that shows growth on serial imaging, when clinical suspicion for malignancy is high, or when there is an uncertainty of the lesion and when a patient may be able to follow up. We'll now review some types of liver lesions. The types of liver lesions can be divided into three categories, benign lesions usually requiring no intervention, benign lesions requiring further intervention, and malignant lesions requiring intervention. Some things to consider when trying to decide whether a lesion is benign or malignant is that benign lesions are more likely in young, healthy patients and often incidentally found. Malignant lesions are more common in elderly patients, those patients with a cancer history, smokers, or underlying liver disease. Metastatic disease should be considered in patients with a high-risk cancer history, and obesity and metabolic syndrome, especially in older patients, have also been shown to have increased risk of malignant lesions. We'll now review some benign liver lesions. So benign lesions usually requiring no intervention are listed here and include hepatic hemangioma, focal nodular hyperplasia, benign liver cyst, and focal fat sparing. Benign lesions requiring further intervention are also listed here and include hepatocellular adenoma, complex cysts, hepatic abscess, granulomatous infection, and inflammatory pseudotumor of the liver. For the purpose of today's talk, we'll be focusing on hepatic hemangiomas, focal nodular hyperplasia, and hepatocellular adenomas as these are the most common benign solid liver lesions. We'll start by discussing hepatic hemangioma. Hepatic hemangioma is the most common benign hepatic lesion. There's typically no relationship between the size of the lesion and its potential complications, and there's a very low risk of rupture and no risk of malignant transformation. For these reasons, these lesions rarely require intervention. Often patients present and they're asymptomatic with an incidental imaging finding. These lesions do occur more often in females who are young and are non-hormonally driven. They're often solitary and small. As you can see in the video here, hepatic hemangiomas are well circumscribed with sharp margins. They are reddish-brown in color, and on CT or MRI, there's peripheral nodular enhancement in the arterial phase with progressive centripetal filling on the venous phase. This is another image of the arterial phase enhancement in the center and the venous phase. You can see here. The diagnosis for hepatic hemangioma is typically made with imaging findings, and ultrasound can be sufficient in cases where the radiology appears typical and lesions are less than three centimeters in size. Biopsy is rarely required unless the patient has chronic liver disease or suspected metastatic disease, and it is important to remember to exclude other causes of abdominal pain if that is your patient's presenting symptom. Management is typically conservative unless patients are symptomatic, and there's no role for serial imaging. We'll now move on to discuss focal nodular hyperplasia. Focal nodular hyperplasia is the second most common benign hepatic lesion. There is minimal risk of rupture and no malignant transformation, and they rarely require intervention. 74% of cases are asymptomatic. These lesions also occur more often in young females and are non-hormonally driven. They are often solitary but can be multiple and may be associated with hepatic hemangiomas. As you can see in the video here, this will show the typical imaging pattern of an FNH on imaging. They have strong enhancement in the arterial phase and become iso-intense on the venous phase. You can also see the classic finding of the stellate central scar. And on the hepatobiliary phase, the liver parenchyma will become bright, and then the lesion itself is also hyper-enhancing. This is another image of a focal nodular hyperplasia on a CT scan, and you can see that classic central scar. Diagnosis is typically made with imaging findings in the absence of underlying liver issues. No treatment is typically recommended unless the lesions are symptomatic. Biopsy may be required for a definitive diagnosis. There's no role for stopping oral contraceptives, and ongoing imaging surveillance is not recommended in the absence of oral contraceptives when there is a firm diagnosis of FNH. If a patient is continuing on oral contraceptives, ultrasound can be completed annually for two to three years to confirm stability. We'll now discuss hepatic adenoma. Unlike the other two lesions, this is a benign lesion, but it may require further intervention. Hepatic adenoma is the third most common benign hepatic lesion, but 10 times less common than FNH. There is a risk for hemorrhage and malignant transformation, which is why this lesion may need to be more closely followed. If there are greater than 10 lesions, it is termed hepatic adenomatosis. These lesions, again, occur more often in females, with about 86% of cases occurring in females of childbearing age. They are hormonally driven, and incidence is 30 times greater with oral contraceptive use versus non-use. Spontaneous progression has been seen with hormone withdrawal. These are some of the most common associations of hepatocellular adenoma, like we talked about, women with oral contraceptive use. They've also been seen in increasing prevalence with obesity and metabolic syndrome. They may be present in circumstances with exogenous steroid use or increased endogenous sex hormones, such as pregnancy, and are associated with some other syndromes, such as glycogen storage disease and maturity-onset diabetes in young. The appearance on imaging can, again, be seen in the video here. These have rapid, intense hyper-enhancement in the arterial phase and become isoattenuating in the venous phase. But then, unlike the FNH, with the hepatobiliary phase, they will appear hypo-intense compared to the surrounding liver tissue. They are soft and fleshy and well-demarcated without a fibrous capsule. This is another picture showing the difference of a hepatocellular adenoma versus an FNH on the hepatobiliary phase imaging. Hepatic-specific contrast is used to differentiate the lesions from each other, and as you can see here, there is decreased intensity in the hepatobiliary phase, supporting the diagnosis of adenoma. The diagnosis of hepatocellular adenoma can also be made on imaging and MRI as the modality of choice. The subtype can be determinative to 80% of the time due to MRI's ability to detect fat and vascular spaces, which will help to differentiate it from FNH. Surgical pathology is how the definitive diagnosis is made, and immunohistochemistry is mandatory. These are the different subtypes of hepatocellular adenoma. They are inflammatory, which is the most common, HNF1-alpha, beta-catenin mutated, and unclassified. More recently, there have been additional subtypes introduced, and the subtype is important to remember because it relates to the risk of hemorrhage and malignancy of these lesions. The risk of hemorrhage in hepatocellular adenoma is about 25%, with the tumor... Other risks include tumor diameter greater than 3.5, location in the left lateral segment, or inflammatory subtype. Risk factors for malignant transformation would include a patient being a male or beta-catenin subtype, and the risk of this is about 5%. Management for hepatocellular adenoma is based on the clinical scenario. It is recommended that all exogenous hormone therapy be stopped at diagnosis, weight loss recommended as an initial approach, and these lesions are most commonly be treated with surveillance versus surgical reception. However, liver-directed therapy can also be considered. Reception is recommended regardless of size, if the patient is male or proven to be beta-catenin positive. Multiple adenomas do not preclude a conservative approach, and pregnancy is not necessarily contraindicated if appropriately managed. We'll now move on to discuss the malignant liver lesions. As you can see, these are some malignant liver lesions listed here. For the purpose of our talk today, we'll be reviewing hepatocellular carcinoma, cholangiocarcinoma, and liver metastasis. We'll just start by discussing HCC. HCC is the second most common cause of death from cancer with more than 70,000 cases worldwide each year. There should be a high index of suspicion in cirrhotic patients or non-cirrhotic patients with chronic hepatitis B. There tends to be a male predominance, and adult patients with cirrhosis are at high risk, are the highest risk for developing HCC. And liver lesions in the setting of cirrhosis should be considered HCC until proven otherwise. As you can see in the video here, these are the most common appearance of HCC on imaging. It's followed by intense arterial enhancement and portal venous washout. Other features that may be seen are focal fact within the lesion, mosaic appearance, vascular invasion. However, it is important to note the features can vary if the lesion has been previously treated. This is another example of the arterial enhancement and venous washout. As you can see on the arterial image, the lesion appears bright, followed by a subsequent portal washout as you go through the portal and late venous phase. Diagnosis for AAFLD guidelines can be made based on non-invasive imaging by using CT and MRI, liver imaging reporting data system, or LIRADS. A LIRADS 5 lesion is considered diagnostic for HCC. AFP should be used, but does offer poor sensitivity and specificity if used alone and not continuously followed. Biopsy is often not needed unless there are atypical imaging characteristics. And it is important to remember that while the risk is low, there is a risk of tumor seeding. Management can be completed with resection, liver transplant, local regional treatment, or systemic therapy. My colleagues today and later talks during this course will also discuss these treatment regimens in more detail. Next, we'll move on to talk about cholangiocarcinoma. There are three different types of cholangiocarcinoma. And for today's lecture, we'll be discussing intrapartic cholangiocarcinoma. Cholangiocarcinomas overall are very aggressive with a 95% overall five-year mortality. There has been an increased incidence of intrapartic cholangiocarcinoma from 0.3 per 100,000 to 2.1 per 100,000 person per year in the past two decades. This may be linked to increases in type two diabetes, cirrhosis, non-alcoholic fatty liver disease, and cholelithiasis. Symptoms can include biliary obstruction with jaundice, dark earring, pale stools, and puritis, but many patients will be asymptomatic. On imaging, these lesions will appear solid and hypo-intense on pre-contrast images, gradually accumulating contrast through the arterial, portal, and venous phases. There's a thin rim of enhancement that is seen in the arterial phase, followed by a thick rim enhancement in delayed phase imaging. As you can see in the image here, there is also capsular retraction. This is the arterial phase image with the more thin wall rim enhancement. And as this progresses, there is the thicker enhancement seen in the delayed imaging. Intra-hepatic cholangiocarcinoma diagnosis is based on a combination of blood values, imaging findings, and clinical suspicion. Diagnostic modalities include CT and MRI, and any atypical lesions seen in cirrhosis should be worrisome for intra-hepatic cholangiocarcinoma. Biopsy may be indicated. Management can include resection, local regional therapy and systemic therapy, or a liver transplant in very specific cases. Finally, today we'll discuss liver metastasis. In non-cirrhotic patients, liver metastasis from other primary sites are the most common malignant liver lesions. This is uncommon in the cirrhotic liver. And patients without cirrhosis should be assessed thoroughly for their primary cancer site. However, the management will depend on what the primary tumor is. Some common pitfalls in evaluating and managing liver lesions include making decisions based on incomplete imaging studies, attributing nonspecific symptoms to incidental liver lesions, and attributing liver lesions in patients with cirrhosis or chronic liver disease to benign etiology. For that reason, some key takeaways that it is important to remember are to obtain dedicated multi-phase imaging with dynamic contrast, to diagnose liver lesions noninvasively when possible, and to remember liver lesions in the setting of cirrhosis or HCC until proven otherwise. I would like to thank you for your attention for this talk. And I would also like to thank the course organizers from the Hepatology Associates SIG, as well as the AFLD for the opportunity to give this talk today. Thank you very much. Hello, I'd like to thank the organizers for the opportunity to review the management of liver lesions, transplant versus surgical options. My name is Ho-Chan Gillis, and I'm the Clinical Program Director for GI Hepatology and Liver Transplant at the Central Virginia Veterans Affairs Healthcare System. I have no financial disclosures relevant to this presentation. In this session, I'd like to discuss the outcomes in hepatocellular carcinoma based on the ABCs, describe the staging and treatment recommendations according to the Barcelona Clinic Liver Cancer Staging System, compare surgical resection and liver transplant as curative treatment options for hepatocellular carcinoma, review key concepts of downstaging for liver transplant consideration, and finally list contraindications for HCC mild exception. There is an exponential increase of HCC in the United States with the majority arising from preexisting cirrhosis. Imaging plays a critical role in the diagnosis of HCC, and due to tumor characteristics, the diagnosis of HCC can be accurately made without biopsy confirmation. The treatment and outcome of HCC depends on the ABCs, A, for anatomic stage, B, for biological aggressiveness, and C, for cirrhosis severity. Early stage lesions with good biology in patients with preserved liver function can be potentially cured by either ablation, resection, or liver transplant. However, this session will focus on surgical resection and transplantation options. Additionally, management decision-making can be improved by a multidisciplinary tumor board and or early involvement with the transplant center. Given the presence of underlying cirrhosis in the majority of cases of HCC, prognosis is determined by the anatomic stage, biology or histologic grade, and the degree of liver dysfunction and performance status. When examining the anatomical stage, large multifocal disease and the presence of extrahepatic spread are associated with very poor outcomes. If pathology is available and reveals poorly differentiated HCC, or the presence of vascular invasion, these features are often associated with rapid growth and high metabolic rate and are also associated with poor survival. And lastly, the presence of advanced cirrhosis may independently define prognosis and limit available treatment options. Significant advances have been made in the management of HCC over the past decade. Therapeutic options can be divided into curative and non-curative interventions. Potential curative options include thermal ablation, liver suction and liver transplantation. Each of these approaches can result in good treatment response and improved survival. Imaging guided interventions and systemic therapies will be covered later in this session. There have been several staging systems that have been introduced. The Barcelona Clinic Liver Cancer may offer the most prognostic information because it includes not only the tumor burden, but also the underlying liver function and performance status. It has additional value, which includes the ability to stratify survival based on stage zero, A, B, C or D disease. Its prognostic ability has been validated in many countries, and the BCLC divides curative treatment options to the left and palliative treatment options to the right and is applied in patient care decision-making. Surgical resection is the treatment of choice for resectable HCC in patients without cirrhosis. In early stage HCC, the ability to tolerate a curative resection is determined by underlying liver function or normal bilirubin and the absence of portal hypertension, specifically in the BCLC stage zero with preserved liver function. In patients with an excellent five-year survival, approximately 74% after resection, in patients with neither portal hypertension or jaundice. While HCCs are rapidly increasing, liver transplantation rates are not due to the limited organ shortage, and also it requires lifelong immunosuppression. Therefore, reducing death from HCC will require greater uses of non-transplant curative options. Similar to the BCLC staging system, the TNM is another common system used to stage liver cancer. T represents tumor, N stands for nodes, M for metastases. In the anatomical staging system, stage 1 disease is defined as a solitary lesion less than 2 cm. Stage 2 is a single lesion 2 to 5 cm or up to 3 lesions largest less than 3 cm, also known as the Milan Criteria. Stage 3 is up to 3 lesions beyond stage 2. In stage 4 are 4 or more lesions of any size or the presence of tumor venous invasion or nodal or distant metastasis. Over 20 years ago, Mazzafara and his group published an important article that concluded that liver transplant was associated with excellent long-term survival rates for HCC within the Milan Criteria in the setting of decompensated liver disease. Only 4 out of the 48 recurred and was associated with a 4-year survival of approximately 75%. Examining the explant pathology, 13 or 27% were under stage and those patients that were under stage had poorer 4-year survival than patients that had path remaining within the Milan Criteria. The outcomes of this study renewed the enthusiasm for transplantation for HCC. Prior to the Milan paper, liver transplantation used to treat HCC achieved unacceptable long-term outcomes and was associated with half the deaths related to tumor recurrence. Since the Milan paper, liver transplant is considered a highly effective treatment for early stage HCC or BCLC stage 0 to A and otherwise candidates for transplant and liver transplant is considered superior to resection by most because it offers optimal treatment for both underlying cirrhosis and HCC and is associated with excellent 5-year survival rates of approximately 70%. A liver transplant candidate receives a milled sodium score that is used for organ allocation and that score is intended to reflect the disease severity or risk of 3-month mortality without liver transplant. When the calculated score does not accurately reflect the candidate's medical urgency, a liver transplant program can request an exception score. A candidate that meets the criteria can be approved for a standardized milled exception for HCC. If the candidate does not meet the criteria, an exception request is considered by the National Liver Review Board. Prior to applying for a standardized milled exception for candidates with T2-HCC, radiologists at the transplant center must review images and verify the number and size of lesions that met the class 5 criteria prior to any local regional therapy. Metastatic disease or extrahepatic spread needs to be excluded. Have to verify that candidates are not eligible for resection. Programs have to document any local regional therapies and document the candidate's AFP level. The prior milled escalator no longer exists and the initial and first extension for an exception score is 6 points. Liver transplantation for HCC with the milled exception requires tumors to be within the Milan criteria. However, there were subsequent studies that found that some beyond the Milan criteria could be transplanted successfully. This approach was termed downstaging and involves ablation or local regional therapy of stage 3 primary tumors and the follow-up imaging showed local regional control with the absence of aggression and to be downstaged or reclassified to stage 2. The key concept is called the blatant wait approach which allows distinction of indolent from aggressive HCC and selects patients with the best prognosis for liver transplant. However, patients still must wait for 6 months from the time of the first request to be eligible for an HCC milled exception score. And chemoembolization and Y90 are widely used to downstage or shrink tumors and prevent progression prior to liver transplantation due to expected wait time. For HCC milled exception extensions, candidates with an approved exception for HCC is eligible for an automatic exception if there's documentation of the tumor by CT or MRI. The type of treatment if number of tumors have decreased since the last request and the candidate AFP level is required. These milled exception extensions are valid for 90 days and any extension after the first extension receives an exception score of the medium milled transplant minus 3 points. Current OPTN contraindications for HCC milled exception approval include stage T1 HCC, the history of ruptured HCC, the presence of macrovascular invasion of the hepatic vein or portal vein, evidence of extrahepatic metastatic disease, a candidate's AFP level greater than 1000, who do not respond to treatment to achieve an AFP less than 500, and other special considerations will require consideration by the National Liver Review Board. In summary, the likelihood of success is dependent on the anatomic stage, biology, and cirrhosis severity. Treatments with early anatomic stage, indolent or low histologic grade, and well-preserved or compensated cirrhosis with good performance status are associated with improved outcomes. Some HCC can be cured by liver transplantation or surgical resection and the best treatment decisions are made with early involvement of a transplant center or within a multidisciplinary group. And as transplant availability shrinks, saving more lives will require that we make better use of non-transplant curative options for HCC. Thank you for your attention and look forward to the question and answer period. Hello and welcome to the AASLD liver meeting. I'm Amanda Chaney and thank you so much to the Hepatology Associates SIG for inviting me to be a part of this presentation on advances in management of liver masses. I'm Amanda Chaney and I'm a nurse practitioner at Mayo Clinic in Jacksonville, Florida, and I chair our advanced practice group at Mayo Clinic in Florida. I have been a part of AASLD for many, many years. It's really exciting to see all of you, even though it's a virtual platform this year, we are very hopeful that we can see each other in person next year. And today I'm going to talk to you more specifically about loco-regional therapies. This is my disclosure slide. So it's important for us to start out knowing the current landscape of hepatocellular carcinoma, the reason why we would do loco-regional therapies. It is the fifth most common cancer and globally it is the second most frequent cause of cancer-related death. So it is very impactful, both in the United States and worldwide. 90% of primary liver cancers is contributed to hepatocellular carcinoma, and there's a related healthcare expenditure of about $2,300 per patient per month in the United States. And that actually goes up to about $13 billion annually just for the United States. So a huge expenditure on our healthcare system, and it can be devastating if we don't treat and identify early. So a lot of us in this talk are going to continue to bring back this slide front and center. And this is the Barcelona Clinic liver cancer classification. It consists of five stages to select the best candidates for the best therapies that are currently available to treat hepatocellular carcinoma. Patients with asymptomatic early tumors are stages 0 to A. They're candidates for radical therapies such as resection, transplantation, or local ablation. Asymptomatic patients with multinodular hepatocellular carcinoma, or stage B, are suitable for transcatheter arterial chemoembolization, or TACE. Possible other higher advanced stages of HCC would further need the systemic treatment approaches, and our next speaker will go into that into more detail. So for the purposes of this talk, we're going to focus on these areas that I've boxed in here for you. And we're going to go a little bit deeper into that. So this is an overview of some local regional therapies for hepatocellular carcinoma. We have the area of ablation you'll see there on the top left, and that includes RFA or thermal ablation with radiofrequency. There's microwave ablation, again, using heat or energy to necrose the tumor. And then there's cryoablation or freezing the tumor to cause cellular death. In the middle there, you'll see chemoembolization. And then the far right, you'll see percutaneous ethanol injection. And these are just a few. We're going to go into more detail of some more in future slides, but this is just a good overview of most of the common ones that you hear about in your own organizations and areas. On the bottom squares, you see that external beam, radio therapy is under investigation. So that isn't one that is supported by practice guidelines at this time, but it is out there. And for most of these therapies, we do need IV contrast and utilization of radiology. So whether that is ultrasound, CT scan, or MRI guidance in order to perform the procedure. All meta-analysis that have included randomized controls trials that compared PEI or the percutaneous ethanol injection with RFA favored RFA over the PEI in terms of overall survival, disease-free survival, and recurrence. As far as cryoablation goes, it is used intermittently for certain cases, certain patient populations. It is a good use in high-risk anatomy due to its ability to actively monitor intra-procedural ice formation, and it can generate larger ablations in RFA, and it does show an improved outcomes for HCC for tumors greater than three centimeters. The rare post-treatment systemic inflammatory reactions that can occur after cryoablation are termed cryoreaction or cryoshock. And so if that is a procedure that your patient has underwent, it's important to watch for signs of those issues following procedure. So who gets therapy? So once again, we have the Barcelona Clinic liver cancer classification, and that guides us into which stage the patient is based on the size of the tumor, how many tumors, etc. So when we go to local regional treatment, local ablation, radiofrequency, or percutaneous ethanol injection is good for those smaller tumors, those tumors that are not appropriate for surgery. When we go to chemoembolization, those are for multi-nodular asymptomatic tumors without vascular invasion, and it's important to mention that, or extrahepatic spread, meaning it hasn't, the cancer has not spread outside of the liver. Then we go to systemic treatment, which again, we're going to go to in a little more detail in the following talk, where there's chemotherapy for patients who have well-preserved liver function, but advanced HCC tumors. And so those are options for those patients. This is just a snapshot of what it looks like for radiofrequency ablation. I'm a very visual person, and so having a visual to go with what we're talking about to me is always very helpful. So with radiofrequency ablation, or RFA, in the procedure, a needle electrode is inserted into the mass. A small hook of electrodes are sent to the liver mass through that needle, and an electrical current is passed through the electrodes into the liver mass, destroying the mass by heat. The ablation is done in a radiological center. At our center, we have interventional radiology, and they are very, very, lots of experience in these sorts of procedures. So that's where we have them done, but it can be done in a surgical suite as well. There was a meta-analysis that demonstrated superior tumor control in favor of microwave ablation over radiofrequency ablation. There was a subsequent randomized trial that did not identify a difference between the two, so there are some conflicting data out there for that. Most of the practice guidelines do reference RFA over MWA. The next one I want to talk about is irreversible electroporation, or IRE. This is a non-thermal approach. It generates electrode and energy to the tumor lethally with the induction of nanoscale technology. It uses electrical fields to generate openings or penetrations within the tumor cells. The response rate for curing the HCC in situations has been anywhere from 77 to 92 percent. It's really beneficial for areas that are not amenable to thermal modalities, so there is some utility for this approach as well. We talked a little bit about the ethanol injection, but I just wanted to take a bit of a deeper dive here. The ethanol, what happens is it causes cellular dehydration, vascular thrombosis to the vasculature that's feeding the tumor, and it results in cellular necrosis. It's very useful to use when treating small tumors, and there are other options that report that it is inferior to the PEI. It can be safely injected next to critical structures such as bile ducts and the bowel, and it's useful in treating, again, small tumors that's right next to high-risk structures. It does have its utility, again, taking into consideration specific patient's anatomy, as well as the kind of tumor that they have. The next piece, and again, this is going up a little bit on the tumor size, is looking into chemoembolization or TACE. Chemoembolization is done by placing a small catheter into an artery in the groin, which can be directed to a liver artery that feeds the liver mass. The medication is directly put to that tumor, so a high concentration of chemotherapy is put onto that mass, and the medication reduces the growth of the mass and small particles that block the blood supply are injected into the vessels. It allows for a high delivery of chemotherapy to a localized area without having the systemic effects of a systemic approach of chemotherapy. It reduces the growth of the mass and necroses the mass to eventually hope for cellular death, limiting cellular death in the adjacent areas that are non-cancerous cells. Many patients will need several treatments of this, so it's not always a one-size, one-procedure-fits-all sort of situation. Many patients do have to have it two or three times to get full necrosis of the tumor. Another piece we want to talk about is Y90. I probably have heard many of you talk about Y90 in your own organizations. We have a lot of patients who come in for transplant who have had Y90 as a bridge before their transplant to get the tumor small enough to get them to transplant. That is a common approach to have TARE, Y90 radioembolization, to be done for those patients to get those tumors small enough to qualify for transplant. When we do that, what we're doing is we are embolizing particles into the hepatic arteries. It puts radioactive material into that area to necrose the tumor. Again, it's not systemic, so there are a limited amount of side effects that the patients will have, but it does go right into that area. When we do have patients who come for transplant who have had Y90 in the past, we do have a notification process to let everyone know that once that liver is explanted, that the pathology staff are aware that they've had Y90 to properly dispose of the organ as well as dispose of the radioactive material. Make sure that that is in place, that process is in place in your own organizations. There was a study that was done comparing the two, comparing TACE and TARE. In one of them, there was an overall survival that was improved. There were less hospital days, and there were less complications. It's interesting when we think about TACE and TARE, which one it was. If I had you as a live audience right now, I would ask you which one you think, hoping that you would get the right answer. The correct answer is TARE. It was in this study found that there was an overall survival improved as far as one and three-year survival. The patient had less hospital days associated with their pedicellular carcinoma treatment and complications, and there were less complications. This was a very interesting study. It was done in 2015, and more studies have been ongoing to look at the difference between the two. Currently in our practice guidelines, TACE seems to be talked about a lot more than TARE does. Another approach that is important for us to know about is a newer approach, but it is out there in our organizations and communities, and so it's important to go through this process and let you know all of them that are available. This is stereotactic body radiation therapy, or SBRT. It's an emerging treatment for the treatment of pedicellular carcinoma. The decision to treat HCC with this option is evaluated at a multidisciplinary setting. We want to think about, is this for downstaging to transplant? Is this as a bridge to transplant? Are we talking about palliation where the tumor is too large, but we want to get it small enough where it's livable, the patient has some sort of quality of life, or a definitive curative treatment? Patients who have this, it's a high dose of radiation in a targeted area. I think a lot of us have heard of proton beam therapy and those sorts of options, and that's what this is. It is highly effective in providing local control for a small HCC tumor, and it is a useful option when we don't have percutaneous or trans-arterial ablative therapy as we don't have those as an option. It has been added to the National Comprehensive Cancer Network practice guidelines. It has not yet been added to EASL or to AASLD practice guidelines, but I did want you to just be aware that this is an option that's out there. It's getting more buzz, if you will, and we may see more in the literature about that. The interesting thing with this approach is that the amount of necrosis is a far less percentage than TACE or some of the other options. I think more research will be done in this area to improve the outcomes, but for now, we still know that TACE is frequently the best approach in many kinds of patient tumors. One of the last ones that I wanted to talk to you about is high-intensity focused ultrasound. With this approach, it delivers a high-energy external compression wave energy piece. It's useful in treating small and recurrent HCCs, and the outcomes are comparable to that of RFA. The downside with this is that there is a long procedure time, and so if technology improves and there's a way to decrease the procedure time, I think this would be a more favorable option, but for now, people do kind of steer away from it because the procedure times are a bit longer than some of the other approaches. Now I want to focus a little bit on the AASLD recommendations that are in our practice guidelines. For local ablation, the mainstay of treatment for non-surgical candidate with the early stage HCC is local ablation. RFA is favored over percutaneous ethanol injections and nodules up to four centimeters. TACE is recommended for intermediate stage HCC, and radioembolization with Y90 can be used for intermediate HCC as well. There are noted to be positive outcomes, but it has not been formally adopted into the practice guidelines, but it is important to know that that option is out there. Now we want to look a little bit at our ESOL recommendations. TACE is recommended, and these were actually just updated in 2018, so fairly recently. I expect that more recommendations will come in the next year or two. TACE is recommended for patients with the cancer stage of B. It should not be used in patients with decompensated liver disease, advanced liver and or kidney disease, macroscopic vascular invasion, or extra hepatic spread. Remember, if the tumor is outside of this area and has spread, it's more of a palliative approach versus any sort of curative approach. TAR using Y90 microspheres has been researched, but more studies are needed to finalize when to use. So again, it's mentioned in the practice guidelines, but there is no formal recommendation within the practice guidelines at this time. So this was a study done in 2020, showing the pathological response to treat pre-transplant local regional therapy was predictive of patient outcomes after liver transplantation for hepatocellular carcinoma. It was part of a U.S. multi-center HCC transplant consortium. And out of 3,439 patients, 23% of them had a complete pathological response, meaning that the tumor necrosed and the whole thing was gone. And so when they take the liver out at the time of transplant, they do the pathology and look under slides, the whole tumor 100% of the tumor is necrosed, and there's no micro or macro vascular invasion. The complete pathological response happened more in patients who are younger, who had a lower MELD, who had lower AFP levels. It also is noted that these patients had a significantly lower one, three and five-year incidence of HCC recurrence after their liver transplant. So good information to know, I think that when we have patients who have had HCC as a transplant, because of HCC, that we've done our due diligence to kill those cancer cells to give them the best outcome post-transplant that they can have. And this sort of study is important to back up that information. Factors predicting the complete pathological response were identified, as you see below, and may help prioritize patients to which patients should be receiving those specific local regional therapies in the future. So it's again, good considerations for us to be aware of. When we think about which patient gets which therapy, this is a tailored approach. This was a study done in 2019. And this goes through very specific information of each of those therapies that we've talked about earlier in the slides, as well as the size of the tumor, if there's any, the anatomy pieces, if there's vascular issues. So this tool is used by our interventional radiologist here at Mayo Clinic in Florida, to go through the approach of which is the best option for this patient. Again, we've talked many times about some of the therapies may work for one patient and not another and really taking the consideration of all of what's going on with the patient, their anatomy, their specific history, it's really important to know which is the best option. And so this is a really great tool that our team uses for that. So in conclusion, some key takeaways that I want you to take home with you. For local regional therapy, there are safe and effective curative therapies for hepatocellular carcinoma using this approach. The modality chosen is based on the patient's presentation as well as the tumor phenotype. Further research is needed to look into other options and to see if some of the newer technology is going to make an impact in this specific part of cancer treatment. Downstaging to bridge as a transplant is possible. And many times we do that. And then patients with this is really for patients with early stage HCC and intermediate stage for those who have larger tumors, and who have more vascular invasion and those sorts of pieces, more of a systemic treatment approach is beneficial. And we'll get into that into the next talk. Thank you so much for having me. I really appreciate your time today. Thank you. Hi, and welcome. Thank you for joining the Associates SIG program. And today I'll be talking about systemic HCC therapies. I'm Vicky Shaw, physician assistant. I am the current solid organ transplant lead APP, the section of hepatology at Rush. I will be the new elected Associates Committee chair, and I'm currently working with CLD editorial board and the NAFLD SIG steering member. So today we're going to be going over all the systemic therapies available. Here are my current disclosures, clinical area for Avian Gilead in viral hepatitis, that includes advisory board and research funding. So our objectives today is learn about systemic treatment recommendations, according to BCLC staging, we're going to discuss first and second line systemic chemotherapies, and review clinical trials that allowed these medications for approvals. So let's present a case study first. This is a 62-year-old Asian female with hep B cirrhosis presented to hepatology for new HCC presentation. The patient was taking tenofovir with PCP for over 10 years without any issues, but did not have any previous hepatocellular carcinoma screening with any imaging or AFP. A CT abdomen and pelvis was completed for abdominal pain she was having for two months. Her labs showed AST of 32, ALT of 45. Her belly was 1.7, creatinine and sodium were pretty stable. Her hemoglobin 13 platelets showed thrombocytopenia, INR was elevated at 1.5 and AFP was 150. She presented with child abuse, B score. And so if we look at the CT scan, abdomen and pelvis with and without contrast, you can see that there was a diagnosis of moderately differentiated HCC in segment eight. So it presented with washout and also, unfortunately, invasion of the right portal vein. So if we look at the Barcelona's criteria, BCLC staging and treatment strategy, this patient would be C. So I have it circled here for advanced stage, which has portal vein invasion. And so this is when you when you look at a patient with HCC, you really want to determine which stage do they present. And there's an algorithm that you can follow of what treatment would be appropriate. So right now we're talking about, you know, pretty much patients that are late B or C, but probably C where resection, transplant, or local regional therapy is not available for this patient. So you're now going to chemotherapy options. So when we look at systemic treatment categories, they're broken down into multikinase inhibitors, and immune therapies. The multikinase inhibitors directly target tumor cells, they inhibit and eugenicists. And this is really important in the highly vascular nature of liver cancer. And it also targets the RAS and RAF pathways that are involved with cellular proliferation. On the other hand, the immune therapies target the body's adaptive immune system. And these are going to fall into categories of anti-PD-1 and anti-VEG-FR. So let's go over the first line systemic treatment options. So I have put down here the three currently available first line treatments and which category they fall into. So we're going to go over each of those. We all know about a SRAFNIB. It was approved many years ago as first line therapy, and was the only one we had for a long time. It has a mean overall survival of 10 to 13 months. It is a multikinase inhibitor, and also surface inhibitor. And it packs the kinases that are part of tumor cell signaling, angiogenesis, and apoptosis. We do see the side effects of the hand foot skin reaction or syndrome, diarrhea, and weight loss. And we also see hypertension. If hypertension is seen, these patients can be treated with hypertension medications with good response. So the SRAFNIB was approved by the famous SHARP study. This is a study that all other current HCC medication approvals compared to. And so they looked at patients with advanced HCC. They were compensated with child PUA and at least one untreated lesion. They also had good performance status of two or less, and no prior systemic treatment. Their life expectancies were expectancy was assumed greater than 12 weeks. And the primary endpoint, as you'll see across the board is overall survival in time for progression. So this was comparing SRAFNIB to placebo. And you can see here that there was a overall survival greater for SRAFNIB and an overall improvement of decreased progression of disease. So this is what we use to compare all other medications to. So the next one that is first line available that was approved after SRAFNIB was Limbatinib. This was approved in August 2018 for first line therapy, and it has a mean overall survival rate of 13.6 months. This is also a multikinase inhibitor and surface. And so the difference between this one to the other two SRAFNIB is that it's a more potent inhibition of FGFR1. So this is good if the cases are resistant to these inhibitors. The side effects can include hypertension, protein urea, the hand foot syndrome, diarrhea, weight loss, decreased appetite and fatigue. So their approval for Limbatinib was based on the phase three study REFLECT, where reviewed this medication against SRAFNIB. It was a multi-center open label phase three study, and it was a non-inferiority study. That means showing that Limbatinib was similar to SRAFNIB. And so the patients again were on resectable HCC, no prior treatment, at least one target lesion, Barcelona criteria of B or C, child PUA score, good performance status of ECOG01 and adequate organ function. So they compared Limbatinib to SRAFNIB with a primary endpoint of overall survival. You can see that Limbatinib and SRAFNIB were similar in their overall survival for 13.6 months versus 12.3 months. So the next one I want to go over is a newer FDA approved combination medication. And so this is a two monoclonal antibodies combined for treatment, and it has a great mean overall survival of 19.2 months. So this is a tensilizumab and bevacizumab. And this is only for patients with child PUA. And one thing to note is that an EGD should be done within six months of completing this, giving this treatment as there's an increased risk of GI bleeding. The other side effects do include hypertension, fatigue, increased AST, proteinuria, as we discussed GI bleeding and also the immune mediated side effects. So if you look at the first publication of this combination treatment versus SRAFNIB, this is not the publication that has received approval, but they were just looking at the overall survival and disease progression. And you can see that the overall survival was greater at 84.8% compared to 72 for SRAFNIB. You can also see the improvement of disease progression of 54.5% versus 37.2%. So now let's look at the actual study that allowed this combination medication to be approved. This is a phase three, I am brave 150 study. And this looked at the combination versus SRAFNIB. You can see that there was 105 total patients, 363 were given combination and 165 were given SRAFNIB. These patients were unresectable HCC with at least one untreated lesion, and also trial pew score of A and good performance status. The survival rate was consistent across all subgroups. And the mean survival was 19.2 versus 13.4. And the survival of 18 months was greater at 52% versus 40%. This is the longest survival seen in a phase three study. So this is a newer combination that is available that we can use for our patients. So say you do treat with SRAFNIB, and then there's been disease progression. Now we're going to go over second line treatment options. So I have again, broken it down by names that we're going to go over. And you can tell the different types of mechanism of action for these for your review. So first, we're going to go over Regorafnib. It was FDA approved in April 2017 as second-line therapy as a mean overall survival of 10.6 months. Like SRAFNIB, it's very similar, but it has a great potency and great broader activity. It is used for patients who have progressed on but tolerated SRAFNIB. It's an oral multikinase inhibitor for intracellular and surface. And it has the side effects of hypertension, hamfoot syndrome, fatigue and diarrhea. So this approval came from the clinical trial resource, which is a phase three trial. And this included patients with BCLC stage B and C documented progression on SRAFNIB with at least 400 milligrams per day, trial PUA and good performance status. And this was compared to placebo. So you can see that comparing Regorafnib with placebo, it had a overall survival of 10.6 months versus 7.8 months. So next would be Nivolumab. This is approved in the United States by the FDA in September 2017. This is a second-line treatment, if ineligible for MKRI or TKI. Please note that this one is actually can be used in trial PUA or even B. So this is an option for patients with more advanced liver decompensation options. So this is a PD-1 inhibitor and has the side effects of fatigue, pruritus, rash, diarrhea, and elevated LTs. These are common but not very severe. So I'm going to go over two clinical trials for Nivolumab. One is a CheckMate 40. And this was a dose escalation study for HCC, where it looked at SRAFNIB naive patients and SRAFNIB experienced patients. And endpoints included response rate, time to response and overall survival. Before I go over the results, I also want to present the second trial, which was CheckMate 459. And this was looking at Nivolumab versus SRAFNIB as a first-line treatment. This was also a phase three trial, and same similar population with no prior systemic therapy, not eligible for local regional therapy. It was a trial PUA group, and good performance status. And they were looking at endpoints of overall survival in time to progression. So this was a direct comparison for first-line treatment. So the results showed that Nivolumab was not approved as first-line because the overall survival was 16.4 months for Nivolumab versus 14.7 months for SRAFNIB. So it did not hit the p-value required for statistical significance. It was approved as a second line after SRAFNIB. It had an overall response rate of 14%, a mean duration response of 17 months and overall survival of 15.6 months. Please note that they did do a CheckMate 40 expansion arm for patients who progress on prior SRAFNIB with a combination medication. So Nivolumab with iplilimumab and the response rate of 31%, the medium duration of 17 months, overall survival of 23 months. But these patients did have immune related side effects that required systemic corticode administration in half the patients. So what they're doing now is looking at phase three trials with this combination versus SRAFNIB or libatinib to get approval for first-line therapy. Carbozatinib was approved in March 2019. And it's a tyrosine kinase inhibitor. It had a mean overall survival of 10.2 months. This was approved by a phase three study called Celestial. And these patients were progressed on prior SRAFNIB. And the most frequent side effect with this medication was hand-foot syndrome. It did include other GI side effects including diarrhea, vomiting, and nausea. They also had fatigue and hypertension. Ram's serum was approved in May 2019. This one is a surface anti-surface or mono-antibody. And it had an overall survival rate on the first clinical trial was 7.8 months on the second one it was 8.5 months. This one is the first therapy that is a biomarker selected medication for a population. So the phase three trial reached to looked at patients that were previously treated with SRAFNIB, but also had an AFP greater than or equal to 400. Side effects were similar to previous treatments of fatigue, edema, hypertension, abdominal pain, puritaneuria, nausea, and ascites. Pembrolizumab was approved in November 2018. This is an anti-PD-1 monoclonal antibody with a mean overall survival of 12.9 months. This was approved by the clinical trial keynote 224. And this included patients who had progression with SRAFNIB or were intolerant to SRAFNIB. The overall response rate was 17% with the complete response with one complete response and 17 partial responses. The response duration was anywhere from three to 16 months. And the side effects were consistent with monoclonal antibodies of immune mediated side effects. So I did include a great slide for review. This comes from the primer for hepatocellular carcinoma in nature reviews, and it goes over all the study names, the treatment names, the overall survival, and most common grade three to four adverse events. So this is a really nice slide that you can refer to in your clinical practice. So key takeaway points is always consider systemic treatments if the candidate cannot get transplant resection local regional therapy. There are now multiple systemic options with the mean overall survival from anywhere from eight months to 19 months. But these patients do require close monitoring for side effects. And so this is what you would see in clinical practice. I want to thank everyone for allowing me to present today, WSLD, the Hepatology Associates SIG Programming. I'd also like to thank Dr. Ishwaran and the rest of the team at Rush University for their support for this presentation. Thank you. This concludes the Hepatology Associates SIG Programming Advances in Management of Livered Masses. I'm Dawn Drasic and on behalf of my co-chair, Tiffany Kaiser and myself, we would like to thank you for joining us. Our presenters are available to answer questions. You may submit a question by typing it into the chat box. As a reminder, the Hepatology Associates course is available to view on demand on the liver meeting digital platform. We would like to invite you to join the Hepatology Associates SIG if you're not already a member. Thank you so much for joining us today.

Hepatology Associates SIG program

management of liver masses

liver lesions evaluation

surgical resection

ablative techniques

liver transplantation

local regional therapies

systemic treatment options

BCLC staging

systemic chemotherapies

clinical trials