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Resectability of HCC

Panelists:Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, Geffen School of Medicine; Riccardo Lencioni, MD, Sylvester Comprehensive Cancer Center; Amit Singal, MD, UT Southwestern Medical Center
Published: Monday, Apr 25, 2016


Transcript:

Ghassan K. Abou-Alfa, MD:
With this said, let’s go back to surgery because, obviously, surgery is going to stay. It’s not going to go away because of what we just discussed in regard to transplant. I have to admit, it will be nice if one of our colleagues from Hong Kong would be here, because these are probably the gurus of surgery and resection of the liver. Richard, why?

Richard Finn, MD: Well, I think when we’re talking about surgery, we’re talking about cure. And the only way to cure liver cancer is either with a resection or with transplant. And we know that with resection, we still leave around a sick organ, and so there’s a high recurrence rate. As we heard, a lot of the selection of patients for surgery is based on their underlying liver disease. But the other component is the oncologic component, the characteristics of the tumor, and that is where the debate arises—and especially in the context of the recently released Hong Kong Staging System. Because I think in the West, surgeons tend to be a little more conservative about what they resect. Check off the box, the patient is physiologically resectable. What are the anatomical considerations? And, as you mentioned, the less cancer there is, the better the outcome, the more curable it is. And then what are contraindications? I think most people will agree extrahepatic disease is contraindication, but liver cancer often invades into the vasculature within the liver before it spreads outside of the liver.

So, for patients with main portal vein invasion, I think there’s probably consensus between the East and the West that those patients should be resected. But then what about a branch of the portal vein, a piece of tumor you see on MRI that’s just invading right next to the tumor? We know the risk of recurrence for those patients is very, very high. And I think most surgeons within the western hemisphere are not going to operate on those patients. But, in the East, I’ve heard it said that, well, the risk of recurrence is not 100%. Maybe it’s well over 50%, 70%, 80%, but that patient deserves a chance for cure because it’s not 100%.

Similarly, talking about size, all of us see these patients who have not had screening. They’ve had known liver disease, they don’t get screened, they come in with a 12-cm tumor, no vascular invasion, and maybe it’s well encapsulated. And you start thinking, do you do a very large resection? Well, again, physiologically, they need to be capable to undergoing that. But is the risk of decomposition and recurrence, is it favorable to the patients? And I think, again, in the East, there’s more of a push for surgery on those patients. And probably even within the West, if it can be resected, I think a lot of surgeons would pursue resection.

Ghassan K. Abou-Alfa, MD: Fair enough. But, to take it from another perspective, to be fair to our colleagues in East Asia, especially, these patients are not cirrhotic. What do you think?

Amit G. Singal, MD: Yes, so I think that definitely influences it. It’s not only the presence of cirrhosis, but also the etiology of the liver disease. I think that once again, if you’re not cirrhotic, we know you can get away with leaving behind a smaller future liver remnant. So, you can do larger resections. The second thing is, at least the data that I’m aware of show that if you are aggressive in terms of resecting people with small vascular invasion or even people with some multifocal disease—so satellite lesions—if you do this in a setting of chronic hepatitis B, you actually have lower recurrence rates than if you do this in the setting of chronic hepatitis C. And so I think it’s not only the absence of cirrhosis, but also the differing etiologies that may influence the prognosis of being more aggressive with surgical resection. That being said, I think it’s a two-way street, and we’re starting to learn that maybe we were too conservative. So, I think you’re starting to see a shift in major academic institutions where people are becoming more aggressive. I can tell you in Dallas, we’ve become maybe a little bit more aggressive in terms of resecting some people with small vascular invasion or a limited multifocal disease, if you can still get away with doing it in terms of a limited resection.

Ghassan K. Abou-Alfa, MD: I would call it “experienced,” with Michael Choti and everybody else, rather than “aggressive.”

Amit G. Singal, MD: And I think that’s important. You need to do this at an experienced center. But in the right hands, I think that you do offer the patients some chance of cure.

Richard Finn, MD: And I think it’s important that—and it’s going to come up again in the context of our interventional radiology discussion—the first question is not, “Can I do it?”, but “Does it help?”’ And the data around a lot of the interventions or procedures is where there’s doubt.

Amit G. Singal, MD: Agreed. I think that’s the key thing, you’re right, that there are no good data showing that this is the right initial approach.

Riccardo Lencioni, MD: Because I really think, Amit, that the risk here is that with improvement in techniques, we’ve become good in doing something, and naturally we’re trying to offer this more and more to patients. So, I definitely do second, Richard, in trying to understand the difference between what can be done technically and what is worth doing. Now, one of the issues—I think in this context—is that not all hepatocellular carcinomas are the same. And, unfortunately, we don’t have many outcome predictors. In general, we try to simplify the discussion: single, multiple, with vascular invasion, without vascular invasion. The role of other parameters is clearly less straightforward. However, in individual patients, they have a role. Alpha-fetoprotein, for instance. In front of the same scenario, a low alpha-fetoprotein versus a very high alpha-fetoprotein can make a difference in understanding how bad the disease is.

Now, an approach that I think is also emerging is the use of interventional therapies to better understand the biology of the disease. This is done in liver transplantation because you correctly defined the Milan criteria. However, for patients who are a bit beyond Milan criteria, if you can downstage them—for instance, with chemoembolization—then they can become candidates for transplantation. So, you can offer them a chance of cure. And, similarly, in a patient with multifocal disease, having a chemoembolization and understanding whether the tumor is truly keen to disseminate rapidly, or is more of an indolent disease, is probably critical. I know this is not in an algorithm and this is why, again, the expert opinion is probably the key.

Ghassan K. Abou-Alfa, MD: Let me try to summarize what’s going on here. This is fascinating because what we thought many years ago, that probably anatomical spread of the disease will probably determine the outcomes. We spoke about another dimension, though—that actually Dr. Singal brought up—which is the cirrhosis versus non-cirrhosis because, of course, if the liver is cirrhotic, the ability to preserve liver function after a certain surgery might be definitely impacted. But he brought up a fascinating point—which can reflect what everybody’s discussing here—which is what we don’t know about. What’s hepatitis B versus hepatitis C, for example? Because it appears to be that what we thought originally, that the process that evolved from the hepatitis infection all the way to the cancer, is probably the same. And already we have data that show it to be different. Remember—and only on a very, very superficial level—hepatitis C, for example, is an RNA virus and does not integrate into the genetic material. It can impair response to DNA damage and repair, lead to the cirrhosis. This is a process to develop the cancer, which is totally different from the one of hepatitis B—which actually is a DNA virus that simply can integrate into the genetic material and, as such, can impose or impact a certain process of the oncogenic transformation that definitely has its impact in regard to the outcome.

And, as such, those determinations were, of course, understandable based on anatomical decisions. But, as you can see, there are many dimensions that are layering themselves, and I think this is where the resource is going to go forward in regard to how to determine resectability per se. With this said, Richard, I go back to you. One of the critical questions—and I’m sure you get this question probably every day from your patients or from your colleagues—adjuvant therapy after resection: yes or no, and why?

Richard Finn, MD: Well, that question’s been looked at, and it’s been answered, and I think currently the definitive answer is no adjuvant therapy. We know when a patient comes to see us after resection, they’ve had a pathology specimen that might show multifocal disease, vascular invasion. We know that the risk of recurrence is quite high. I think the starting point is a recurrence rate for all resections, probably about 50%, and then you add on those factors and it goes up higher. The STORM study looked in the adjuvant setting for patients who were high-risk on sorafenib for 4 years post resection. And that study read out that the use of that drug did not delay recurrence or ultimately improve survival. Given that sorafenib is the only drug that’s been shown to be active in advanced disease, it’s the one that’s been best studied in the adjuvant setting. At this point, there are no data that anything, other than maybe continued surveillance, is appropriate for these patients.

Ghassan K. Abou-Alfa, MD: So, this is very important to note that, unfortunately, what we all wished for and all of us and we’re anticipating is that at the moment, there is no role for sorafenib or any other therapy in regard to adjuvant treatment. But that does not mean that we might not witness studies going forward in regard to that important question.

Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Ghassan K. Abou-Alfa, MD:
With this said, let’s go back to surgery because, obviously, surgery is going to stay. It’s not going to go away because of what we just discussed in regard to transplant. I have to admit, it will be nice if one of our colleagues from Hong Kong would be here, because these are probably the gurus of surgery and resection of the liver. Richard, why?

Richard Finn, MD: Well, I think when we’re talking about surgery, we’re talking about cure. And the only way to cure liver cancer is either with a resection or with transplant. And we know that with resection, we still leave around a sick organ, and so there’s a high recurrence rate. As we heard, a lot of the selection of patients for surgery is based on their underlying liver disease. But the other component is the oncologic component, the characteristics of the tumor, and that is where the debate arises—and especially in the context of the recently released Hong Kong Staging System. Because I think in the West, surgeons tend to be a little more conservative about what they resect. Check off the box, the patient is physiologically resectable. What are the anatomical considerations? And, as you mentioned, the less cancer there is, the better the outcome, the more curable it is. And then what are contraindications? I think most people will agree extrahepatic disease is contraindication, but liver cancer often invades into the vasculature within the liver before it spreads outside of the liver.

So, for patients with main portal vein invasion, I think there’s probably consensus between the East and the West that those patients should be resected. But then what about a branch of the portal vein, a piece of tumor you see on MRI that’s just invading right next to the tumor? We know the risk of recurrence for those patients is very, very high. And I think most surgeons within the western hemisphere are not going to operate on those patients. But, in the East, I’ve heard it said that, well, the risk of recurrence is not 100%. Maybe it’s well over 50%, 70%, 80%, but that patient deserves a chance for cure because it’s not 100%.

Similarly, talking about size, all of us see these patients who have not had screening. They’ve had known liver disease, they don’t get screened, they come in with a 12-cm tumor, no vascular invasion, and maybe it’s well encapsulated. And you start thinking, do you do a very large resection? Well, again, physiologically, they need to be capable to undergoing that. But is the risk of decomposition and recurrence, is it favorable to the patients? And I think, again, in the East, there’s more of a push for surgery on those patients. And probably even within the West, if it can be resected, I think a lot of surgeons would pursue resection.

Ghassan K. Abou-Alfa, MD: Fair enough. But, to take it from another perspective, to be fair to our colleagues in East Asia, especially, these patients are not cirrhotic. What do you think?

Amit G. Singal, MD: Yes, so I think that definitely influences it. It’s not only the presence of cirrhosis, but also the etiology of the liver disease. I think that once again, if you’re not cirrhotic, we know you can get away with leaving behind a smaller future liver remnant. So, you can do larger resections. The second thing is, at least the data that I’m aware of show that if you are aggressive in terms of resecting people with small vascular invasion or even people with some multifocal disease—so satellite lesions—if you do this in a setting of chronic hepatitis B, you actually have lower recurrence rates than if you do this in the setting of chronic hepatitis C. And so I think it’s not only the absence of cirrhosis, but also the differing etiologies that may influence the prognosis of being more aggressive with surgical resection. That being said, I think it’s a two-way street, and we’re starting to learn that maybe we were too conservative. So, I think you’re starting to see a shift in major academic institutions where people are becoming more aggressive. I can tell you in Dallas, we’ve become maybe a little bit more aggressive in terms of resecting some people with small vascular invasion or a limited multifocal disease, if you can still get away with doing it in terms of a limited resection.

Ghassan K. Abou-Alfa, MD: I would call it “experienced,” with Michael Choti and everybody else, rather than “aggressive.”

Amit G. Singal, MD: And I think that’s important. You need to do this at an experienced center. But in the right hands, I think that you do offer the patients some chance of cure.

Richard Finn, MD: And I think it’s important that—and it’s going to come up again in the context of our interventional radiology discussion—the first question is not, “Can I do it?”, but “Does it help?”’ And the data around a lot of the interventions or procedures is where there’s doubt.

Amit G. Singal, MD: Agreed. I think that’s the key thing, you’re right, that there are no good data showing that this is the right initial approach.

Riccardo Lencioni, MD: Because I really think, Amit, that the risk here is that with improvement in techniques, we’ve become good in doing something, and naturally we’re trying to offer this more and more to patients. So, I definitely do second, Richard, in trying to understand the difference between what can be done technically and what is worth doing. Now, one of the issues—I think in this context—is that not all hepatocellular carcinomas are the same. And, unfortunately, we don’t have many outcome predictors. In general, we try to simplify the discussion: single, multiple, with vascular invasion, without vascular invasion. The role of other parameters is clearly less straightforward. However, in individual patients, they have a role. Alpha-fetoprotein, for instance. In front of the same scenario, a low alpha-fetoprotein versus a very high alpha-fetoprotein can make a difference in understanding how bad the disease is.

Now, an approach that I think is also emerging is the use of interventional therapies to better understand the biology of the disease. This is done in liver transplantation because you correctly defined the Milan criteria. However, for patients who are a bit beyond Milan criteria, if you can downstage them—for instance, with chemoembolization—then they can become candidates for transplantation. So, you can offer them a chance of cure. And, similarly, in a patient with multifocal disease, having a chemoembolization and understanding whether the tumor is truly keen to disseminate rapidly, or is more of an indolent disease, is probably critical. I know this is not in an algorithm and this is why, again, the expert opinion is probably the key.

Ghassan K. Abou-Alfa, MD: Let me try to summarize what’s going on here. This is fascinating because what we thought many years ago, that probably anatomical spread of the disease will probably determine the outcomes. We spoke about another dimension, though—that actually Dr. Singal brought up—which is the cirrhosis versus non-cirrhosis because, of course, if the liver is cirrhotic, the ability to preserve liver function after a certain surgery might be definitely impacted. But he brought up a fascinating point—which can reflect what everybody’s discussing here—which is what we don’t know about. What’s hepatitis B versus hepatitis C, for example? Because it appears to be that what we thought originally, that the process that evolved from the hepatitis infection all the way to the cancer, is probably the same. And already we have data that show it to be different. Remember—and only on a very, very superficial level—hepatitis C, for example, is an RNA virus and does not integrate into the genetic material. It can impair response to DNA damage and repair, lead to the cirrhosis. This is a process to develop the cancer, which is totally different from the one of hepatitis B—which actually is a DNA virus that simply can integrate into the genetic material and, as such, can impose or impact a certain process of the oncogenic transformation that definitely has its impact in regard to the outcome.

And, as such, those determinations were, of course, understandable based on anatomical decisions. But, as you can see, there are many dimensions that are layering themselves, and I think this is where the resource is going to go forward in regard to how to determine resectability per se. With this said, Richard, I go back to you. One of the critical questions—and I’m sure you get this question probably every day from your patients or from your colleagues—adjuvant therapy after resection: yes or no, and why?

Richard Finn, MD: Well, that question’s been looked at, and it’s been answered, and I think currently the definitive answer is no adjuvant therapy. We know when a patient comes to see us after resection, they’ve had a pathology specimen that might show multifocal disease, vascular invasion. We know that the risk of recurrence is quite high. I think the starting point is a recurrence rate for all resections, probably about 50%, and then you add on those factors and it goes up higher. The STORM study looked in the adjuvant setting for patients who were high-risk on sorafenib for 4 years post resection. And that study read out that the use of that drug did not delay recurrence or ultimately improve survival. Given that sorafenib is the only drug that’s been shown to be active in advanced disease, it’s the one that’s been best studied in the adjuvant setting. At this point, there are no data that anything, other than maybe continued surveillance, is appropriate for these patients.

Ghassan K. Abou-Alfa, MD: So, this is very important to note that, unfortunately, what we all wished for and all of us and we’re anticipating is that at the moment, there is no role for sorafenib or any other therapy in regard to adjuvant treatment. But that does not mean that we might not witness studies going forward in regard to that important question.

Transcript Edited for Clarity
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