Hello, and welcome to today's webinar, HCC Staging and Treatment. It's presented by AASOD's Hepatology Associates Special Interest Group. Today's webinar presenter is Vicki Shaw. Ho-Chung Gillis will serve as our moderator. Today's webinar will be available on demand on AASOD's online learning platform, Liver Learning. Be sure to connect with us on Instagram, LinkedIn, Facebook, and Twitter. Also tune into our YouTube channels to view our videos. If you're not an AASOD member, today's a great time to join. As a member, you can join as many special interest groups as you would like. Listed are a few other member benefits. The Hepatology Communications Journal features open access research in hepatology. Our articles are freely available to read, download, and share. AASOD has many upcoming meetings covering a variety of topics. Visit aasod.org slash calendar for a full list of our events. The Liver Meeting 2019 is November 8th through 12th in Boston, Massachusetts. Deadline for early registration, pricing, and housing for the Liver Meeting is Friday, October 11th. Please visit our website at www.aasod.org for detailed information. You can help support the future leaders in hepatology by giving a donation to the AASOD Foundation. Your donation in any amount is tax deductible. Visit aasodfoundation.org slash donate to learn about ways to give back. Please feel free to submit questions throughout the presentation using the Q&A box at the top or bottom of your screen. All questions will be answered during the Q&A portion of the webinar. Now I'll turn it over to the moderator, Ho-Chung. Thank you, Dominique. My name is Ho-Chung Gillis, and I am the chair for the Hepatology Associates Special Interest Group. And the mission of our Hepatology Associates SIG is to enhance member engagement through networking, mentorship, education, and career development opportunities. If you are not a member of our SIG, please go to the AASOD website and join. And it is my pleasure to introduce to you Vicky Shaw, who is a PA, a physician assistant who received a Bachelor's of Science in biochemistry with a minor in mathematics from California State University in Long Beach. After completing her neuroscience research at UCLA, she graduated from the Midwestern University in Downers Grove, Illinois, with a master's in medical science and physician assistant studies. She first started in underserved internal medicine and urgent care in Southern California. She became interested in gastroenterology after caring for a father who had esophageal cancer. She practiced in gastroenterology for five years at the Carle Hospital with the University of Illinois in Urbana. And Vicky joined the hepatology team at Rush University in 2016. She has a strong dedication to providing education as an instructor to the PA program, and she is also a national lecturer for conferences and the APP Medical Advisory Chair for the American Liver Foundation. She's very active in the American Association for the Study of Liver Disease as a member of the Associates Committee, and she's also very active in our special interest group. She is also an editorial board for the Clinical Liver Disease Multimedia Journal with AASOD and is a reviewer for the Fundamentals of Liver Disease. I'd like to turn this over to Vicky. I want to thank everyone for joining us today. So I'll be talking about HCC staging and treatments, and specifically, we're going to be talking about systemic chemotherapy. That's going to be a big part of our lecture today. So my disclosures include advisory board for AbbVie, Gilead, and Intercept, which is nothing relevant to my presentation today. So our objectives, we're going to learn about treatment recommendations according to the Barcelona Clinic Liver Cancer Staging System. We also are going to discuss curative options of resection, transplant, and ablative therapies, and more importantly, we're going to review past and newer non-curative therapies, including systemic chemotherapy. So management of HCC, we're going to be talking potentially curative. We're looking at liver transplant, resection, and different types of imaging guided interventions. Our curative options include percutaneous ethanol injection and radiofrequency thermal oblation. Some options that can definitely help prevent progression for a couple months and improve overall survival include tear and tear or chemoembolization and radioembolization to include Y90 and also external beam radiation. The other option we do have now is a systemic chemotherapy. So when we look at the Barcelona Clinic Liver Cancer handout, this allows us to aid us in the outcome production and treatment planning for HCC. The system takes into account tumor stage, liver functional status, patient performance statics, and recommends the most suitable approach to cure or palliative care. So I wanted to go over if you've never seen this handout. So if you look in the top boxes, it first tells you the definition. So very early stage is zero, early stage is A, we've got B, C, and D. Below that, you can see the actual nodule size. So if you have a single lesion that's less than two centimeters, that would be early stage or very early stage. Early stage is a single nodule or three or less than nodules that are less than three centimeters. Underneath that, we're looking at the child PUS score, which is the liver functional status, A, B, or C. And then PS stands for the performance status. So the performance status is the ECOG rating. So if someone has a lower score, they're at better overall physical performance. So a performance status of zero would be that the patient is fully active, more or less as they were before getting HCC. A score of four would be that you are in bed or a chair pretty much all day and need complete care from another individual. And so the first portion of this lecture, we're just going to go over the early stages. So when you look at an individual and they have a single lesion or very small lesions in their child PUA, and they're a potential candidate for liver transplant, or they want a liver transplant, you have to ensure that they are willing to go through that. You could definitely consider transplant, especially if you see high portal pressure and elevated bilirubin, indicating more advanced disease. If they're not a candidate and their overall liver function status does not indicate a lot of portal hypertension, you can consider a resection or ablation. And so these are considered curative treatments. And so when you talk to a patient, ensure that these options in early HCC have really good overall survival. So I wanted to look over those numbers with you. So if we look at resection in a very early stage of zero, and they have good liver function, they have a 70% five-year survival rate. And transplant, if they're stage zero to A, and they're a candidate for transplant, of course, you're going to see 60-70% five-year survival. In ablation for stage zero to A, and the tumors that cannot be surgically removed or not a candidate for transplant, we're looking at 40-70% five-year survival. So for liver transplant, there was a landmark trial done in Milan, Italy, to evaluate patients with HCC to determine the risk of reoccurrence in post-transplant. Those within criteria had a significant lower rate of reoccurrence post-transplant. The Milan criteria determines if a patient is eligible for transplant and is defined as having a single tumor less than or equal to five centimeters, or less than three tumors each have to be less than or equal to three centimeters. There has to be no vascular invasion, including portal vein thrombosis or invasion, and no distant metastases. For some tumors that can fall out of this Milan criteria, they can become transplant eligible with liver-directed therapies like the chemoembolization or radioembolization. So that is an option that you can see, but you wouldn't know that until they were treated and re-imaged and re-staged on their Milan criteria. The other thing is when you do liver-directed therapy, you have to also, their liver function may decrease if they're a little bit more advanced disease, so you have to watch out for decompensation after getting liver-directed therapy. The next thing we had spoke about was ablation. So radiofrequency ablation utilizes a electric current and is appropriate for tumors less than two centimeters, two centimeters or less. The other option is microwave ablation, and it uses electromagnetic energy and has advantages that include that it's more predictable with uniform treatment of a slightly larger area. It is also less affected by the cooling effects of surrounding blood vessels termed as heat sink. And so if you look at the pictures, you can actually see that the top one is radiofrequency ablation, the bottom one is microwave ablation, and the outline in red is the area of treatment, and you can see with the microwave ablation, it's a little bit more uniform and slightly larger. So we had discussed that first section of the BCLC staging, so early stage. We're now going to move over into the intermediate stage, or B. So we're looking at large, multi-nodular, so on both sides of the lobe, and they can have Child-Pugh score of A or B with a very good performance status, or ECOG number of zero. This is on the bottom of, it shows you your options is TACE, but also should include TARE on this slide. So we're going to talk about TACE and TARE. So liver directive therapy can be offered in the form of TACE or TARE. The response rate is about 20 to 60%, and it really relies on the arterial hypervasculation of the tumor. In both procedures, TACE and TARE, the hepatic artery is accessed, the tumor is identified, and the chemo beads, or Y90 spheres, are injected into the tumor. The blood supply is then embolized, which leads to target tumor necrosis. TARE is considered to be a little bit safer and better tolerated in more advanced HCC, including cases complicated by portal vein thrombosis and large tumor burden. When you look at the studies that compared TACE and TARE, there is a significant longer time of progression in the TARE group. However, there is no difference in survival. So you really want to try to treat with TACE or TARE, because there is advantages to survival benefit with these treatments, especially in advanced stages of HCC. Lastly, this is where most of our lecture is going to be about. We're looking at the advanced stage, where there is extra hepatic spread, so outside of the liver, the cancer has spread, and portal invasion, child P to A or B, with slightly decreased performance status of the patient. For 10 years, the only treatment option we did have was Seraphinib, and that's what's on this slide, but we can actually add six more options, and so we're going to be going over all the new treatment options that are now available to us in the United States. So currently approved for first-line systemic treatment options, so we're looking again at the more advanced stage, BCL staging C. So when you think about chemotherapy for HCC, it's separated into two categories. One is multikinase inhibitor, and the other one is immune therapies. Multikinase inhibitors like Seraphinib and Linatmid target the tumor cells directly by inhibiting proliferation and angiogenesis. Inhibiting angiogenesis is really important, given the highly vascular nature of HCC. RAS and RAF pathways are involved in cell proliferation, and these are the major targets for multikinase inhibitors. So you guys all know about Seraphinib. I just want to do a quick overview, because Seraphinib is like the initial med that we've had for HCC, and all future, and more recently, trials are compared to Seraphinib and its results. And so Seraphinib was approved in November 2007 as first-line therapy in HCC. It is a oral tablet, and it is an inhibitor of intracellular, or RAS, and surface multikinase. And so VEGFR-123 and PDGFR-beta, and these kinases are the ones that are involved in tumor cell signaling, angiogenesis, and apoptosis. So the side effects of Seraphinib, as all of us are pretty much aware about, is the hand-foot-skin reaction on the palms of their hands and the soles of their feet, diarrhea, weight loss, and hypertension. This tablet does come in a 200-milligram tablet, and the initial starting dose is 400 BID. So you guys have heard about the SHARP study that got the approval for Seraphinib, and this was a landmark study, and the patients were with advanced HCC, very well compensated with Child's A, and a performance status less than 2, or ECOG score less than 2. There was about 300 patients, and they were randomized to Seraphinib versus placebo. The primary endpoints were overall survival. Secondary endpoints were time to progression, a disease, control rate, and safety. And so for most of our HCC trial endpoints are overall survival, time to progression, progression for survival. So when we look at the other drugs coming up, this is what we compare it to. So the Seraphinib results on the SHARP trial showed that when compared to placebo, there was a three-month overall benefit of survival and a three-month longer time to progression, both which were significant. Our next one, Lidnabatinib, was just approved in 2008 as first-line therapy. It comes in 4-milligram and 10-milligram tablets, and it is a weight-based treatment. Like the other, it targets service kinase, so VEGFR, and PDGF-alpha on the surface kinase. And it's set apart because it's actually more potent inhibition of FGFR1, which may play a role in the VEGF inhibitor resistance, so patients who are resistant to Seraphinib. And so there's, unfortunately, a higher rate of hypertension and proteinuria on subjects on this medication when compared to Seraphinib, and the hypertension should be managed medically. So if we look at the study that got the approval, it was called REFLECT. REFLECT trial was designed as a phase III non-inferiority international study. Again, it was unresectable, HCC, well-compensated. They had 478 in the Lidnabatinib group and 476 in the Seraphinib group. And the primary endpoint was overall survival. Secondary endpoints were progression-free survival, time to progression, overall response rate, and quality of life. The results showed that there was no difference in overall survival. So therefore, it actually satisfied its aim to prove to be equal to Seraphinib. In the sub-analysis not shown here, there was an improvement in overall survival in patients with a higher AFP. More importantly, in Lidnabatinib, there was a significant improvement in time of progression and progression-free survival. So here's all the new fun stuff. So we went over multi-kinase inhibitor and how it prevents proliferation and angiogenesis on the tumor cells. The other class is immune therapies like nivolumab, which targets the body's adaptive immune system. So we're going to go through all our newer medications. And so this is an overview of what's been recently approved. So our first one is regorafenib. This is a second-generation seraphinib. It was approved in April 2007 as a second line for those who progress but tolerated seraphinib. It's similar to seraphinib, but it has a broader activity and a little bit more potent. This is an oral medication supplied in a 40 milligram tablet with a dosage of 160 milligrams per day. Unlike seraphinib, it targets the intracellular RAF pathway and the VEGFR pathways, but unlike Seraphinib, it also targets a fibroblast growth inhibitor, receptor 1 and 2, and PDGFR-alpha. The side effects to do include are similar to Seraphinib to include hypertension, hand, foot, skin reaction, fatigue, and diarrhea. So, if we look at the study that led to FDA approval for Rigorafanib, it was a phase 3 trial. Again, patients had unresectable HCC, good liver function status with child A, and good performance status. It was per guest HCC with Seraphinib. They were randomized 2 to 1 to Rigorafanib and placebo. The primary endpoints were overall survival, secondary were progression-free survival, time to progression, and overall response rate and disease control. It was a double-blind study. There was a significant improvement in overall survival of less than 3 months in Rigorafanib compared to placebo. The impact on survival with Rigorafanib was 10.6 months when compared to placebo of 7.8 months. The precise mechanism of which Rigorafanib improves survival after Seraphinib is unknown. With a longer progression-free survival and time to progression, given these results, patients that tolerate but progressed on Seraphinib, Rigorafanib should be considered an option for these patients. So Novolabab was FDA approved in September 2017. It was approved as second-line therapy and it's an intravenous medication and it is a program death one or PD-1 inhibitor. Because it's an immune mediated therapy, you can get some immune mediated side effects. Some of the most common side effects include fatigue, pruritus, rash, diarrhea, and elevated LFTs. This was common, but the elevations were not severe. So Novolabab's approval clinical trial was track date 040 and it was patients that were Seraphinib naive and Seraphinib experienced and a minority of patients were on a dose escalation phase. The rest of the patients got a fixed dose of 3 milligrams per kilogram. These patients did include hep C patients, hep B patients, and also those that were not infected with viral hepatitis. Given that Novolabab is immune therapy, they did evaluate viral loads to make sure that there was no increased rate of a viral flare. The endpoints included overall response rate, time to response, and overall survival. So the phase 1 to 2 studies included 262 patients with and without previous exposure to Seraphinib. The response rate was 14% by Resist, 18% by EmResist, with overall survival of 15.6 months, which is a long time. Therefore, FDA granted accelerated approval for Novolabab with advanced stage HCC previously treated with Seraphinib. So 20% of the results on the track date 040, 20% of Seraphinib naive patients had a objective response by Resist criteria. 19 and 14% in experienced Seraphinib patients in the escalation arm and in the experienced arm. So we saw an overall survival of Seraphinib naive patients was actually 28 months and 15 months for those experienced. So this data was very promising, and so the thought was could they prove that Novolabab was actually more superior than Seraphinib as a first-line treatment. So they started a study, Checkmate 459. It was a phase 3 style trial to determine if Novolabab could be first-line therapy over Seraphinib. They did publish some data, and it did not reach its primary end points of being significant compared to Seraphinib. While it didn't reach its end points, the results still showed improvement of overall survival similar to Seraphinib. So I think before that was published, a lot of us thought that Novolabab was going to be our new first-line therapy over Seraphinib, but they weren't able to document significant improvement when compared to Seraphinib. But it is a very good choice, a different option, especially if you have someone who has been resistant to Seraphinib and continues to have progressions. So our next one, we're going to start to get a little bit into the newer medications that you might or might have not heard about. Cabozanidib was FDA approved in March of this year, and it's a tyrenine kinase inhibitor. And the trial that allowed the approval was a phase 3, a trial called Celestial, and it was for patients who had HCC progression on prior Seraphinib. The overall survival was 10.2 months versus 8 months on placebo. And the most frequent side effect that had the higher grade of 3 to 4 was hand-foot skin reaction. Other side effects did include diarrhea, fatigue, decreased appetite, nausea, hypertension, and vomiting. So here's another newer medication, Ramsuramamide. It was FDA approved in May 2019 of this year, and it's actually a monoclonal antibody, so it falls into the category of immune therapy, anti-VEG-FR2. And it is actually the first HCC medication we have that is directed towards a biomarker. And so the REACH-2 study, it was a phase 3 study with patients previously treated with Seraphinib. It was for patients who had an AFP that was greater or equal to 400. So this is the first medication we have that is based on a biomarker. Overall survival was 7.8 months versus 4.2 months with placebo, and they had a second trial that showed 8.5 months versus 7.3 months. Side effects were a little bit all over the place. Fatigue, peripheral edema, hypertension, abdominal pain, decreased appetite, proteinuria, nausea, and ascites. And a lot of these seem to be possibly mild decompensation with if they had, you know, maybe a child that would help you be. So the last medication, Pembrolizumab, it was approved last year in November, so also just recently. It is a anti-PD-1 monoclonal antibody, which also falls under the immune therapy class group. And this trial for approval was the Keynote Trial 224, and it was patients who progressed on Seraphinib or were intolerant to. And so you have to understand because there was, as we had discussed, that you've got the multikinase inhibitors and the immune therapy options. So someone who might be resistant to Seraphinib or intolerant, they might be able to take an immune mediated type of therapy. And so it definitely is worth trying if you have that option. On the trial, the overall response rate was 17% with one complete response and 17 partial response. We saw the response durations range from 3.1 to 16.7 months, and the overall mean survival of 12.9 months. The side effects on this medication, because it's been approved from multiple other cancers, and there was multiple studies, please review the side effects before you give it to a patient because a lot of the side effects were immune mediated. You've got GI issues with colitis, you've got skin reactions, a lot of, because they've had a lot of studies, there are multiple side effects. And so please review that before prescribing this medication for a patient. So that sums up. Hopefully this was a nice little review of especially all the new medications that have come up in the last two years or so. I know that's something all of us have to be aware of. For myself, our practice, we try to keep on top of all the new treatments, but with all of them coming out so quickly, it's been hard to keep track of. So hopefully this lecture was able to summarize everything. And so now you guys have a better handle of what everyone is doing. So at this point, if you guys have any questions, I'm going to turn it over back to Ho-Chung. Great. Thanks, Vicky. An excellent presentation as usual. And there was one question that was asked around 12-15 about what does associated disease mean? Let's see. So I think when they mean by associated diseases, if you guys see that under early stage A and you go all the way down and they have multiple nodules, it says associated diseases. If they say yes, you do ablation. And then if you say no, you go to transplant. So I'm assuming this is more related to comorbid conditions. So someone who has significant cardiac or pulmonary disease and they're not a transplant candidate, you might consider ablation over transplant. And so that's what I believe that's the answer to that question. Great. And then, Vicky, the next question is they wanted to get your consensus about SBRT, which is radiation versus TACE. Yeah. So are we looking at external beam radiation? It's definitely an option. And this is going to also, just like TACE and TARE, it's going to fall under the category of it's not a curative option, but it is definitely a great option for our patients. Usually, when we are sitting in our tumor board review, we have our radiation oncologist and they will tell us if that patient is a candidate for that type of treatment. But yes, we do use that and that it would fall under the category of TACE and TARE also for those patients. So we're looking at that category of intermediate stage disease or B, which is currently on the slide in front of you. Great. There are some limitations too, right, Vicky, about radiation. Sometimes the lesions are, you know, either too close to the stomach or other organs that may be prohibitive in getting the optimal dose to that area. But what, has that been your experience as well? Yeah. And usually the medical oncologist is the one that really can tell us if that patient is going to be able a candidate for that. But I have a question for you, Vicky. You know, it sounds like you have a multidisciplinary group at your site and I was wondering, you know, there are certain centers that hepatology kind of drives the treatment or systemic therapy and as new agents have come up and I was wondering does, what's your practice at your center? Do you have certain clinics that hepatology runs or a medical oncology or is it kind of a collaborative joint clinic? Just wondering what your relationship with oncology is at your facility. Yeah, so I think if there's an option where you can do systemic chemotherapy, we give our recommendation because sometimes, especially out in the community, our local oncologists might not know the more recent developments in our treatment options. And so we like to recommend. Sometimes insurance really limits and only approves maybe seraphinib as first-line treatment, whereas lidnapnib is also an option. So we give recommendations to the oncologist if it is a community center. Here in our actual practice, we do carry our patients and provide them treatment and see them in the office. Understand that because of the side effects in the hepatology office, we have to see them frequently. If you feel like they need more comprehensive care, eventually like palliative care or hospice, then we will refer to oncology. But if they're doing very well in their systemic chemotherapy, we'll keep them with us. But we always give our opinion on what the patient should be started on. Great. So the next question is, systemic therapies are not very effective. Do you still recommend these PD-1 antagonists? So the PD-1 antagonists are always a great option. The thing is you have to discuss with the patient is that concern of immune-mediated side effects where, you know, we see colitis, autoimmune hepatitis, all that. So it is a conversation with the patient because first, you're talking about cost and survival. Some of them, as you saw on the slides, the survival were a couple months. So it's a conversation to have. But every person is very different and each cancer is different. So it is worth trying on that patient because they might see stable. The progression might just halt for a couple months. And so it's worth trying. And if the side effects are intolerable, it can be stopped. And as a colleague of mine, Patrick Horne, who's probably on the call, we were talking this weekend. He said, you know, with taste or tear, if we decompensate them a little bit, we can't reverse it. However, you know, medications, we can stop them and a lot of their side effects would go away. And so I think that's a good point on that. And so it's always worth trying if you have a patient who is willing to do it. And then the next question was, do you recommend Pembrolizumab in a patient with renal dysfunction? Because one of their patients had a baseline AKI that was worsened after the medication. Yeah. Remember, I had discussed that that medication does have significant side effects. So I think you're going to have to find your ideal candidate for that medication. For me personally, it wouldn't be my first option. First, you know, with all the significant immune mediated side effects. But it's just knowing that there are other options and maybe discussing with your oncologist who might have more experience with this and other cancers, if that is appropriate, especially in kidney disease patients. And perhaps that you may already spoke about it, but the audience is asking, which study had a positive results for tear? It was in the gastro study, Saleem Ars, and it was that it showed a longer time to progress or of progression after tear. However, there was no difference in survival when you compared chase and tear. And so both options is reasonable. It's just tear it tends to be a little bit more tolerated in patients who had complicated portal vein thrombosis or a larger tumor burden. Are there any more questions from the field? There were great questions. Under what settings would you do like bland versus, you know, chemoembolization? I couldn't tell you that answer. You can tell. Ho-Chung, you could probably answer that. Well, I think sometimes, I think it depends on the, you know, the experience of the center. Some people think that if you're on that cusp of, you know, that, you know, that bilirubin or they think that it can be a little bit more tolerated if you have, if you're pushing the limits of, you know, of liver function. But, you know, some centers only do bland embolization. So, and you, and some people think that there's less pain associated with it. So, hold on. I think we tend not to do bland just because we're, you know, we, we are very selective on our patients on who we try to do local regional therapy on. Yeah, they mentioned something about the pembrolizumab is that we give in patients who had creatinine clearance more than 30 and renal dysfunction is likely as, as you already stated. Yeah. They also wanted to thank you about your great webinar. Hopefully, it was just a nice summary of, you know, the medications that you're going to be seeing in the future. No, it's been great because, you know, in the past 10 years, all we had was seraphinib and there was really not much activity and it's really great to see such a variety of medications that are available because in the past, you know, we didn't really have much to offer if they failed or were intolerant to seraphinib. So, it's really, you know, wonderful that, you know, that we're seeing some progression and progress in, in treatment modalities for this, you know, very difficult disease state, especially in advanced HCC. And I think, yeah, I think that's, I don't see any additional questions and I don't have any. So, we just want to ensure that everyone, if you have any more questions, you're more than willing to contact myself or Ho-Chung. Our emails are now on the, on the PowerPoint. So, please feel free to email us with any other questions. And then, I also want to say thank you to the Associates SIG for allowing me to do this talk and also one of my attendings is a HCC specialist, as I would call her, Dr. Sheila Swarren. And so, I appreciate her help with this, this lecture also.

hepatocellular carcinoma

Barcelona Clinic Liver Cancer Staging System

curative options

systemic chemotherapy

multikinase inhibitors

immune therapies

clinical trials

individualized treatment plans