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Risk/Benefit of Expanding Liver Transplant Criteria

Panelists: Richard S. Finn, MD, Geffen School of Medicine; Jordi Bruix, MD, Hospital Clinic University of Barcelona; Amit Singal, MD, MSCS, UT Southwestern Medical Center; Richard H. Marshall, MD, University Medical Center New Orleans; Arndt Vogel, MD, PhD, Hanover Medical School
Published: Wednesday, Jul 19, 2017



Transcript:

Richard S. Finn, MD:
As we’ve discussed, we know who is at risk—patients with chronic liver disease. We think screening can make a difference, by finding the disease early. We find the disease early. Why is that good? I know the goal is to cure the disease, and one of the main ways of doing that is probably through liver transplant. Amit, can you give us some background about who’s the best candidate for liver transplant and how we assess that?

Amit Singal, MD, MSCS: Taking a look at liver transplant, just historically, when we first started, the outcomes with liver transplant in hepatocellular carcinoma were bad. There was actually a question as to whether we should even perform liver transplantation for HCC. And then, as Jordi had said, Dr. Mazzaferro came up with the criteria, currently known as the Milan criteria, for defining a subset of patients who had very good outcomes after transplant with low rates of recurrence. And so, when you apply the Milan criteria—that is, 1 tumor less than 5 cm or 2 to 3 tumors less than 3 cm each, with no vascular invasion and no extrahepatic disease—you have a low risk of recurrence, around 10%. Now, when you have something good, there’s always a stretch in medicine to say, “Can we push the boundaries even further?”

And now, there have been several expanded criteria that have been proposed. Probably, the most famous are the UCSF (University of California, San Francisco) criteria, which have said we can do transplant with slightly larger tumors. I live in Texas, and Texas also has their own expanded criteria. I would say that everything is bigger in Texas, and so, we also have bigger criteria. And when you look at the data, the data suggest that you can have pretty good outcomes. They’re not as good as Milan criteria, but the recurrence rates aren’t awful.

Now, while this may benefit that individual patient, I think we also have to consider the greater good. We have a limited amount of organs available, and when you take an organ and you give it to somebody with “expanded” criteria, you’re, in essence, also taking an organ away from that patient who has a MELD score of 36 in the intensive care unit.

Richard S. Finn, MD: And no cancer.

Amit Singal, MD, MSCS: And no cancer. We’ve seen, in the United States, an increasing proportion of the list “eaten up” by patients with HCC. I think we really have to think about what we’re doing, in trying to push these criteria. There have been several criteria, once again, that have been proposed, and the outcomes are reasonable. One of the more recent ones proposed is the Toronto criteria, and the Toronto criteria takes a look at the alpha-fetoprotein, symptoms, and then the actual histology. These criteria were proposed, and they’ve just recently been validated—in terms of selecting patients who are outside of Milan criteria and who can have a good outcome and low risk of recurrence. In my opinion, these criteria have limited utility in clinical practice because you need histologic data. Most patients on the transplant list aren’t getting a biopsy to have that histologic data available prior to transplant.

Richard S. Finn, MD: Arndt, you had a comment?

Arndt Vogel, MD, PhD: Yes. In HCC, it’s always a little bit more difficult, and there are some points we need to consider. In some countries, for example, if a patient is, at some point, out of Milan criteria, he will never be a candidate for liver transplantation. In Germany, once you are out of the Milan criteria, even if you have good local treatment and your tumor is then within Milan criteria, you will not be able to get a liver transplantation. This is, I think, the case in some countries.

I’m not sure whether this is good. You have seen that patient that can be successfully downstaged, and they can also be a good candidate for liver transplantation. I think we have to rethink it. And then, it’s also, again, the question about the underlying liver disease. In several countries, patients with liver cirrhosis due to alcohol abuse will not get a liver transplantation. If you have an overuse of alcohol, and your HCC and your cirrhosis is caused by alcohol, even if you have a tumor within the Milan criteria, you will not be a candidate for liver transplantation.

Richard S. Finn, MD: Even after abstinence?

Arndt Vogel, MD, PhD: In Germany, we require 6 months of abstinence.

Richard S. Finn, MD: Like in the United States.

Arndt Vogel, MD, PhD: Which makes it a little bit difficult, sometimes. You have the tumor, and they have the liver cirrhosis. You need to apply a treatment that might harm the liver, which makes it more difficult. And we have the time on the waiting list. It’s not only that you need to have 6 months without alcohol, you have your time on the waiting list, which can be up to 1 or 2 years.

Amit Singal, MD, MSCS: I think Arndt brings up a good point, actually. The Milan criteria were defined as a surrogate for tumor biology, but it’s an imperfect surrogate for tumor biology. What we can see, as you follow people on the list, is that you can actually select patients who have good tumor biology and bad tumor biology. I would argue, in somebody who’s outside of Milan criteria, who gets treated with locoregional therapy, had a decrease in tumor burden, and is able to stay within criteria, then for 6 or 9 months, that patient has shown that they have a very good tumor biology.

Alternatively, in somebody who has a very small tumor—2 cm—who we treat with locoregional therapy as bridging therapy while they’re waiting on the transplant list, and whose tumor continues to grow but is fortunate enough to stay within Milan criteria, they actually have a bad tumor biology. And that patient, probably, has a higher risk of recurrence.

We really have to rethink the way that we define criteria. In the United States, now, all patients with HCC have to wait on the list for at least 6 months. The idea, here, is to get a sense of tumor biology—what the tumors are doing while they’re on the list. I think, over time, we’re going to see a shift away from a static 1-time measurement to, really, how the tumor changes over time in terms of defining the best candidates for transplant.

Richard S. Finn, MD: So, without a doubt, it’s a moving target. I think the take-home message would be, given its moving criteria and even regional, patients deserve to be assessed at a transplant center because those rules are changing so rapidly.

Jordi Bruix, MD: I would say they should be assessed in a place that they have access to all the options, not only in a transplant center. There are transplant centers that do not have the other options, and what needs to be defined is all the options that are effective. This information should be available.

Transcript Edited for Clarity

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Transcript:

Richard S. Finn, MD:
As we’ve discussed, we know who is at risk—patients with chronic liver disease. We think screening can make a difference, by finding the disease early. We find the disease early. Why is that good? I know the goal is to cure the disease, and one of the main ways of doing that is probably through liver transplant. Amit, can you give us some background about who’s the best candidate for liver transplant and how we assess that?

Amit Singal, MD, MSCS: Taking a look at liver transplant, just historically, when we first started, the outcomes with liver transplant in hepatocellular carcinoma were bad. There was actually a question as to whether we should even perform liver transplantation for HCC. And then, as Jordi had said, Dr. Mazzaferro came up with the criteria, currently known as the Milan criteria, for defining a subset of patients who had very good outcomes after transplant with low rates of recurrence. And so, when you apply the Milan criteria—that is, 1 tumor less than 5 cm or 2 to 3 tumors less than 3 cm each, with no vascular invasion and no extrahepatic disease—you have a low risk of recurrence, around 10%. Now, when you have something good, there’s always a stretch in medicine to say, “Can we push the boundaries even further?”

And now, there have been several expanded criteria that have been proposed. Probably, the most famous are the UCSF (University of California, San Francisco) criteria, which have said we can do transplant with slightly larger tumors. I live in Texas, and Texas also has their own expanded criteria. I would say that everything is bigger in Texas, and so, we also have bigger criteria. And when you look at the data, the data suggest that you can have pretty good outcomes. They’re not as good as Milan criteria, but the recurrence rates aren’t awful.

Now, while this may benefit that individual patient, I think we also have to consider the greater good. We have a limited amount of organs available, and when you take an organ and you give it to somebody with “expanded” criteria, you’re, in essence, also taking an organ away from that patient who has a MELD score of 36 in the intensive care unit.

Richard S. Finn, MD: And no cancer.

Amit Singal, MD, MSCS: And no cancer. We’ve seen, in the United States, an increasing proportion of the list “eaten up” by patients with HCC. I think we really have to think about what we’re doing, in trying to push these criteria. There have been several criteria, once again, that have been proposed, and the outcomes are reasonable. One of the more recent ones proposed is the Toronto criteria, and the Toronto criteria takes a look at the alpha-fetoprotein, symptoms, and then the actual histology. These criteria were proposed, and they’ve just recently been validated—in terms of selecting patients who are outside of Milan criteria and who can have a good outcome and low risk of recurrence. In my opinion, these criteria have limited utility in clinical practice because you need histologic data. Most patients on the transplant list aren’t getting a biopsy to have that histologic data available prior to transplant.

Richard S. Finn, MD: Arndt, you had a comment?

Arndt Vogel, MD, PhD: Yes. In HCC, it’s always a little bit more difficult, and there are some points we need to consider. In some countries, for example, if a patient is, at some point, out of Milan criteria, he will never be a candidate for liver transplantation. In Germany, once you are out of the Milan criteria, even if you have good local treatment and your tumor is then within Milan criteria, you will not be able to get a liver transplantation. This is, I think, the case in some countries.

I’m not sure whether this is good. You have seen that patient that can be successfully downstaged, and they can also be a good candidate for liver transplantation. I think we have to rethink it. And then, it’s also, again, the question about the underlying liver disease. In several countries, patients with liver cirrhosis due to alcohol abuse will not get a liver transplantation. If you have an overuse of alcohol, and your HCC and your cirrhosis is caused by alcohol, even if you have a tumor within the Milan criteria, you will not be a candidate for liver transplantation.

Richard S. Finn, MD: Even after abstinence?

Arndt Vogel, MD, PhD: In Germany, we require 6 months of abstinence.

Richard S. Finn, MD: Like in the United States.

Arndt Vogel, MD, PhD: Which makes it a little bit difficult, sometimes. You have the tumor, and they have the liver cirrhosis. You need to apply a treatment that might harm the liver, which makes it more difficult. And we have the time on the waiting list. It’s not only that you need to have 6 months without alcohol, you have your time on the waiting list, which can be up to 1 or 2 years.

Amit Singal, MD, MSCS: I think Arndt brings up a good point, actually. The Milan criteria were defined as a surrogate for tumor biology, but it’s an imperfect surrogate for tumor biology. What we can see, as you follow people on the list, is that you can actually select patients who have good tumor biology and bad tumor biology. I would argue, in somebody who’s outside of Milan criteria, who gets treated with locoregional therapy, had a decrease in tumor burden, and is able to stay within criteria, then for 6 or 9 months, that patient has shown that they have a very good tumor biology.

Alternatively, in somebody who has a very small tumor—2 cm—who we treat with locoregional therapy as bridging therapy while they’re waiting on the transplant list, and whose tumor continues to grow but is fortunate enough to stay within Milan criteria, they actually have a bad tumor biology. And that patient, probably, has a higher risk of recurrence.

We really have to rethink the way that we define criteria. In the United States, now, all patients with HCC have to wait on the list for at least 6 months. The idea, here, is to get a sense of tumor biology—what the tumors are doing while they’re on the list. I think, over time, we’re going to see a shift away from a static 1-time measurement to, really, how the tumor changes over time in terms of defining the best candidates for transplant.

Richard S. Finn, MD: So, without a doubt, it’s a moving target. I think the take-home message would be, given its moving criteria and even regional, patients deserve to be assessed at a transplant center because those rules are changing so rapidly.

Jordi Bruix, MD: I would say they should be assessed in a place that they have access to all the options, not only in a transplant center. There are transplant centers that do not have the other options, and what needs to be defined is all the options that are effective. This information should be available.

Transcript Edited for Clarity
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