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Coffee Chat: Best practice in managing the unique needs of non-viral HCC
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Coffee Chat: Best practice in managing the unique needs of non-viral HCC
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Segment:0 .
RACHEL JENKINS: Hello, everyone. And welcome to today's coffee chat brought to you by Oncology Central in which we are discussing the best practice in managing the unique needs of non-viral Hepatocellular Carcinoma patients including the latest evidence and clinical practice. My name is Rachel Jenkins, and I'm the host for today's event. I'm delighted to be joined by two key opinion leaders in liver cancer today at ESMO 2023, Dr. Andrea Casadei Gardini and Dr. David Pinato.
RACHEL JENKINS: Within this coffee chat, we will explore three key topics. First, the current management of people with non-viral HCC, next up, overcoming challenges in the clinical management of people with non-viral HCC, and finally, meeting the unique needs of people with non-viral HCC. To start things off, David and Andrea, could you please briefly introduce yourselves?
DAVID PINATO: Hi. My name is David Pinato, and I'm a consultant medical oncologist. I work at Imperial College in London where I lead a program of developmental therapeutics.
ANDREA GARDINI: I am Andrea Casadei Gardini. I am an associate professor in medical oncology at San Raffaele University in Milan.
RACHEL JENKINS: Perfect. So the first section is current management of people with non-viral HCC. So what is the current pathway for managing a person with non-viral HCC?
ANDREA GARDINI: So the non-viral patient is completely different from viral patient, in particular because in a non-viral patient, we don't have a screening program for our patients. This is a-- in my opinion is the big problem for our patient because about 30% of all population have a metabolic disease, but we don't have a screening program. And the other problem is that we don't-- for ours, is not possible to identify the patient with higher risk from metabolic disease to cirrhosis, cirrhosis to hepatocellular carcinoma.
ANDREA GARDINI: My opinion is an important medical needs for our clinical practice in daily clinical practice.
DAVID PINATO: Yeah, that is true. I mean, the reality is that these patients are fairly disadvantaged. For the vast majority of their life, they wouldn't even think that they are ill or that they are developing chronic liver damage. I think there is a lot that we don't understand in terms of how the progression of the disease goes from having simple fat accumulation within the liver to developing proper fibrosis to cirrhosis.
DAVID PINATO: And in my clinical practice, very often patients don't feel that they had an opportunity to be tested earlier. There is also this very strong psychological sense of regret, of not knowing, of not understanding why the disease has happened. The other thing to say is that in non-viral, there are a lot of different categories. So you have alcohol, which is a completely subset-- different subset of patients where, for instance, there is alcohol abuse.
DAVID PINATO: Sometimes that is still active. And so that is really something that sometimes plays a role in the compliance of patients to treatment. And so these patients often require a lot more of a support network around them because of alcohol dependence. And also, you have the metabolic patients that you were referring to that are sometimes a bit of a mystery in terms of pathogenesis.
DAVID PINATO: I agree with you.
RACHEL JENKINS: So does this management vary from one kind of practice center to the next? And if so, why?
DAVID PINATO: I think the-- one of the biggest reasons for variation in my view is the fact that not all the centers have got the same amount of non-viral patients, if you want to put it this way. So there is a lot of geographical heterogeneity in terms of the percentage of people that will present with this particular etiology as a background. And so for instance, the easy example is to think about the Far East where, for instance, hepatitis B is the most prevalent risk factor and other instances where, for instance, hepatitis C.
DAVID PINATO: This used to be the case in Europe and, for instance, in certain areas of Italy. Is this something that resonates with you?
ANDREA GARDINI: Yeah, yeah. It's completely-- I completely agree with you. And the problem is we have probably four, five categories of patients. And in particular, our clinical practice and our hospital is-- in general, the hospital is very difficult to follow this patient because we have several etiologies with different problem with different answer and different result for this patient.
RACHEL JENKINS: So how has this clinical practice evolved as a result of the latest evidence?
DAVID PINATO: Well, I think, to be honest, there has been more and more convincing evidence to suggest that looking at the characteristics of the underlying chronic liver disease is an important factor to be taken into consideration. I think one of the reasons why I feel this big group of non-viral patients is disadvantaged is because unlike, for instance, hepatitis B or hepatitis C where you have clear guidance in terms of when to initiate treatment-- And treatment literally comes in the form of a tablet.
DAVID PINATO: So you either prescribe an eradication course for hepatitis C or you put the hepatitis B patients on tenofovir. And you measure the DNA levels going down and then being very well controlled. For non-viral patients, there are a lot more challenges to be implemented in terms of treating the underlying chronic liver disease. I mean, we all know that, for instance, exercise, good eating, treatment of diabetes, those are things that are important in managing liver function, for instance.
DAVID PINATO: And going back to the etiological factors, try to change the natural history of that damage. But we also know that these are very difficult aims to achieve. I mean, controlling diabetes is quite difficult. Sometimes-- a lot of my patients, for instance, are on a lot of medicines.
ANDREA GARDINI: It's very difficult. And the other point is about-- probably in Italy, but it's the same in UK or in Europe, that 30% of population have this problem. And the problem is where patient I follow for the increased risk of cirrhosis and after for hepatocellular carcinoma. The other problem is probably that the patient with hepatocellular carcinoma and NASH metabolic disease, the problem is less-- have less cirrhosis compared, for example, hepatitis B or C.
ANDREA GARDINI: The other problem-- this is a question. The hepatitis C that have a virological complete response, for example, from five, six years, is hepatitis C patient or have a mixed etiology? This is another important question. For example, we see in our hospital patient with hepatitis C but have diabetes or have hypertension or have fat.
ANDREA GARDINI: And probably, this patient have a mixed etiology. And this is another problem for our clinical practice.
DAVID PINATO: Yeah, totally. I might have a question for you on that. So in my practice, we've started through a multidisciplinary team approach to try and look at all these factors, so try and optimize diabetes control, for instance, and try linking patients with support groups, for instance, for alcohol. We mentioned that as being a problem. Is this something that happens in Italy as well? Do you tend to share these work with others?
ANDREA GARDINI: It's more difficult in Italy because we have several patients with progressing hepatitis C. Probably our error is that we think that this patient, this patient is hepatitis C patient, but probably, now have a mixed histology and is-- we follow the patient for hepatitis C, but we don't see the other problem correlated, diabetes--
DAVID PINATO: And the comorbidities.
ANDREA GARDINI: Comorbidities, this is completely different. And in my opinion, change our clinical practice in the last five years probably, no?
DAVID PINATO: Yeah. I mean, I know that you've done a lot of research on this. And sometimes these comorbidities impact your choice of systemic therapy, for instance, and the presence of the choice of one treatment versus another, right?
ANDREA GARDINI: Yes.
RACHEL JENKINS: So moving on to the next section is overcoming challenges in the clinical management of people with HCC. So how does the prognosis of non-viral patients compare to viral causes of HCC?
ANDREA GARDINI: The prognosis of our patient probably is more correlated with the presence of cirrhosis or not. The metabolic patient, because now we have several definition of NASH metabolic patient, have less cirrhosis, probably have-- this patient have a lesser risk of liver failure and probably have a better outcome compared, for example, patient with hepatitis B because they have more risk of cirrhosis.
ANDREA GARDINI: The other problem is the best choice for our patient, in particular, for systemic therapy because-- I have a question-- two questions. OK, we have several etiologies with different carcinogenesis, and we have several drugs now. And the question is probably we don't have the same result with the drugs in several etiologies. This is an important question in our clinical practice.
DAVID PINATO: Yeah, I completely agree. I think there are a number of challenges. The first one perhaps is the definition, because you mentioned NASH and the fact that now we are moving on from a global NASH definition, which means simply nonalcoholic. And if you think about even the question itself, non-viral, so what does non-viral mean?
ANDREA GARDINI: I don't know.
DAVID PINATO: It's a diagnosis of exclusion. So we really need to think about how do we think about the positive determinants that define that characteristic patient population. And so if we bring them down-- you mentioned some of them, the diabetes, the hypertension, the metabolic dysfunction profile of the patient. And I think it is true. Those are encompassing more broadly all the other etiologies as well.
DAVID PINATO: They are not exclusive to a group of patients, but they might be more prevalent in one group of patients as opposed to the other. Challenges that I see is to try and identify whether there are any molecular vulnerabilities that we could utilize to treat these patients.
ANDREA GARDINI: [INAUDIBLE].
DAVID PINATO: And I think that is really what is lacking, is to try and get to the biology of the disease, understand whether certain specific molecular pathways are up or down regulated, and create a precision medicine approach.
ANDREA GARDINI: Yes, clearly, now is not possible. But probably, if we see the etiology, we have a secondary pathway. If we see a different pathway-- but we know very well why these different pathways have a different impact for our patient, for example.
RACHEL JENKINS: So the next question is, what challenges do you face in the management of non-viral HCC? So I don't know if there's anything else you want to add from what you've already discussed.
DAVID PINATO: I think from an individual patient perspective, a lot of the patients with-- who do not present with the diagnosis of hepatitis, they often are unaware of having had cirrhosis for a protracted period of time. Not all of them have cirrhosis. So some of them have mild fibrosis and still hepatocellular carcinoma presenting. So there is a lot of heterogeneity at the point of presentation.
DAVID PINATO: And to be honest, they are not used to the idea of requiring a pathology follow-up or they've never seen a liver doctor. And very often, they present with a concomitant chronic liver disease problem undiagnosed before as well as liver cancer. So that requires very quickly an integration of specialties when it comes to formulating a treatment plan because you need to make sure that if they're decompensated, they try and recompensate quickly.
DAVID PINATO: And very often, there is this sort of negative tendency, negative train of thought to say, well, if we have a decompensated patients with active hepatitis C, we could treat hepatitis C and hope for recompensation. I guess a lot of the patients that unfortunately have decompensated on a background of non-viral chronic disease have got way less weapons to fight the chronic liver disease as opposed to the viral patient.
DAVID PINATO: Does that happen in your center?
ANDREA GARDINI: Yes, I completely agree. For example, a patient that take the alcohol, the first step is to stop the alcohol. In metabolic patient, we-- probably, we don't think that first, we treated the metabolic disease. And after, it's possible to cure the hepatocellular carcinoma better because we have a better cure, the metabolic disease.
DAVID PINATO: And it would take time as well to reverse all the metabolic dysfunction. Surely, like whenever we've done hypertension clinics when we were medical students, it takes months to years to get to a good level. And sometimes you don't have that luxury in patients.
ANDREA GARDINI: And probably in our multidisciplinary team is important to add new field. For example, the cardiologist for the hypertension, for the diabetes, the endocrinologist, or dietitian for our patients to program a diet.
RACHEL JENKINS: So leading on from that, what are the unique needs for people with non-viral HCC have compared to people with viral HCC?
ANDREA GARDINI: For the treatment?
RACHEL JENKINS: Yeah.
ANDREA GARDINI: OK. So probably in early stage in my opinion, not impact the viral versus non-viral impact of the cirrhosis of the patient. In advanced HCC or in patient that we treated with systemic therapy, we published several papers that highlight an important difference between the outcome between immunotherapy and lenvatinib in particular in non-viral patient.
ANDREA GARDINI: For example, we see that in hepatitis B patient, the immunotherapy is the best choice for our patient. In hepatitis C patient, probably, we have several type of hepatitis C patient, but we have the viremic patient that is completely different from the patient that had the past viremic hepatitis C. And we have a non-viral patient that we see a better efficacy of lenvatinib in this setting.
ANDREA GARDINI: Probably changed my opinion in the last year because before, my opinion is that the immunotherapy is less efficacy in NASH metabolic patient. Now, we see that the immunotherapy is efficacy the same in all etiologies, but probably lenvatinib is more efficacy in the metabolic patient in my opinion.
DAVID PINATO: To be honest, this has been one of the most heated debates when thinking about systemic therapy. At all the conferences, there is always the question about viral versus non-viral patients. And I think in my mind, this particular debate recaps the complexity of this particular segment of the patient population. Everything that we have said so far, so the fact that they present late, they have less weapons to fight the chronic liver disease, sometimes they are disadvantaged compared to other patients might play a role.
DAVID PINATO: And so there is this real question of, are the differences that we are seeing in association effects with the characteristics, the way the patients present or is there anything biological that truly drives the disease in a different way in this subset of patients? We have high-level evidence from a very important Nature paper published by-
ANDREA GARDINI: [INAUDIBLE].
DAVID PINATO: Mathias Heikenwalder, which was very interesting because it did look in mouse models that the presence of a non-viral type of insult was characterized with the emergence of specific subclones of T-cell responses which might have a paradoxical effect against immunotherapy. This has been really the origin of all these debates. And then obviously, you, Andrea, you publish a lot of results on the basis of the hypothesis. And there is a lot more that needs to be done.
DAVID PINATO: I think what is missing, in my view, is the fact that we are lacking a unified definition. So as we were saying before, we keep taking all the negatives.
ANDREA GARDINI: It's very difficult.
DAVID PINATO: But we don't really know what are the positives. And I was looking at some presentations of drug development in nonalcoholic fatty liver disease in metabolic disorders, whereby there is a strong tendency now to subcategorize stereotactic liver disease across different processes. So for some being more fibrotic. For others being more dismetabolic. And I think even the etiology itself is not really fully understood.
DAVID PINATO: And there might be different mechanisms that justify within the broader group of the ex-NASH patient population, the ex-non-viral, many different avenues that could be used for treatment. So I think this is really an area of unmet need where we do need collaboration from pharmaceutical industry to try and tackle that heterogeneity. The reason being that non-viral patients are on the rise. And so the prevalence of metabolic disorders is on the rise and will, if it's not already becoming the key risk factor for HCC, especially in the Western world.
DAVID PINATO: Don't you think?
ANDREA GARDINI: I completely agree. And the other problem is that the comorbidity of this patient, that probably we choose different treatment because the patient have comorbidities that is not possible to choose a drug or other drugs-
DAVID PINATO: Yes, absolutely.
ANDREA GARDINI: In clinical practice
DAVID PINATO: I mean, the opposite would be true. For instance, for hepatitis B patients, they tend to be very young, not all of them have cirrhosis. So you can see how the differences are also accumulating in other disease areas. And so they might lead to the differences that we're seeing in some of the studies.
RACHEL JENKINS: So moving on to the last section, which is meeting the needs of people with non-viral HCC, so have there been any recent advances in evidence or clinical practice which has helped address the challenges that you've just spoken about?
ANDREA GARDINI: The challenges for our patient. In non-viral patient, but probably, the first one is the definition of patient. The second one is better characterization of cirrhosis and the background for our patient in non-viral patient, because we have several different populations. And the other one is to choose the better treatment for our patient.
ANDREA GARDINI: In my opinion, this is the future and the very challenge for us.
DAVID PINATO: Yeah, I think to be honest, the great disadvantage has been the definition, so the fact that really we're starting to understand and to get to the basis of what the problem is in non-viral patients. And I think I'm yet to see a prospective clinical trial that tries to tackle this problem. It's a very difficult problem from a pharmaceutical company's perspective, I must say, to invest specifically on a subset. If we think about the global prevalence of HCC, hepatitis B remains one of the biggest risk factors.
DAVID PINATO: So the idea of making non-viral patient a specific population, where to test drugs or even within that, to subcategorize, would mean having trials that would need to recruit across millions of sites.
ANDREA GARDINI: There's a problem.
DAVID PINATO: The heterogeneity will be very difficult. So I think it's good that we're thinking about it, but running prospective studies in this particular population is actually quite difficult for that reason.
ANDREA GARDINI: If not to change the definition of metabolic.
DAVID PINATO: Exactly, exactly, yeah. That's true.
ANDREA GARDINI: Because in the last year, it changed three times?
DAVID PINATO: Yeah, yeah.
RACHEL JENKINS: So this ties into the next question, which is, are there any areas that need to be addressed yet to and challenges still to be overcome?
DAVID PINATO: Well, I think the first one, as we said before, is finding treatments that are specifically tailored to this patient population. And I think, for now, the evidence rests on retrospective studies, rests on registry data. I think we are really in a position where we need to find level 1 evidence before we change our practice more solidly. But also I would be inclined to say that it's not only about changing practice.
DAVID PINATO: It's about finding novel targets for treatment. And I think that's really where the opportunity lies. HCC is unfortunately a tumor where there is not a potential for delivering procedures, medicine. I mean, in other tumors, cholangiocarcinoma-
ANDREA GARDINI: It's [INAUDIBLE]..
DAVID PINATO: We thought it was never possible, but it's now changed in a few years. So my wish for the future would be to maybe try and understand the more fundamental level where the non-viral patients, as we imperfectly label them now, they do actually have some areas, some molecular targets that are enriched which we can use to treat them more effectively.
ANDREA GARDINI: Yes, I agree with you, David. The other point is clearly we don't have a phase III trial. And probably, in the future, it's not possible to have a phase III trial. The other point is that probably the real-world data now is more important than in the past. Clearly, it's not possible to change our clinical practice. But we have several answers to the question that we don't have from a phase III trial.
ANDREA GARDINI: For example, from a phase III trial, it's not possible to have a very large population. In real-world data, it's possible. And for this reason, it's possible to have data from particularly on a very small subgroup of patients that for our clinical practices is fundamental.
RACHEL JENKINS: So as a final thought, and you've already touched on this, but what are your own hopes in terms of overcoming the challenges facing patients?
DAVID PINATO: OK, so hopes, I think broadening the reach of effectiveness of systemic therapy in these patients, but also broadening the reach of active anti-cancer therapy more in general. I'm also thinking about the earlier stages of the disease, for instance. So we know that, for instance, transplant lists are very much changing in terms of the indication for requirement of the transplant.
DAVID PINATO: And with now a lot of patients that can be very easily managed from the perspective of quick hepatitis C eradication, we don't see a lot of liver failures getting into transplant as much as we are seeing maybe metabolic disorders getting to transplant very often with HCC. And so this is actually changing a little bit also the landscape in the earlier stages of the disease. My hope is that we can keep broadening the reach for these patients and for more patients to get access to anticancer care.
DAVID PINATO: I still have the feeling and maybe the lived evidence for a lot of the patients that we discuss at our MDT that come to us already decompensated because of this unnoticed change in liver function that has happened chronically. I think fundamentally there is a big call for the hepatology community to address the issue of screening in these patients more broadly so that we can get more patients treated in general, no matter what drug, no matter what therapeutic strategy.
ANDREA GARDINI: So I completely agree with David, because in my opinion, probably the scenario of HCC completely change in one, two years because in the future, probably, we have an adjuvant therapy for our patient. But the problem we open to question because after one year of treatment, the curve is not good, and probably we continue with immunotherapy.
ANDREA GARDINI: And the other point is when to add in transplantation list, this patient. The other point is the intermediate stage because the intermediate stage is fundamental, the best stage for our patient because in this patient, we have a stage migration. It's possible to perform more curative treatment. Now, we have several drugs that it's possible to have an efficacy in terms of response and the stage migration.
ANDREA GARDINI: In the future, probably, we have the association of locoregional therapy and immunotherapy or TKI. And my opinion has completely changed the clinical practice in two, three years.
DAVID PINATO: We'll have a lot of work to do to keep up with all those changes. It's really changing at a very rapid pace and-- which brings a responsibility to all of us to be always aware of the new data coming through. Absolutely.
ANDREA GARDINI: From one drug to one with the best choice for our patients is a question of every day.
DAVID PINATO: Absolutely. Absolutely. It's a day-to-day struggle.
RACHEL JENKINS: Thank you both so much for joining us.
DAVID PINATO: Thank you.
ANDREA GARDINI: Thank you.