Dr. Frenette offers the best practices for treating hepatocellular carcinoma (HCC).
Let's go on to our first speaker this morning Doctor Carrie fernet, who is a medical director, liver transplantation at Scripts Green Hospital and she's also the director of the liver and prostate cancer program at the scripts M. D. Anderson Cancer center. So there's no one more qualified to speak to you on this topic systemic therapies for hepatitis for HCC. What does the gastroenterologist need to know? Carrie thank you so much paul and thank you everyone for joining us again for this conference. I was really so happy with how yesterday went. And I'm looking forward to today. So uh today I'm going to talk about systemic therapies for HCC. And what does the general gastroenterologists need to know about these? Um as I'm sure you're aware there's been a ton of movement in the last couple of years. Um let's see here these are my disclosures and I do work with a lot of different companies and I will be discussing off label therapies for therapies for immune checkpoint inhibitor toxicities. So the N. C. C. N. Is the National Comprehensive Cancer Network. And they really they release guidelines every year for every type of different types of cancers. And this is the latest update that was put out about two months ago now where really as you can see there's a lot of different therapies now that we have for systemic therapy for HCC. So um it is now recommended that the preferred regimen for HCC. That requires systemic therapy is a Tiso bev. And I'm going to show you some of that data. But really when I'm thinking about what does the gastro neurologist need to know about these therapies? This has gotten complicated enough that General G. I. S. Are not really involved necessarily in choosing therapies in deciding what happens next. Um I think a lot of our patients come to us and ask well what do you think because you know, we've been taking care of them for a very long time. Um but really the main thing that gash neurologists are involved in is helping to manage the toxicities, especially in our patients with underlying cirrhosis and liver disease. And I really thought that was the best thing to discuss today. Now I do want to just remind you and show you the oddities above data. So, um the Iron Brave 1 50 study was the inaugural study. It was published in the new England Journal of Medicine last year, but there was an update to the data that was presented by Rich Finn at ASco G this year, virtually in january. So I did want to show you those that update. So just to remind you about the study design, this is patients with either locally advanced or metastatic HCC and no prior systemic therapy and they were randomized in a 2 to 1 ratio of a Tiso bev every three weeks I. Ve versus Serafin it, which has been the standard of care of systemic therapies for about 13 years now. And the primary endpoints were overall survival and progression free survival. And of note and I'm going to talk more about this. All patients had to have had an endoscopy within six months of enrollment and any various he's had to have been treated per the institutional standards. Um and that's really because of the risk of bleeding with devices, a map that we've known about for years as it's been treated with colon used with colon cancer treatment. So the latest survival update that was just published showed the median overall survival for a teaser Bev was 19.2 months and it was 13.4 months with sarafin iB. So that's about a 44% 34% decreased chance of mortality, Six months survival 85, 12 months, 67% and 18 months 52%. So you can see the median overall survival really is longer than a year and a half. Which is really remarkable considering that, you know, 10 years ago we were happy when we had 10.7 months. So really these patients are living a lot longer with the therapies that we have now and that really makes the gastro neurologist and hepatology ist so much more important also in maintaining their liver function and keeping them healthy to be able to continue on these therapies. Safety summary was also updated and you'll notice that it is oh bev had a longer treatment duration than sarafina, which you can imagine because the patients responded. Um There was patient, quite a few patients that needed to have their Bevis is um have discontinued. Um and if you look at all grade adverse events it was about the same. But there was concerns about treatment related serious adverse events that were a little bit higher with the T. Is above compared to sarafina 23% vs 16%. So that's um you know something to keep in mind. We all think of it is oh bev as oh you know its immunotherapy and immunotherapy is quite safe but we have to make sure that we have these patients managed for their treatment related adverse events. We did also see that dose discontinuation was higher with the eighties above arm 10% 22% overall versus 12% with sarafina. Although of course sarafina did require more dose modifications because there really isn't a dose modification for a Tiso Bev. The other thing to realize is that even though we have all this data about potentially higher treatment related adverse events, the patient reported outcomes meaning quality of life was much much better with the Tiso Bev. So as long as we're managing the risk of serious adverse events, patients can actually feel better for longer. So the Kaplan meier curves that you see here is time to deterioration of quality of life. So using various quality of life um questionnaires and what they found was that the quality of life, time to deterioration was 11.2 months with the Tiso Bev versus 3.6 months with sarafin iB. So not only did patients live longer but they also felt better longer so that really engenders on us to help keep them safe through the therapy. So um why does this work? Why are we care? Why you know, why are G. I. Is involved? So remember that Bevis is a mob is a V. Jeff inhibitor. So it's anti angiogenic. It also does have immuno modulator, very modular torrey effects. So what happens is the best. This is a map is anti angiogenic. So the tumor vasculature can't progress necessarily. But it also normalizes the tumor vasculature which increases the ability of the immune cells that are activated by the T. Cell. Is a mob. The immunotherapy to be able to actually get into the tumor. And we know with immunotherapy and I'm going to talk a little bit more about this. The more T cell infiltration you have in the tumor, the better response you're going to have. So the baby system that actually helps with that. So it's more than just that vasculature change. So really this combination does make sense. And that Bevis is a map alone. Doesn't have active as much activity in HCC. But it really enhances the metabolism of efficacy so that we really can allow that to the T. Cell infiltration and the response. Now it's anti angiogenic. So we worry about various is so why do we care? Okay. What why is this even being brought up? So this is a map and really all of our T. K. I. S. Do have effects on VHF which is vascular endothelial growth factor. So when we inhibit that that changes and inhibits the end epithelial integrity in the lining of our vasculature. Okay. Um So in patients with H. C. C. We know that they are at risk for various is and there was a lot of Phase two studies using devices a mob and you can see and you know they're very small studies but grade three bleeding is severe enough that patients are actually ending up in the hospital. And in these great Phase two studies it was 9 to 20% of patients being treated with a. This is a map that had grade three bleeding which is much higher than what we would expect in other TK I therapies In this. I am brave 150 study that I just showed you again. They required treatment of viruses prior to enrolment and they still saw 7% of patients with gi bleeding and 2% of patients actually had bleeding that resulted in death. So um we really have to think about this and we have to make sure that patients get that endoscopy before they start this therapy. And so you may get a call from your oncologist saying hey I've got this guy with HCC. Can you scope them this week? So we can start therapy. You really got to get on this and get these patients there endoscopy ease so that they can be treated now. Um The other thing to realize is that patients with HCC actually have a higher risk of viruses compared to patients just with underlying cirrhosis. So we you know, we're pretty comfortable Um with cirrhosis. We know that there's um the Chino criteria where if you have a normal platelet count and a transient last geography, less than 20 that the risk of viruses is low. Well that does not hold true in patients with HCC. So you cannot use the bovino criteria. So this was an example. So this is a retrospective cohort study of patients who are diagnosed with HCC. Now this is in ASIA. So some of them didn't even have cirrhosis. Um but they actually looked at about 1700 patients And they looked at whether they have portal vein tumor thrombosis or no portal vein tumor thrombosis. Now, 90% of these patients where child Pugh a cirrhosis. So those patients are actually at lower risk of various is when you have earlier liver disease. But what they found is that even in patients without portal vein tumor thrombosis, the presence of viruses was 26.5% without tumor thrombosis and nearly 40% with tumor thrombosis. And high risk viruses with the risk that really risk of bleeding was 13.3 and 23%. And there was also gastric Pharisees. So this is much higher rates than what we would expect to see just based on their underlying liver disease. We also know that if patients with HCC have portal vein tumor thrombosis, there also at higher risk of bleeding. So again, even if they have the bovino criteria that says they don't need an endoscopy, their risk of bleeding is nearly 20% if they have portal vein tumor thrombosis. So especially those patients, even if they don't have underlying cirrhosis, strongly recommended to get an endoscopy prior to initiating any therapy with the vet Geoff inhibitor. So the first thing that gastroenterologists need to know about systemic therapy is just about all of our systemic therapy inhibits by Jeff. Now a Tiso bev does Seraphine, it does land that does all the T. K. I. S. So all of these patients need to have an endoscopy prior to initiation of their systemic therapy. Which means you have to get them in soon if they have high risk various is you have to treat them. So that's including large paris's any patients with high Ristic Mata or if they have child be cirrhosis and have any viruses. even small viruses, that's actually a high risk, high risk viruses. Also. Now you can treat them either with banding or with non selective beta blocker. But you do have to remember that they have to have adequate non selective beta blockers. So you have to really improve, increase that beta blocker and get their heart rate down and get them adequately beta blocked, which is something that often isn't done very easily. So something to remember for these patients. Now, the other thing that gastro neurologists are really going to be involved in is side effect management. Okay, and so that's really what I'm going to spend the rest of us the talk talking about now the tires and kinase inhibitors, Sarafina blend catnip cables, antenna brother rafi Niv. They all have diarrhea as a side effect and the rate of these Tks can cause diarrhea of 20 to 50% of even severe diarrhea. That can be bad enough that patients can end up in the hospital. Oftentimes oncologists manage this by themselves, they're pretty used to these drugs now but occasionally they will come to you and say I need help with this guy's diarrhea and so that's what we really need to understand. The diarrhea typically occurs early in therapy within the first couple of months and the mechanism really is not very well understood. There's some dis regulation and ion transport inflammation, mucosal injury and there's actually even been reports of development of collage anus Kaleida specifically related to T. K. I. S. So oftentimes we have to manage these with dose reductions or dose interruptions. Um But often times we want to try to get these managed as best we can without interfering with their cancer treatment. So what do we do for T. K. I. Induced diarrhea. We really manage diarrhea. So always remember to rule out other causes infections. C diff dietary lactose deficiency very common. So we have to you know talk to them about that. And sometimes I'll even have patients do a dietary or stool diary to try to figure it out. Um A lot of times these patients are on lac pillows and maybe their dose of lactose needs to be adjusted when they start their TK. I. Therapy. We know that things like caffeine, alcohol, spicy and fatty foods dairy and highest in soluble fiber foods are also increased the diarrhea. So I have them avoid foods like that. Probiotics can be helpful. So I'll often add probiotics. You need to monitor their electrolytes because sometimes they can have hyponatremia, hippo magna xenia related to diarrhea. I usually start with the paranoid um and I do two capsules to start and then up to two capsules four times a day if needed. If that doesn't work then I'll go to the diclofenac slit atropine which is low model. And occasionally we'll have to get even more advanced with Austria tied tincture of opium or even coolest army and all that. You have to remember. The coolest are mean, can also absorb their drugs so you have to separate that by all medications by at least four hours. So this can be a little difficult and it's oftentimes a trial and error until you figure out what really works best for the patient. Um And again, oftentimes the oncologist manage this without us, but it is important to be aware of Now. The other thing is that I think is more important for us to talk about today. There is the immune checkpoint inhibitor colitis and hepatitis. And there was recently an A. G. A. Clinical practice update that was published in gastroenterology this year. And I would strongly recommend everyone read this article. It's really a fantastic review and a fantastic paper for us to be familiar with. So let's first remember how the immune therapies work. So there's two types of immune therapy drugs, there's the PD one PD L one medications and the C. T. L. A. For medications and both of these basically inhibit the immune responses off switch. Okay, so PD one is programmed death. One it's expressed on T cells and other immune system cells and activation occurs within the tumor within the peripheral tissues. The C. T. L. A four is side of toxic T lymphocyte associated protein four. This is always expressed on the t regulatory cells and it's up regulated on other T cells when they get activated and the activation for this is a little different actually occurs in the lymph nodes in the earlier stages of the immune response. So just to show you what this looks like. So RPG one PD L. One basically they inhibit these receptors. So the tumor cells actually will express the PD L. One themselves. And what happens with this is that the tumor cell tells the T cell to shut off. Okay so the antigen presenting cells in the tumor cells interact with the T cells and say shut off. We don't need to kill this. This is how our own immune system now will prevent over activation and auto immune diseases. Okay. The tumor cells use that to evade our immune system's response and our immune system is really important in managing cancer. This, as I said, the C. T. L. A four happens more in the lymph node with the dendritic cells but also the tumor cells use that to again shut off the T cells. Um And it also is involved in the t regulatory cells which again shut off our own immune response to prevent over activation and autoimmune diseases. So when we use these checkpoint inhibitors this is our immune systems. Checkpoint to say you don't have to work so hard. So when we use these checkpoint inhibitors are immune system now can recognize the cancer and kill it. But it also takes away the checkpoint of it affecting other tissues. And so when we think about the side effects that we get from immune checkpoint inhibitors, it's really just about any autoimmune disease you can possibly imagine because again our immune system is not stopping. Okay, it's just continuing to go now. There's lots of different checkpoint inhibitors approved by the FDA. Um Epple um Ahmad is currently the only C. T. L. A four that's approved although there are more coming and then there's multiple PD one PD L. Ones and they are involved in just about every cancer that you can imagine. Um As far as FDA approval and the ones that aren't on this list are actively being studied and this has really changed the outcomes of all cancers in general remarkably well often use these in combination. So PD one plus C. T. L. A four. So now you're taking away two checkpoints of our immune system. And again as you can imagine, taking away two checkpoints also increases the chance of auto immune side effects because of taking away that check. So when we think about what organs are really most affected by our immune related adverse events or I. R. A. S. So the G. I. S. Track is the most common of almost all of the side effects that we get. So this is why it's so important for gastroenterologists who know these and know how to treat them. Skin is the next most common. And then we also see under Quran liver which is how we get involved as hepatology. Ists and then also lung. And you'll notice the purple which is the combination of the P. D. One plus. C. T. L. A. Four has higher rates of the immune checkpoint adverse events compared to just a single agent. In addition the C. T. L. A. Four is more common to cause adverse events than the PD one. So you just want to realize that any combination treatment which we are using now in HCC can increase the chance of getting um immune related adverse events. Now it's also really really important that we treat these things quickly. So this is a study that came out a long time ago now but it actually still holds true. But often times we're using steroids and I'll show you how we do this. But when we look at starting steroids within five days of trio the symptoms, The improvement is seen in 92%. Okay? But if treatment is delayed and it's longer than five days it is much more likely that patients are going to get worse and that patients are going to need the 2nd 2nd line immune suppression. So it's really important that these things get treated quickly. So that's just something to keep in mind. Oftentimes you don't want to just sort of say, okay well let's see if it gets better with just holding the drug, you need to get them on treatment. So first let's talk about checkpoint inhibitor colitis And again, any of the G. I. Tract can be affected often times it is the colitis. It can also be the small intestine. And it's also even been reported to cause immune checkpoint inhibitor gastritis. So that's important to know. Also we do grade these. Um And it's important when we're talking about the side effects to say what grade of colitis or enteritis colitis. This is um So grade one, mild increase. Um or they're asymptomatic and maybe just a little bit of clinical or diagnostic information. Grade II, we're now at 4-6 stools over baseline and patients can have abdominal pain, mucus or blood in the stool. Grade three. And we're now at seven stools over baseline. They have to be hospitalized and they're not able to do their normal activities of daily living. They can have fevers, they can have alias they can have peritoneal signs. These are the really sick people. Grade four are life threatening consequences. This is when you're ending up in the ICU. Because of entra colitis and then grade five is death. So it gives you an idea of what levels you can see. Okay now um checkpoint inhibitor colitis. Um we often think of it similar to inflammatory bowel diseases and again it can look like inflammatory bowel diseases. So this is two examples of the I. C. I. Colitis or immune checkpoint inhibitor colitis. You can have an all sort of colitis pattern where you get diffuse and patchy era thema um loss of vasculature, fry ability, even some exit dates. Or you can get more of a Crohn's colitis pattern where you get cobble stoning, you get these deep. Sir pigeon is ulcers. Um and it can be not uh it can be more patchy through the colon. So really either one of these can um present as an immune checkpoint inhibitor colitis. Now again, um the paper that I showed you does have a really nice algorithm on how to treat, depending on how bad the patient's symptoms are. Important to realize. You always want to rule out other infections. You need to check the stool active. Sheraton lacked affair and how protect in imaging if they're very sick and then you want to do a colonoscopy or flex sig with biopsies and you have to withhold therapy. Um if a negative exam on a lower then you need to do an upper endoscopy with biopsy, the mild colitis. So again, just a few stools over baseline, they're not very sick. Those you can try missile. Mean you decimate is only recommended for use if patients have microscopic colitis, not the more severe colitis is otherwise you're not recommended to do you designate they actually need oral or ivy corticosteroids. If somebody's refractory for three days to chorale's you need to go to ivy and if they're still refractory then you need to go to the next level which would be either inflicts a map or Vettel is a map. Those are the two that are recommended. And again that's just after three days. Okay. Oftentimes the veto and inflicts a mad patients will respond very quickly. They'll respond just within a few days. Um if you have a mild and they go into remission you can resume your immune checkpoint inhibitor, moderate or severe. If it's really quite poor then you may have to hold completely for further immune checkpoint inhibitors and you do need to monitor them with repeat scopes. There's also been um reports of fecal microbiota transplant being used for immune checkpoint inhibitor colitis. Now let's go on to my favorite. Which of course is the immune checkpoint inhibitor hipaa toxicity and again this can occur as many different things. Hepatitis is most common but you can also get cholangitis, pancreatitis or vanishing bile duct syndrome. This is usually within the first few weeks two months. But it can't any of these immune checkpoint inhibitor toxicities can occur even after your therapy is stopped. So if you have somebody that's coming in then again you need to make sure that you get the history of their cancer treatment. Um you don't necessarily have cross reaction. So if somebody had a reaction to the C. T. L. A. Four they may not necessarily recur with PD one. Um And treating them it's not clear if giving someone steroids or more immune suppression actually inhibits the anti tumour response. And we've had patients that actually continue to have a favorable response. Even if we have to stop their immuno therapies. The I. C. I. Hepatitis is more common when you're combining your immune checkpoint inhibitor with tires and highnesses or chemotherapy and will occur earlier in the treatment course as well. Now again the distribution that we see is much more common to happen and patients with the combination therapies and it's actually more common to get hepatitis in non HCC patients compared to HCC patients. So that's a little bit comforting because of course we would worry about hepatitis in patients with underlying liver disease. So you do have to think about your differential diagnosis. Hepatic metastases, thrum thrum symbolic disease, biliary compressions, profusion, all injury, opportunistic infections, other drug reactions. Okay. Um for the R. A. G. A. Guidance all patients should avoid alcohol and then avoid other potentially hipaa toxic medications or dietary supplements and they should have liver tests done prior to each infusion. And then if their liver tests increase, you need to make sure to rule out other causes, including all the viral hepatitis is including hepatitis E B V C M. V and HSV radiologic exam and anything that's great too. Or worse, you need to consider a liver biopsy and maybe admission to the hospital important to realize if you have concurrent hepatitis and colitis, you should not use inflicts a mob. So while you're using inflicts a mob for your colitis if someone has hepatitis, it is not recommended because the infliction map can actually cause a hepatitis as well. So that's a really important thing to remember. Um If you are giving people steroids, you need to consider um prophylaxis as we stand or do. Uh and then discontinue other potentially hip pad a toxic medications if feasible. Now, when we think about what grades. So grade one, we're really monitoring. That's up to 150 A. S. T. L. T. Grade two is 2 50. Grade three and four are the ones that you may need to admit. Uh 10 times over 2 50 billy Rubin over about four. These are the scary ones. Our Grade one checkpoint inhibitor hepatitis you can continue but you need to monitor your labs every 1 to 2 weeks, not just prior to the next therapy. And then if they get worse again, you need to jump on it, treat it early and they're going to have a better outcome. Grade two, you have to hold the checkpoint inhibitor and you begin predniSONE at 0.5 to one mg per kilogram per day. Now important to realize with all of the immune checkpoint inhibitor adverse event treatments. This is not a short steroid course, you want to taper it over at least a month. Um There's also no data for use of buddhist Sinead with immune checkpoint inhibitor hepatitis. So just like we shouldn't be using that with colitis unless it's microscopic colitis do not use B destiny for hepatitis as well. Great to you can resume once your steroid doses less than 10 mg, a day. grade three or four they have to discontinue completely. You want to give them I. V. Steroids so they need to be in the hospital and again three days is where you should see at least a 50% improvement. And if they haven't had a 50% improvement after three days of steroids you're gonna do your alternate agents. Okay now our alternate agents that we think about is ivy or Oral Cellcept michael. Finally mafia till or potentially as a thigh a print. Now I personally do not use as a thigh a print for this. And the reason is because it takes too long to get back your TMP T genetics. And also we know as a fire print takes a little bit longer to start to work. And I wanted I wanted to kick in faster. So I do michael Fennelly mafia till 500 to 1000 mg twice a day. Um if that doesn't work, then you're going to be moving on to tackle imus or potentially even anti china site globulin in these patients. You really need to think about transitioning them to a specialty center, a transplant center or somewhere that use it. That treats a lot of these severe hepatitis is because these patients are really at high risk of developing liver failure and they need to be monitored very, very carefully in a center that has experience with this. Now, one word on Hepatitis B and immunotherapy. So we should be checking hepatitis B reactivation or hepatitis B. Serology is in anyone getting immuno therapies and especially in people that have immunotherapy related adverse events that we may end up having to give them steroids or more advanced immuno suppression. Just like we would do otherwise standard of care. Now, a lot of oncologists do not check hepatitis B prior to initiation of immunotherapy. So if you're treating the immunotherapy adverse events, you need to check it before you actually start your, we'll get it drawn before you start your steroids and then hopefully get it back. There have been several case reports of be reactivation in patients receiving immune checkpoint inhibitors. Okay, so this is definitely something that we see and if you see a hepatitis, you need to check for hepatitis B. As part of this, There was a cohort study in Hong Kong that actually showed hepatitis B surface antigen positive patients. About 40% of those will actually have hepatitis after treatment with uh immuno therapies. Although interestingly there's also been a report of someone actually having hepatitis B surface antigen zero clearance while on therapy. Now, one other thing is the immunotherapy and transplant patients, of course we're stimulating the immune system and we have to remember that these patients have a very high rate of graft rejection if they're getting immuno therapies after liver transplant, 25% graft rejection and potentially death related to graft rejection. This can happen with all transplants of course. But a liver transplant we do worry about. In addition, using PD one inhibitors after transplant really doesn't work very well. So, median overall survival in the literature is about one month after starting immunotherapy. And median progression free survival is 1.8 months. So we are strongly against using immunotherapy is in the post transplant setting. So key takeaways all patients with immune checkpoint inhibitors need to have on baseline evaluation of liver chemistry's pre treatment screening for hepatitis B. You need to think about alternative ideologies. Maybe biopsy imaging endoscopy for your colitis. Um You need to see therapies response within three days of of starting steroids. And if you're not seeing a response for either the hepatitis or colitis within three days you need to move on to that next level treatment. Um And really we start the second line therapies. It can be um uh inflicts a mob or vandalism ab and your colitis microphone like Moffett deal with your hepatitis. Um Again I encourage you to read that paper. I found it to be super helpful. I thank you for listening. Um I do think this is where G. I. And it's going to be involved in our patients with uh HTC and systemic therapies to help keep our patient symptomatically controlled and being able to continue on therapy as best as possible. Thank you.
