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Liver Transplant Candidacy in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, UCLA; Laura M. Kulik, MD, Northwestern University Feinberg School of Medicine; R. Kate Kelley, MD, University of California-San Francisco; Riad Salem, MD, Northwestern University Feinberg School of Medicine
Published: Friday, Feb 17, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
This already brings me to one of the critical components of curative intent, which is liver transplantation. Riad, so who goes to transplant?

Riad Salem, MD: In general, the criteria for transplantation are based on a seminal article, in the New England Journal of Medicine in the mid-90s, talking about the ability to provide long-term survival in patients with HCC. The criteria refer to the ability to transplant a patient with 1 lesion of 5 cm or less or 3 lesions less than 3 cm. Those are often called the Milan criteria. But these are what we review in a multidisciplinary tumor board, and if feasible and if they display these tumor types, then liver transplantation is something to consider, possibly a curative intent.

Ghassan K. Abou-Alfa, MD: Laura, you are from the same institution, do you go beyond the Milan? Tell us what does it mean to go beyond the Milan?

Laura M. Kulik, MD: Going beyond Milan would be a larger tumor greater than 5 cm or more than 3 lesions or 1 greater than 3 cm. And I think we and many people—the Milan criteria have served us well since its implementation—feel that this is too stringent. There are people that we think would do better with a transplant; it’s the only potential curative option in many patients. So, what we try to do is downstage patients with a liver-directed therapy, give them a test of time. And this has now been seen in UNOS, which governs transplantation, that patients are now mandated to wait 6 months before their actual scoring system of points, that awards them priority on the transplant list, starts to kick in. Because what they’re trying to do is weed out patients who have a very aggressive behavior, despite the fact that they’re within the Milan criteria. But there are patients who are beyond the Milan criteria who don’t have an aggressive tumor. By using liver-directed therapy to show downstaging and also AFP levels that go down to normal, those are patients that we think would probably benefit from transplantation.

Ghassan K. Abou-Alfa, MD: I like what you’re saying. But also to change the point, in other words, you’re bringing here a variable that probably in the beginning was not looked at, which is a dynamic component that was rather more defined. But the “metro ticket” story is still valid. So, tell us what “metro ticket” is and, at the same time, what it means.

Laura M. Kulik, MD: The concept is if you are on a train, the longer you go on the train, the higher the price.

Ghassan K. Abou-Alfa, MD: This is Europe, not here.

Laura M. Kulik, MD: So, the analogy is, the larger the tumor burden, the greater the chance. And we’ve known that, but once you start reaching a tumor burden of 5 cm, there’s about a 50% chance that you’re going to have vascular invasion present and explant, which has been the highest chance of recurrence. And post transplant, once people recur, this is their number 1 cause of death, and we don’t have great treatments for them after that happens. Obviously, you want to try to prevent that from happening. So, yes, you’re right. We want to make sure we’re not going beyond, but there are so many people who would benefit, and we’re transplanting people with very early disease. With the role of liver-directed therapy—and we can probably talk a little bit more about this—we may challenge that some of the liver-directed therapies may be considered curative for a 2-cm solitary lesion as opposed to going right to transplant and then shuffling those livers to patients who have more advanced disease beyond the Milan criteria.

Ghassan K. Abou-Alfa, MD: Before I tackle surgery or anything else in regard to curative intent, I think Laura brings a very important point. Katie, what’s downstaging, especially in the transplant setting?

R. Kate Kelley, MD: I think many of our groups, including my colleagues at UCSF in hepatology and liver transplant, have done a lot of work looking at which patients with tumors larger than Milan criteria can have equivalently good outcomes after transplant. What we’ve seen across a variety of studies in multiple institutions is that patients whose tumors can be decreased in size within Milan criteria—with the use of interventional radiology—downstaging such as chemoembolization or Y-90, increasingly, can have equivalent outcomes to a patient who started out within Milan criteria. And this is akin to what we see in colorectal cancer, too. Patients who are converted to resectable over time often will have as good of an outcome as those who started out resectable to begin with. In the case of downstaging, we think—and the data bears out—that patients who can be converted to the Milan criteria by a combination of liver-directed arterial therapies have the same outcome as patients who started within Milan over time. There are poor prognostic factors that suggest patients won’t make it in downstaging or fall off the waiting list during this process. A high alpha-fetoprotein value greater than 1000 is one of the cut points that has been looked at or lack of response to downstaging. So, a tumor that doesn’t respond well to TACE, those patients often don’t make it in the downstaging process and are weeded out by poor biology tumors. But, in general, patients who respond well to TACE, who have an AFP response, and a response decrease to less than 1000 can do as well as patients who started out within the Milan criteria.

Ghassan K. Abou-Alfa, MD: Fascinating. No doubt that the transplant field was put into a highly choreographed and well-designed approach, as Dr. Salem referred to Mazzaferro’s study from the New England Journal of Medicine. But, obviously, no doubt that we are still trying to understand that field better. And the points that you heard about—especially expanding beyond the Milan and especially a new advent of the UNOS, like the 6-month wait before the points start kicking in to consider who’s coming for transplant with HCC—add to the downstaging. And they will probably invite any of the physicians to make sure that we have a patient who really is still in the local disease setting to make sure at least to get one opinion from a transplant center and to make sure that these options are definitely visited and looked into.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
This already brings me to one of the critical components of curative intent, which is liver transplantation. Riad, so who goes to transplant?

Riad Salem, MD: In general, the criteria for transplantation are based on a seminal article, in the New England Journal of Medicine in the mid-90s, talking about the ability to provide long-term survival in patients with HCC. The criteria refer to the ability to transplant a patient with 1 lesion of 5 cm or less or 3 lesions less than 3 cm. Those are often called the Milan criteria. But these are what we review in a multidisciplinary tumor board, and if feasible and if they display these tumor types, then liver transplantation is something to consider, possibly a curative intent.

Ghassan K. Abou-Alfa, MD: Laura, you are from the same institution, do you go beyond the Milan? Tell us what does it mean to go beyond the Milan?

Laura M. Kulik, MD: Going beyond Milan would be a larger tumor greater than 5 cm or more than 3 lesions or 1 greater than 3 cm. And I think we and many people—the Milan criteria have served us well since its implementation—feel that this is too stringent. There are people that we think would do better with a transplant; it’s the only potential curative option in many patients. So, what we try to do is downstage patients with a liver-directed therapy, give them a test of time. And this has now been seen in UNOS, which governs transplantation, that patients are now mandated to wait 6 months before their actual scoring system of points, that awards them priority on the transplant list, starts to kick in. Because what they’re trying to do is weed out patients who have a very aggressive behavior, despite the fact that they’re within the Milan criteria. But there are patients who are beyond the Milan criteria who don’t have an aggressive tumor. By using liver-directed therapy to show downstaging and also AFP levels that go down to normal, those are patients that we think would probably benefit from transplantation.

Ghassan K. Abou-Alfa, MD: I like what you’re saying. But also to change the point, in other words, you’re bringing here a variable that probably in the beginning was not looked at, which is a dynamic component that was rather more defined. But the “metro ticket” story is still valid. So, tell us what “metro ticket” is and, at the same time, what it means.

Laura M. Kulik, MD: The concept is if you are on a train, the longer you go on the train, the higher the price.

Ghassan K. Abou-Alfa, MD: This is Europe, not here.

Laura M. Kulik, MD: So, the analogy is, the larger the tumor burden, the greater the chance. And we’ve known that, but once you start reaching a tumor burden of 5 cm, there’s about a 50% chance that you’re going to have vascular invasion present and explant, which has been the highest chance of recurrence. And post transplant, once people recur, this is their number 1 cause of death, and we don’t have great treatments for them after that happens. Obviously, you want to try to prevent that from happening. So, yes, you’re right. We want to make sure we’re not going beyond, but there are so many people who would benefit, and we’re transplanting people with very early disease. With the role of liver-directed therapy—and we can probably talk a little bit more about this—we may challenge that some of the liver-directed therapies may be considered curative for a 2-cm solitary lesion as opposed to going right to transplant and then shuffling those livers to patients who have more advanced disease beyond the Milan criteria.

Ghassan K. Abou-Alfa, MD: Before I tackle surgery or anything else in regard to curative intent, I think Laura brings a very important point. Katie, what’s downstaging, especially in the transplant setting?

R. Kate Kelley, MD: I think many of our groups, including my colleagues at UCSF in hepatology and liver transplant, have done a lot of work looking at which patients with tumors larger than Milan criteria can have equivalently good outcomes after transplant. What we’ve seen across a variety of studies in multiple institutions is that patients whose tumors can be decreased in size within Milan criteria—with the use of interventional radiology—downstaging such as chemoembolization or Y-90, increasingly, can have equivalent outcomes to a patient who started out within Milan criteria. And this is akin to what we see in colorectal cancer, too. Patients who are converted to resectable over time often will have as good of an outcome as those who started out resectable to begin with. In the case of downstaging, we think—and the data bears out—that patients who can be converted to the Milan criteria by a combination of liver-directed arterial therapies have the same outcome as patients who started within Milan over time. There are poor prognostic factors that suggest patients won’t make it in downstaging or fall off the waiting list during this process. A high alpha-fetoprotein value greater than 1000 is one of the cut points that has been looked at or lack of response to downstaging. So, a tumor that doesn’t respond well to TACE, those patients often don’t make it in the downstaging process and are weeded out by poor biology tumors. But, in general, patients who respond well to TACE, who have an AFP response, and a response decrease to less than 1000 can do as well as patients who started out within the Milan criteria.

Ghassan K. Abou-Alfa, MD: Fascinating. No doubt that the transplant field was put into a highly choreographed and well-designed approach, as Dr. Salem referred to Mazzaferro’s study from the New England Journal of Medicine. But, obviously, no doubt that we are still trying to understand that field better. And the points that you heard about—especially expanding beyond the Milan and especially a new advent of the UNOS, like the 6-month wait before the points start kicking in to consider who’s coming for transplant with HCC—add to the downstaging. And they will probably invite any of the physicians to make sure that we have a patient who really is still in the local disease setting to make sure at least to get one opinion from a transplant center and to make sure that these options are definitely visited and looked into.

Transcript Edited for Clarity
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