Based on clear metrics, transplant hepatologist Neil Mehta, MD, presents diagnostic criteria for hepatocellular carcinoma, then shows how UCSF’s HCC team reaches decisions on treatment for individual cases – with plans ranging from resection or ablation to downstaging drugs and transplantation. Learn why UCSF is doing more transplants than ever for this most common form of liver cancer.
Hello. My name is Neil Meta, and I'm an associate clinical professor of medicine here at the UCSF division of Gas Neurology, and I'm a transplant Hepatology ist in the director of our HTC Clinic. Today, I'd like to talk to you about the management of early and intermediate stage have had a stellar carcinoma, or HCC, including with the focus on liver transplantation. And those are overview in terms of the management of early and intermediate stage HCC. We'll start by talking about the epidemiology diagnosis and staging, including addressing our multidisciplinary tumor board. We'll also talk about how to refine selection criteria for liver transplantation for HCC patients. And finally, I'd like to discuss our UCSF efforts at improving access to transplant for patients beyond conventional transplant criteria, patients who are so called in the so called down staging or all comers protocols. HCC is the fifth most common cancer worldwide in the third leading cause of cancer related deaths in Asia and sub Saharan Africa alone. There are over half a million new HCC cases that develop each year in most HTC cases are associated with an underlying risk factor in terms of specifically who's at risk for HCC. This really convey oil. Down to two large categories of patients, namely patients who either have cirrhosis or patients with hepatitis B independent of cirrhosis can also develop liver cancer, while other causes of chronic liver disease can lead to liver cancer Independent of cirrhosis In general, we think of patients with hepatitis B or cirrhosis as most at risk. Now, as I mentioned earlier, I am the director of our HCC in Liver Tumor Clinic, which meets every Friday from eight AM to two PM I have an excellent team, including Dr Francis Yahoo's in a world expert on the management of Happened a cell carcinoma. Also staffing. Our clinic includes Dr Sherman, one of my partners, and transmit Hepatology, and Jeff McKinney, one of our nurse practitioners. Additionally, patients were seen on the same day in addition to their hepatology evaluation by interventional radiology, indoor surgery as needed, with both, with both of these groups having expertise in HCC and liver tumor treatments. Also, when indicated, we can directly refer patients to R two g i oncology for consideration of systemic therapy, including clinical trials. I'd like to start by describing a case of a 55 year old male with alcoholic associative cirrhosis found on screening ultrasound to have a three centimeter lesion in the right lobe. The patient then undergoes a quad phase C. T. Of the abdomen that confirms the presence of a 3.5 centimeter lesion in the right lobe of the liver, along with Mild decides on physical examination. The patient has no spider nearby, but his spleen tip is palpable. His laboratory evaluation shows a billiard in a 1.7 and lt of 28 a nasty of 42 an albumin of 3.5 with a slightly elevated I N R. Of 1.3 in a low plate account of 85,000 with an elevated Alfa feed, a protein of 36. So this is a very common patient that would present to our HTC clinic. And really, the questions that we initially have to ask are What are the typical characteristics of HCC on this C T scan? And does this patient need a biopsy? Over the last five years, there's been, ah, quite paradigm shift in the reporting of liver lesions on now, all liver lesions and patients at risk for HCC are giving a liar, ads or liver imaging reporting and data system designation, and here are the major diagnostic criteria of liar ads. These include, uh, lesions that have arterial phase hyper enhancement as well as delayed phase washout. Lesions can also have a pseudo capsule, and lesions that are cancerous can obviously grow. And we do have growth thresholds within liar ads. It's important to note that we have different diagnostic criteria for larger lesions over two centimeters, compared to smaller lesions under two centimeters, which are less likely to be HCC now. The reason why we perform quad phase imaging is because of the specific radiographic characteristics of HCC. In general, the power cell carcinomas were fed by the hepatic artery, whereas the whereas the rest of the liver gets most of its blood supply from the portal vein. Therefore, in this picture on the left, you'll see that they order is bright and we're in arterial phase imaging, and the lesion appears bright or hyper enhancing compared to the rest of the liver, because it's getting its blood supply from the paddock artery now on the right, where in the portal venous phase now the rest of the liver is getting its the blood supply so gets bright, but the cancer is now washing out because it's lost its a paddock arterial blood supply. This is the classic appearance oven HTC, with arterial hyper enhancement and delayed washout. And as I mentioned earlier, lesions in the delayed phase can also have a pseudo capsule. So when we put all this together, lesions are designated between periods one in five or liar adds four lesions. Air, probably HCC and liberals. Five Lesions Air considered definite HCC. The way that radiologist come up with these designations is based on the different diagnostic criteria. Again, those four criteria mentioned earlier arterial phase enhancement, washout, capsule and growth as well as different designations based on the size of the lesion. Now, certainly these criteria don't need to be memorized. But, uh, it's important to realize that is what these are. The criteria that radiologists are going through when they're giving each Legion ally reds designation now is how is the accuracy of lie rats? Well, it's pretty good. As you can see. Liar. It's five lesions are 95% of the time turned out to be HCC when correlating radiology with X with pathology specimen in 98% of the time, turned out to be malignant. Larry. It's four lesions or probable HCC lesions. About three quarters of the time are HCC and about 80% of the time or malignant in the end. Determinant. Liar. It's three lesions about 40% of the time. Turn out to be HCC now. There's also a designation called Areas in which we haven't Gone into, but M stands for malignant and so on. Lee. About 37% of the time. These lesions are HCC, but 95% of the time they're about these lesions do turn out to be a malignancy. Now, Laura M. Lesions almost always require liver biopsy. However, biopsy is not typically necessary to confirm in HCC diagnosis. If the lesion meets radiologic criterion appropriate clinical setting, meaning that if a patient has an underlying risk for HTC and has a liar, it's five lesion. We call that an HTC without without biopsy. This is in part because false negative biopsies air common and may lead to a delay in diagnosis and treatment, and there is a rare but important risk of tumor seating along the biopsy track and up to 2% of patients. So we really Onley biopsy patients in selected cases if there's a typical radiologic appearance or the, for example, like rise M designation or lack of a strong risk factor for HCC. So at UCSF, we have a biweekly multidisciplinary liver tumor board that meets every Tuesday and Thursday from 4 30 to 6. This is where we review all of our imaging studies and patients who have concerning lesions, uh, including those with a padded cell carcinoma. Participants include hepatology ist liver surgeons, interventional radiologists, radiologist with expertise and abdominal imaging, G. I oncologists and radiation oncologists with the objective really to confirm the diagnosis in stage, uh, the suspected cancer as well as determined treatment stat strategies. Now we also recently instituted in HTC Virtual Tumor Board program that's also led by Julie Burns in a C. C. Virtual Tumor Board is a virtual tell, a mentoring program for health care professionals interested in the treatment of HCC and complex liver lesions. Local HTC providers present challenging and de identified cases to our team of UCSF HTC experts, who then provide clinical recommendations. We launched this program in August of 2019 and currently are working with three community based health care for partners. And we've had more than 50 cases presented to date. And one of the goals of this is really to facilitate referrals to our UCSF liver transplant program. Uh, in patients who meet conventional transplant criteria now, going back to original case after a tumor board review, we confirmed that this CT scan showed a 3.5 centimeter arterial enhancing lesion, the right lobe with washout, and we're calling this a liar, adds five lesion or definite HCC. So now we're not planning on biopsy of this lesion, but instead our focus just tow. What treatment would you recommend? Should we have this patient undergo resection either in an atomic or non atomic reproach? Should we recommend liver transplantation, or should we consider an ablation procedure for this patient? Now I'm thinking through this option these options, as I mentioned earlier, we do have patients meet with our interventional radiologists and often are surgeons as well. And some of the variables that we would look at in this patient are that the patient does have evidence of portal hypertension, including with the sides. Ah, palpable spleen tip in a low platelet count, and they also have an elevated Billy Rubin. Therefore, this is this is not likely to patient to be a patient that's going to tolerate a reception. Also, because the lesion is over three centimeters. This maybe too large to consider ablation alone. And therefore we really think liver transplantation, maybe the best strategy for this patient now. I mentioned earlier that resection may not be a good option, and this is basically one of the seminal studies that suggested that patients who either have no portal hypertension and no builder in a normal bilirubin thes air the patients who really do the best with reception. However, when you're thinking about a patient who has either portal hypertension or a patient who has both portal hypertension in an elevated Billy Rubin, you can see that survival after resection decreases dramatically. And so these are really the variables that we pay most attention to along with, Really, when we're considering resection, how maney segments of the liver are we going to have to remove thio in the reception procedure? Can the procedure be done laparoscopically or not? So these are the questions we tend to ask ourselves. But in general, a patient that we're considering for resection should not have clinically significant portal hypertension and should have a normal Billy Rubin. So to summarize, the ideal candidate HCC patient that we're considering the section on should have good liver function and particularly a child, a child, Pugh, a patient with no clinically significant portal hypertension. And we really look at a plate that kind of 100 as a good threshold. We'd like to have them would like them to have a normal Billy Ruben and really, when we're considering, uh, the tumor features. Ideally, the patient have a single lesion up to five centimeters as patients with either multifocal disease or patients with larger tumors are much more likely to have tumor recurrence after a section. And finally, in terms of the the extent of resection, if a patient has tumor in the left lobe, often the surgeons can only take out two segments and therefore this would be a minor section and maybe could be done laparoscopically so the ideal candidate would have a tumor in the left lobe. But we certainly can do resection on patients with H D. C and other locations. Now, as we mentioned, we think this patient is likely a good candidate for liver transplantation. With the 3.5 similar lesion, this patient meets the Milan criteria or the current gold standard for selection of liver candidates for, uh, for a section of liver transplant candidates. Uh, with HCC, patients can either have a single lesion upto five centimeters or 2 to 3 lesions, none greater than three centimeters. Also, it's it's will fulfill them along criteria. Patients cannot have macroscopic vaster invasion or HCC outside of the liver. So within the Milan criteria, we break up thes criteria into either stage of T one or very early stage HCC with a single lesion up to two centimeters in these patients are not eligible for modeled exception points as a pathway deliver transplantation. Instead, only patients with stage to Stage T two criteria or the rest of Milan criteria are eligible for meld. Exception, a za pathway for priority listing. Patients who fulfilled these criteria who undergo transplant have excellent five year outcomes, including a five year survival of 75 to 80% with relatively low HTC recurrence rates of 10 to 15%. Now with the institution of the Milan criteria for determining priority for liver transplantation for HC patients, we've seen a rapid rise in the proportion of adult patients who are who undergo transplantation for HTC. Back in 2000 and six Onley, 22 of our transplants, or about 15% of our transplants, were done for a padded cell carcinoma versus fast forwarding to the last few years, nearly half of our adult patients undergo liver transplantation. Foreign indication for her Patty Saylor carcinoma. So I'd like to switch gears and talk about a second case. This is a 56 year old man with chronic hepatitis B who's well suppressed on antiviral therapy. He receives inadequate HTC surveillance and ultimately was diagnosed with two Lear. It's five tumors in the right lobe measuring five centimeters and three centimeters. The patient appear Aziz well and is asymptomatic and has a good performance status, doesn't have any substance abuse or any significant medical history, and therefore appears to be a relatively good liver transplant candidate on laboratory examination. The patient's hematocrit is 42.4, which is normal. Playlets air again low at 84,000 crannies normal at 0.6. Billy Rubin is normal 0.9 with a normal album at 4.2. And so the patient does appear to have relatively well compensated disease and on antiviral therapy. The patient Hepatitis B DNA is zero. The patient does have an elevated alphabet, a protein of 49. You can see here the patients, uh, C T scan that shows two very similarly located lesions measuring again five and three centimeters. And really, the question becomes, What treatment should we recommend for this patient? I should note that the designation again is both. Lesions are thought to be liar. It's five tumors or definite HCC tumors. Should we consider resection or ablation? Should we go straight to systemic therapy, for example, with Sarafin, um, or we shall we try to downstage the patient into Milan criteria and then follow that with liver transplantation? Now we went through the Milan criteria earlier in this patient exceeds that because they have to tumors, with the largest being five centimeters and again this patient. Even though the two lesions air next to each other on the right lobe, the patient does appear tohave clinically significant portal hypertension and so we do not think that reception would be a good option. Therefore, in this patient we would likely try to pursue down staging. And once the patient was within Milan criteria, we would try to list them for transplant. So down staging of HTC is defined as a reduction in the size of tumor, using local regional treatments to meet acceptable liver transplant criteria. The tumor responses based on the radiographic measurement of the size of only viable tumors and so we don't include the area of necrosis from the local regional therapy and in this manner, down staging in conjunction as a selection tool toe. Identify patients with tumors with more favorable biology that responded down staging treatments and also are likely to do well after liver transplantation. So this is a separate patient. But a patient who appears to have to move beyond Milan criteria with about a 6.5 centimeter lesion in the dome of the right lobe. Now, in the middle slide, you can see after the patient undergoes a single local regional therapy. Ah, lot of the lesion looks dark with Onley, the lesion in the bracketed actually appearing viable and So that's the That's the measurement we would then make. And so if we said this was now 3.5 centimeters, this patient would then been with in Milan criteria. Now, after the patient undergoes subsequent local regional therapies on the right, most slide, you can see that the patient appears now to have a complete response to treatment and hopefully would have complete necrosis on pathology examination. So how do we accomplish this? What our local regional treatment options for patients with the pilots are cell carcinoma? Well, certainly one of the most common is trans arterial chemo, embolization, or taste, which can either be done conventionally or with drug eluting beads. We often, occasionally will often will use ablation therapy with currently microwave thermal ablation being most common. But cryo ablation, radio frequency ablation can also be used. Ablation is can be done either laparoscopically or per cutaneous. Lee, with open approach, is rarely needed. The new kid on the block, or at least over the last 5 to 7 years, has been trans arterial radio embolization or on this is performed using ITRI Um, 90 and then finally, external radiation is another approach on this is termed SP R T or Steri, attacked IQ body radiation therapy. So here's what a taste would look like on an angiogram and a taste is a selective embolization of the hepatic arterial supply to the tumor via the common femoral artery. Again, this is done by the interventional radiologists, and typically they would, once they identify the tumor, an angiogram they can, and they can inject side a toxic agents such a CIS platinum or Dr Robison and on conventional taste that would be mixed with Lippi dollar gel foam particles. Potential complications of tastes include fever, abdominal paid infections such as an abscess. Or you can have a paddock, arterial injury or hepatic decompensation. Now there's been several studies over the years that have looked at the survival benefit of taste compared toa suboptimal therapy or placebo. In this meta analysis, really confirmed that taste does provide an overall survival benefit compared thio two previous dinner of care or placebo therapy. As I mentioned earlier, another option for local regional therapy is why 90 radio embolization, which is either delivered through glass microspheres called thera spheres or resin microspheres called Sears, fears why 90 has extremely high radiographic response rates approaching 90% though there is a risk of radiation damage. Typically, we reserve Y 90 for patients who have preserved liver function or relatively preserved liver function with a Billy Rubin up to about 3 mg per deciliter. But why 90 because of its radiation effect can be used for larger tumors and also can be used for tumors. With segmental vascular invasion, there's only been one, Ah, well done randomized controlled trial that's compared these to treatment modalities. Or why 90 versus taste. And that was called the premier trial that was published in Gosh Neurology a few years ago. And this is a relatively small, randomized controlled trial with, As you can see, a little under 25 patients in each arm on this really did show a significant improvement in timeto radiographic tumor progression with patients who underwent Y 90. Compared to patients who underwent conventional tastes, however, and an intention to treat survival, they did not see any survival differences between the two treatment arms. Now we have done at UCSF, we've tried to become ah leader in the approach to down staging of patients to Milan criterias, followed by subsequent liver transplantation. And so we have a consortium of multi center and multi regional consortium that's tried to answer this question when downstate and patients requiring down staging. So here you can see in the blue line. Patients who underwent taste is their first down staging treatment. And in the red line you can see patients who underwent y 90 and you can see we saw no differences in the cumulative probability of successful down staging tore them along. Criteria on both cases was approached 90% So both appear to be very successful treatments. We also saw no differences in the probability of our time to successful down staging for taste versus why 90 as that initial down staging treatment. So currently it's it's hard to give ah recommendation. We think that both options are quite good as initial down staging treatment choice. Now, as I mentioned, we tried toe be a leader in this field, and we did develop a UCSF down staging protocol with inclusion criteria of patients who are just beyond Milan criteria. For example, if a patient has a single lesion, it's greater than five centimeters because they exceed Milan but cannot be larger than eight centimeters and you can see similar criteria for patients who have between two and five lesions, with a total tumor diameter up to eight centimeters. Now this protocol wasn't adapted by the region by our entire region. Five. After we showed that patients who were initially in the down staging group who underwent down staging, followed by deliver transplantation compared to AH control group of patients with HTC who are always within Milan criteria. Here at UCSF, we saw note significant differences in their post transplant survival even after very long post transplant follow up. And we also saw no differences in post transcend HTC recurrence because of these exciting single center data. We then established a multi center cohort and with this region, five multi center cohort, including several centers in California, we again saw excellent five year post transplant survival at 80% with with very low rates of HTC or currents at approximately 10%. Largely based on this data, this protocol has been adopted as national policy for automatic priority listing and patients who have been successfully downstage with the Milan criteria. Therefore, our patient, in case to who has two lesions the largest five centimeters in total tumor diameter. Up to eight centimeters would meet criteria for this, you know, down staging protocol. So one of our questions is, could we replicate thes exciting data on a national scale? So this is an analysis of the Yunos database or the national database that we performed that investigated almost 4000 patients with H C C. Who underwent liver transplantation, and you can see about 11% exceeded Milan criteria but met the Yunos down staging criteria. And then about 3% of patients had mortimer back burden than the Yunos downstage and criteria. And we call these the so called all comers. And really, the question we have is do these patients who exceed downstage and criteria How did they do with liver transplantation? So here's the Here are the results of this retrospective national study, and this figure is really showing three year post transplant survival stratified by initial tumor burden criteria where the line in green is the patients who are always within Milan and they had about 83% 3 years survival. The line in red are the patients who met the you knows down staging group in there three years survival was slightly lower, but not significantly different at 79%. And then the all commerce patients who were exceeded. You noticed down staging criteria. But then we're able to be successfully downstage into Milan. Before listing, Those patients had a lower three year survival at 71% and that was significantly different than the Milan group. So really, we do think that, you know, is down. Staging patients do quite well with transplant. But given this reduced survival for all comers patients, currently they are selected on a case by case basis by the National Liver Review Board. So I'm going back to our patient. We do decide to go with radio embolization therapy. So this is the planning angiogram that shows these two tumors being fed by ah branch off the hepatic artery and before any injection of radio therapy in patients beyond Milan criteria, we do a pre procedure, uh, planning study to determine toe actually determining. Is there any shunting in the tumor that might, uh, put the patient at risk for radiation to go in other parts of the liver so the patient doesn't have a large shunt fraction so can undergo. Why 90 therapy and you can see one month after the Y 90 therapy, we already start to see a good amount of internal necrosis and the two Toomer's. Then the patient subsequently undergoes a 2nd 1 90 therapy. And so now you can see, Really, there is quite an impressive response with most of the two Toomer's looking pretty dead. So to summarize this patient undergoes to my 90 procedures in the C T abdomen one month later shows no residual enhancing disease. Unfortunately, this patient has an A f P decrease from 49 to 7. So the last thing I'd like us to consider in this patient is Is there an optimal Alfa feed a protein cut off prior liver transplantation in our HCC patients? There's been quite a lot of data on this topic, including out of a multi center study from France that showed that as a patient's alfa feta protein goes up prior to transplant, their post transplant outcome gets worse and worse such that if a patient has an ape of 100 to 1000 their five year survival after transplant, only 51% and if the AP exceeds 1000 their post rants on survival at five years is under 40%. Now this is our single center data that shows very similar findings that really a patient with a napi over 1000 or should not be considered good candidates for liver transplantation due to poor post transcend outcomes driven by high rates of HTC recurrence. In this study, we saw that applying an alphabet of protein cut off of 1000 to patients with in Milan criteria would only exclude 5% of patients, but would allow for a 20% overall reduction in post transplant HCC recurrence. Therefore now on a national stage, we have enacted policy whereby candidates with allegiance meeting T to conventional transplant criteria but with an AP have greater than 1000 are no longer eligible for standardized melt exception until the tumor marker falls to under 500 with local regional therapy, and at that time the candidate would be eligible for exception points. So one of the other questions is, Does this national policy regarding alfyed a protein makes sense now we tryto study this by analyzing almost 400 patients who had an Alfa feet of protein of greater than 1000 in our national database at some point while they're awaiting liver transplantation, and what you can see mapped out here is what are the patients? Alfyed, a protein. At the time of liver transplant, you can see if the AP remained greater than 1000. As expected, they had a poor 50% 5 years survival after transplant. But if they were able to reduce the Alfa feta protein to 100 to 500 their five year survival improved significantly to almost 70%. And if they're, HP was able to come down to under 100 with local regional treatment, their five year survival approach 90%. And this really gets at the important prognostic ability of Alfa food, a protein as a really good marker of tumor biology. So therefore, even though the policy says would like patients to be under 500 alphabet, a protein reduction under 100 is prior to transplantation is ideal. Now, how do we put all this together? Well, this is a really neat example, and this is called the Metro Ticket 2.0, calculator on. This was a multi center study out of Europe that really looked at HCC specific survival based on how much tumor you had on either the last imaging study to transfer prior to transplant or on the X plant combined with your alphabet of protein going into transplant. And really, as you can see here, the more tumor you have and the higher your alfa feta protein is, the higher your chance of HTC recurrence after transplant and the worst your ultimate outcome is going to be so. This is a really nice example of how we can, uh, combine tumor burden with Alfa feta protein to really prognosticate how patients will do with liver transplantation. So going back to this patient after the treatments, the patient's alphabet, a protein decrease from 49 to 7. And so when thinking about an optimal alphabet, a protein cut off recurrence risks really begins to increase that an alfa pita protein around 20. But really, as your Alfa PD, a protein increases further, especially when it's higher than 100 you are the higher than 1000. You see extremely poor outcomes, but Alfa Peter Protein of seven would be quite acceptable. So if you do have a patient with either HTC or liver tumor. Uh, here's our information on how to refer the patient to our clinic, including our phone number and fax number, as well as our website, where you can refer patients in access or referral forms. Our clinic, our location and directions is also listed here and again. We meet every Friday from eight am to two PM on the patients are hepatology group as well as potentially are interventional radiologist In our surgeons, I'd really like to thank you for listening to this presentation on the management of early and intermediate stage Jupiter sailor carcinoma. Thank you.