HCC Locoregional Therapies for Bridging to Transplant

[Chris Beck]
What treatment modalities do you guys offer for locoregional therapy, and did you feel like within your group, that there's any institution or training bias towards one treatment over another?

[Isabel Newton]
So even though we're not able to offer radioembolization ourselves at the VA in San Diego, we very much consider it as a tool in our toolbox, and we continue to refer patients for that treatment when it is indicated… Our liver tumor board is a very collegial one. There's no real bias towards or against any treatment modality. We really consider all the different options as important tools and we combine them in a way that is best for patients… And then once the patient undergoes one treatment, we always reassess to see how they perform. Because, as we know, the data shows that response to treatment, particularly it's been looked at with local-regional therapy, gives you good sense about prognosis after transplant, but also just in the long haul, how well they respond to treatment. I call the very first TACE that I do with a patient or ablation, the “getting to know you” procedure. And I tell them, "This is where you tell me how you respond, not only to treatment, but also to sedation or general anesthesia, if we have to use that." And it tells me how you're going to stand up over time. Later on, we may have to use a systemic therapy or we take our friends from rad onc and ask them to help with a lesion that's a little bit hard to ablate, but we can give them fiducials, or if we're still lucky, they can go onto transplant. We do get some idea about how they are, how their physiology is, and what their tumor biology is like.

[Chris Beck]
Jennifer, do you have any preferences or biases with regards to locoregional therapies?

[Jennifer Berumen]
Every patient is pretty much different on that end, and it really depends on a lot of different factors. And it's like Isabel said, sometimes TACE is your first way to go and then you end up having to do something different because they don't respond or whatever needs to be done needs to change. So I'd say we don't necessarily have a preference. It does seem like thermal ablation, if the tumors are right, is better for those patients to get that. But no, no preference.

[Chris Beck]
You touch on a little bit of thermal ablations. Is that something that the hepatobiliary surgeons also participate in, like open microwave, or either microwave or radiofrequency ablations?

[Jennifer Berumen]
Yes. And here at UCSD, and I believe the VA also, we do microwave ablation. And so if it’s something that radiology thinks they want us to be involved with, then we'll absolutely do laparoscopic exposure of the liver and then we'll come in and do microwave ablation, either with or without radiology, depending on how it works out.

[Chris Beck]
Knowing that survival is correlated to complete pathologic response, has this changed the way interventional radiology approaches any HCC lesions from a technical perspective, or is it just something you know ahead of time and you still have to go ahead and treat to see what the response is going to be?

[Isabel Newton]
What we're getting at when we say, "How well is someone going to respond to this therapy?" is really a question of “What is the tumor biology?” You don't want to waste a precious organ, when they're in low supply, on someone who's ultimately not going to do well. It's not good for the patient. It's a very morbid surgery to go through if it's not going to benefit them and improve their quality of life and their lifespan. It also diminishes the number of transplants that are available to patients who might actually benefit. What we try to do when we treat with locoregional therapy is [produce] the most durable responses we can. If we can't do ablation, we'll do a combination of chemoembolization and ablation or Y-90 for a segmentectomy or Y-90 to treat more diffuse disease. These are all with the intent to eradicate as many tumor cells as possible. But until we really know what type of tumor cells we're talking about, this question of tumor biology, it's still a rather blind approach, and it's one where we're finding things out afterwards. Really, I find out a lot about their tumor after I treat them the first time or first two times.

[Chris Beck]
Patients who progress through or have stable disease after locoregional therapy…that’s not a good sign, but it's not necessarily exclusion from a liver transplant, is that fair to say?

[Jennifer Berumen]
Yes, that's absolutely fair to say. And I'd say those are patients that we really are going to look at closely and take any little lesion in their lung seriously and not give them the transplant until we've worked up that little lesion.

[Isabel Newton]
I think we have a patient who comes to mind, who fits that criteria, who otherwise is very healthy, and has had basically all of the different treatments that we have to offer, with the exception of transplant, but is awaiting transplant. So resection, thermal ablation, TACE, Y-90, and we keep following this person. And so this, the classic kind of quintessential example of bridging to transplant, because this patient also had some non small-cell lung cancer that was treated in the lungs, and so we're waiting for them to fall out of the window of time in which that would disqualify them. But we really do take each patient's situation as a unique situation and consider all of the factors at play. Because you can have someone who has what seems to be favorable tumor biology, but if they are not going to be able to follow up with their visits, they don't have support at home, they struggle with substance abuse, they're still smoking, those kinds of things are very, very important to consider as well. And we work hard to try to get patients to the point where they need to be so that they can receive a liver transplant. But the sad reality is, at least at the VA, it is a minority of patients who are able to swing all of the different factors that need to be in place in order to get a liver, and then, also, to get one in California, which is quite difficult.

[Chris Beck]
In the transplant world, is there discussion about moving more towards biopsying these tumors and having a better sense of tumor pathology being reflective of aggressive tumor biology that people are thinking about and looking for as far as prognostic information?

[Isabel Newton]
In the future, I think we will probably go back to taking biopsies of these tumors and asking more questions than just grade. Now, we see an association between a grade 2 and a higher risk of recurrence. But grade is still a very sort of rough look at how aggressive the tumor is. And I think a lot of the research is focusing on parsing out which tumors are going to be the ones that'll be a higher risk of recurrence. We won't have to use these surrogates of response to locoregional therapy or grade, or even AFP, which is very imperfect, because so many tumors don't even express it, to have an idea of what the response rate is going to be to look to either transplant or any of the treatments we have to offer.

[Jennifer Berumen]
Ideally, we would be able to biopsy the tumors to get an answer for how bad the tumor biology is, but in reality, there are a lot of risks to biopsying hepatocellular carcinoma, mainly seeding. If we seed the tumor outside the liver, then we really can't take them to transplant either. So, we don't do it regularly, because the imaging is so good to see what the tumors actually look like. The only real negative prognostic factor we can get from the imaging is the size and macro vascular invasion. If the tumor is invading any of the large vessels in the liver, then they're not a candidate for transplant. We can also assess, with the TACEs and multiple locoregional therapies, how badly the tumor's growing, and we can also look at laboratory factors like Alpha-fetoprotein. Those all give us some picture, but we don't really get an exact picture until the tumor is out, until the liver's out and the pathologist has looked through the tumor and can give us an idea of exactly what we can expect.

[Isabel Newton]
So during our liver tumor board conversation, we definitely do take into consideration some factors, like whether or not a patient has hepatitis-C virus. And we look at whether or not their tumors are in Milan criteria and their MELD score. We don't talk so much about the NLR, and we don't really talk about AFP so often, except unless there is a poor response. But many of our patients don't have, or not many, but a significant proportion, don't express AFP. So afterwards, if there isn't really a change, if they still have an AFP that's what you'd expect for cirrhotic, we don't pay much attention to it. But if they have an astronomical AFP after treatment, then it is something we consider. But I have to say that in our liver tumor board, we rely very much on Jen's assessment to chime in to let us know.

[Jennifer Berumen]
So I think what we can really say about that, is there are a lot of patients that we suspect are probably not going to have as great an outcome with liver transplant as other patients, and we can look at that. And none of that is really that surprising. High AFP levels, we know that that tumor is probably more active than other tumors. But it's not always going to give us the right answer. It's really hard to look at those patients who need a transplant and say, we don't want to give you a transplant, because we're worried that you might do worse than other people, when there are going to be individuals in those categories who still do really well. So, right now, without guidance from UNOS, as far as who we should and shouldn't transplant with those characteristics, we just use it as something that we can look at to say how we think they're going to do afterwards. And we know they might be higher risk, but we think the benefit to them is still going to be there, and so we'll still go forward with transplant.